Advanced Solid Tumor, Solid Tumor
Conditions
Keywords
VX14-803-001, VX-803, M4344, Advanced Solid Tumor, Cytotoxic Chemotherapy, Carboplatin
Brief summary
The purpose of this study was to evaluate the safety and tolerability of multiple ascending doses of single-agent M4344 administered twice-weekly (BIW), twice daily (BID) or once daily dose schedule in participants with advanced solid tumors. This investigation is a three part study examining M4344 alone and in combination with carboplatin to determine the safety and maximum tolerated dose.
Interventions
DRUGM4344 10 mg BIW
Participants received M4344 at a dose of 10 milligrams (mg) orally twice weekly (BIW) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
DRUGM4344 20 mg BIW
Participants received M4344 at a dose of 20 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
DRUGM4344 40 mg BIW
Participants received M4344 at a dose of 40 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
DRUGM4344 80 mg BIW
Participants received M4344 at a dose of 80 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
DRUGM4344 160 mg BIW
Participants received M4344 at a dose of 160 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
DRUGM4344 300 mg BIW
Participants received M4344 at a dose of 300 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
DRUGM4344 450 mg BIW
Participants received M4344 at a dose of 450 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
DRUGM4344 700 mg BIW
Participants received M4344 at a dose of 700 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
DRUGM4344 1050 mg BIW
Participants received M4344 at a dose of 1050 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
DRUGM4344 1200 mg BIW
Participants received M4344 at a dose of 1200 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
DRUGM4344 100 mg BID
Participants received M4344 at a dose of 100 mg orally twice daily (BID) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
DRUGM4344 150 mg QD
Participants received M4344 at a dose of 150 mg orally once daily (QD) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
DRUGM4344 250 mg QD
Participants received M4344 at a dose of 250 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
DRUGM4344 350 mg QD
Participants received M4344 at a dose of 350 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
DRUGM4344 400 mg
Participants received M4344 at a dose of 400 mg orally on Day 2 and Day 9 until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
DRUGM4344 500 mg
Participants received M4344 at a dose of 500 mg orally on Day 2 and Day 9 until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
DRUGCarboplatin
Participants received intravenous infusion of Carboplatin at a dose of Area Under Curve5 (AUC5) on Day 1 of 21-day cycle until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
Sponsors
Merck KGaA, Darmstadt, Germany
EMD Serono Research & Development Institute, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Part A, A2 and A3: Participants with one histologically or cytologically confirmed malignant advanced solid tumor, for which no standard therapy is available which may convey clinical benefit * Part B1: Participants with one histologically or cytologically confirmed malignant advanced solid tumor, for which no standard therapy is available which may convey clinical benefit and/or participants must have progressed after at least 1 prior chemotherapy regimen in the metastatic setting, and for which carboplatin would be considered standard of care. * Part C: Participants with 1 histologically or cytologically confirmed malignant advanced solid tumors for which no recommended standard therapy is available (that is, participants who have exhausted all standard of care options according to National Comprehensive Cancer Network \[NCCN\] Guidance) which may convey clinical benefit, and whose tumor has at least 1 of the following biomarkers as determined by a central trial assay or by an assay with appropriate regulatory status: - C1 or C4: loss-of-function mutations in the gene ARID1A - C2 or C5: loss-of-function mutations in the genes ATRX and/or DAXX - C3 or C6: loss-of-function mutation in the gene ataxia telangiectasia mutated (ATM) - This mandatory biomarker assessment must be conducted during screening on a fresh tumor biopsy (or a biopsy obtained after the end of the previous treatment regimen). If this is not possible for medical reason(s), available archival tumor material can be used (historical data should not be used to confirm biomarker status) * Measurable disease either according to RECIST criteria (Version 1.1) * WHO performance status of 0 or 1 * Life expectancy of greater than or equal to (\>=)12 weeks * Hematological and biochemical indices within acceptable ranges at Screening * Other protocol defined inclusion criteria could apply
Exclusion criteria
* Radiotherapy, unless brief course for palliative therapy, endocrine therapy, target-specific therapy, immunotherapy, or chemotherapy during the 4 weeks (6 weeks for nitrosoureas and Mitomycin-C, and 4 weeks for investigational medicinal products) or 4 drug half-lives before first dose of study drug, whichever is greater * Part B1: More than 6 cycles of prior therapy with carboplatin * Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the investigator should not exclude the participant * Part B1: Any known history of Grade 4 thrombocytopenia with any prior chemotherapy regimen * Brain metastases unless asymptomatic, treated, stable, and not requiring steroids for at least 4 weeks before first dose of study drug * Female participants who are already pregnant or lactating, or plan to become pregnant within 6 months of the last dose of study drug are excluded. Female participants of childbearing potential must adhere to contraception guidelines. Female participants will be considered to be of nonchildbearing potential if they have undergone surgical hysterectomy or bilateral oophorectomy or have been amenorrheic for over 2 years with a screening serum follicle-stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal females. * Male participants with partners of childbearing potential must agree to adhere to contraception guidelines. Men with pregnant or lactating partners or partners who plan to become pregnant during the study or within 6 months of the last dose of study drug are excluded. * Major surgery less than or equal to (\<=) 4 weeks before first dose of study drug or incomplete recovery from a prior major surgical procedure * Serious co-morbid medical conditions, including clinically-significant cardiac disease * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | up to safety follow-up visit (Week 124.9) | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. Serious AE: AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs are defined as AEs that were reported or worsened on or after start of study drug dosing through the Safety Follow-up Visit. TEAEs included both serious TEAEs and non-serious TEAEs. |
| Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | up to safety follow-up visit (Week 124.9) | Laboratory parameters: hematology and chemistry. Blood samples were collected for analysis of following hematology parameters: Hemoglobin, Erythrocytes, mean corpuscular hemoglobin (MCH), MCH concentration, Mean corpuscular volume, Reticulocytes, Platelets, Leukocytes, Eosinophils, Basophils, Neutrophils, Lymphocytes, Monocytes. Blood samples were collected for analysis of following chemistry parameters: Glucose, Blood urea nitrogen/Urea, Creatinine, Sodium, Potassium, Calcium, Chloride, Magnesium, Bicarbonate, Inorganic phosphate, Total bilirubin, Direct bilirubin, Total protein, Albumin, Creatine kinase, Alkaline phosphatase, Aspartate aminotransferase, Alanine aminotransferase, Lactate dehydrogenase, Uric acid, Thyroid stimulating hormone. Number of participants with Grade 3 or 4 (\>20% of total) in laboratory parameters were reported as per NCI-CTCAE v4.0 graded from Grade 1 to 5. Grade 1: Mild, Grade 2: Moderate; Grade 3: Severe. Grade 4: Life-threatening and Grade 5: Death. |
| Part A: Number of Participants With Clinically Relevant Findings in Vital Signs | up to safety follow-up visit (Week 124.9) | Vital signs included body temperature, heart rate, systolic and diastolic blood pressure and respiration rate. Number of participants with clinically relevant findings in vital signs were reported. Clinical relevance was decided by Investigator. |
| Part A: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | up to safety follow-up visit (Week 124.9) | ECG parameters included PR interval, RR interval, QT interval, QRS duration, QTc intervals (derived using Fridericia's correction method) and heart rate. A 12-lead ECG was recorded with the participant in a supine position after a rest of at least 5 minutes using an ECG machine. Clinical significance was decided by investigator. Number of participants with clinically significant abnormalities in 12-Lead ECGs were reported. |
| Part A: Maximum Tolerated Dose (MTD) of M4344 Administered Twice Weekly (BIW) | up to Cycle 1 (each cycle is of 21 days) | MTD as per NCI-CTCAE v4.0 is defined as highest dose for a given schedule at which there is no more than 1 dose- limiting toxicity (DLT) in 6 participants. DLT: as related/possibly drug-related: Neutropenia Grade (Gr)4 for \> 7 days duration/requiring hemopoietic growth factors; Febrile neutropenia; Infection with Gr3/4 neutropenia; Thrombocytopenia Gr3; Thrombocytopenia Gr4 for \> 7 days duration/requiring hemopoietic growth factors; Gr3/4 toxicity to organs other than bone marrow; Gr3/4 increase in bilirubin unless increase is due to inhibition of bilirubin glucuronidation; Death due to drug-related complications; Cardiac: QTc prolongation, Gr2/greater ventricular arrhythmia, severe sustained/symptomatic sinus bradycardia, persistent supraventricular arrhythmia, Symptoms suggestive of congestive heart failure, Troponin-T level consistent with myocardial infarction; drug-related toxicity causes interruption of treatment for \> 2 weeks. |
| Part A2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | up to safety follow-up visit (Week 39) | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. Serious AE: AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs are defined as AEs that were reported or worsened on or after start of study drug dosing through the Safety Follow-up Visit. TEAEs included both serious TEAEs and non-serious TEAEs. |
| Part A2: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | up to safety follow-up visit (Week 39) | Laboratory parameters: hematology and chemistry. Blood samples were collected for analysis of following hematology parameters: Hemoglobin, Erythrocytes, mean corpuscular hemoglobin (MCH), MCH concentration, Mean corpuscular volume, Reticulocytes, Platelets, Leukocytes, Eosinophils, Basophils, Neutrophils, Lymphocytes, Monocytes. Blood samples were collected for analysis of following chemistry parameters: Glucose, Blood urea nitrogen/Urea, Creatinine, Sodium, Potassium, Calcium, Chloride, Magnesium, Bicarbonate, Inorganic phosphate, Total bilirubin, Direct bilirubin, Total protein, Albumin, Creatine kinase, Alkaline phosphatase, Aspartate aminotransferase, Alanine aminotransferase, Lactate dehydrogenase, Uric acid, Thyroid stimulating hormone. Number of participants with Grade 3 or 4 (\>20% of total) in laboratory parameters were reported as per NCI-CTCAE v5.0 graded from Grade 1 to 5. Grade 1: Mild, Grade 2: Moderate; Grade 3: Severe. Grade 4: Life-threatening and Grade 5: Death. |
| Part A2: Number of Participants With Clinically Relevant Findings in Vital Signs | up to safety follow-up visit (Week 39) | Vital signs included body temperature, heart rate, systolic and diastolic blood pressure and respiration rate. Number of participants with clinically relevant findings were reported. Clinical relevance was decided by Investigator. |
| Part A2: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | up to safety follow-up visit (Week 39) | ECG parameters included PR interval, RR interval, QT interval, QRS duration, QTc intervals (derived using Fridericia's correction method) and heart rate. A 12-lead ECG was recorded with the participant in a supine position after a rest of at least 5 minutes using an ECG machine. Clinical Significance was determined by investigator. Number of participants with clinically significant abnormalities in 12-lead ECGs were reported. |
| Part A2: Maximum Tolerated Dose (MTD) of M4344 Administered With a Dose Dense Schedule | up to Cycle 1 (each cycle is of 21 days) | MTD as per NCI-CTCAE v5.0 is defined as highest dose for a given schedule at which there is no more than 1 dose- limiting toxicity (DLT) in 6 participants. DLT: as related/possibly drug-related: Neutropenia Grade (Gr)4 for \> 7 days duration/requiring hemopoietic growth factors; Febrile neutropenia; Infection with Gr3/4 neutropenia; Thrombocytopenia Gr3; Thrombocytopenia Gr4 for \> 7 days duration/requiring hemopoietic growth factors; Gr3/4 toxicity to organs other than bone marrow; Gr3/4 increase in bilirubin unless increase is due to inhibition of bilirubin glucuronidation; Death due to drug-related complications; Cardiac: QTc prolongation, Gr2/greater ventricular arrhythmia, severe sustained/symptomatic sinus bradycardia, persistent supraventricular arrhythmia, Symptoms suggestive of congestive heart failure, Troponin-T level consistent with myocardial infarction; drug-related toxicity causes interruption of treatment for \> 2 weeks. |
| Part B1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | up to Safety follow-up (Week 92.3) | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. Serious AE: AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs are defined as AEs that were reported or worsened on or after start of study drug dosing through the Safety Follow-up Visit. TEAEs included both serious TEAEs and non-serious TEAEs. |
| Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | up to Safety follow-up (Week 92.3) | Laboratory parameters: hematology and chemistry. Blood samples were collected for analysis of following hematology parameters: Hemoglobin, Erythrocytes, mean corpuscular hemoglobin (MCH), MCH concentration, Mean corpuscular volume, Reticulocytes, Platelets, Leukocytes, Eosinophils, Basophils, Neutrophils, Lymphocytes, Monocytes. Blood samples were collected for analysis of following chemistry parameters: Glucose, Blood urea nitrogen/Urea, Creatinine, Sodium, Potassium, Calcium, Chloride, Magnesium, Bicarbonate, Inorganic phosphate, Total bilirubin, Direct bilirubin, Total protein, Albumin, Creatine kinase, Alkaline phosphatase, Aspartate aminotransferase, Alanine aminotransferase, Lactate dehydrogenase, Uric acid, Thyroid stimulating hormone. Number of participants with Grade 3 or 4 (\>20% of total) in laboratory parameters were reported as per NCI-CTCAE v4.0 graded from Grade 1 to 5. Grade 1: Mild, Grade 2: Moderate; Grade 3: Severe. Grade 4: Life-threatening and Grade 5: Death. |
| Part B1: Number of Participants With Clinically Relevant Findings in Vital Signs | up to Safety follow-up (Week 92.3) | Vital signs included body temperature, heart rate, systolic and diastolic blood pressure and respiration rate. Number of participants with clinically relevant findings in vital signs were reported. Clinical relevance was decided by Investigator. |
| Part B1: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | up to Safety follow-up (Week 92.3) | ECG parameters included PR interval, RR interval, QT interval, QRS duration, QTc intervals (derived using Fridericia's correction method) and heart rate. A 12-lead ECG was recorded with the participant in a supine position after a rest of at least 5 minutes using an ECG machine. Clinical significance was determined by Investigator. Number of participants with clinically significant abnormalities in 12-lead ECGs were reported. |
| Part B1: Maximum Tolerated Dose (MTD) of M4344 (Monotherapy) Administered in Combination With Carboplatin | up to Cycle 1 (each cycle is of 21 days) | MTD as per NCI-CTCAE v4.0 is defined as highest dose for a given schedule at which there is no more than 1 dose- limiting toxicity (DLT) in 6 participants. DLT: as related/possibly drug-related: Neutropenia Grade (Gr)4 for \> 7 days duration/requiring hemopoietic growth factors; Febrile neutropenia; Infection with Gr3/4 neutropenia; Thrombocytopenia Gr3; Thrombocytopenia Gr4 for \> 7 days duration/requiring hemopoietic growth factors; Gr3/4 toxicity to organs other than bone marrow; Gr3/4 increase in bilirubin unless increase is due to inhibition of bilirubin glucuronidation; Death due to drug-related complications; Cardiac: QTc prolongation, Gr2/greater ventricular arrhythmia, severe sustained/symptomatic sinus bradycardia, persistent supraventricular arrhythmia, Symptoms suggestive of congestive heart failure, Troponin-T level consistent with myocardial infarction; drug-related toxicity causes interruption of treatment for \> 2 weeks. |
| Part C: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related AEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | up to Safety follow-up (Week 31.1) | AE: any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with use of a medicinal product, regardless if it is considered related to medicinal product. Serious AE: AE that resulted in any of following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs: AEs that were reported/worsened on/after start of study drug dosing through the Safety Follow-up Visit. TEAEs included both serious TEAEs and non-serious TEAEs. Treatment related AEs: reasonably related to the study drug/study treatment. AE could medically (pharmacologically/clinically) be attributed to the study drug/study treatment under study in this clinical study protocol. |
| Part C: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | up to Safety follow-up (Week 31.1) | Laboratory parameters: hematology and chemistry. Blood samples were collected for analysis of following hematology parameters: Hemoglobin, Erythrocytes, mean corpuscular hemoglobin (MCH), MCH concentration, Mean corpuscular volume, Reticulocytes, Platelets, Leukocytes, Eosinophils, Basophils, Neutrophils, Lymphocytes, Monocytes. Blood samples were collected for analysis of following chemistry parameters: Glucose, Blood urea nitrogen/Urea, Creatinine, Sodium, Potassium, Calcium, Chloride, Magnesium, Bicarbonate, Inorganic phosphate, Total bilirubin, Direct bilirubin, Total protein, Albumin, Creatine kinase, Alkaline phosphatase, Aspartate aminotransferase, Alanine aminotransferase, Lactate dehydrogenase, Uric acid, Thyroid stimulating hormone. Number of participants with Grade 3 or 4 (\>20% of total) in laboratory parameters were reported as per NCI-CTCAE v5.0 graded from Grade 1 to 5. Grade 1: Mild, Grade 2: Moderate; Grade 3: Severe. Grade 4: Life-threatening and Grade 5: Death. |
| Part C: Number of Participants With Clinically Relevant Findings in Vital Signs | up to Safety follow-up (Week 31.1) | Vital signs included body temperature, heart rate, systolic and diastolic blood pressure and respiration rate. Number of participants with clinically relevant findings in vital signs were reported. Clinical relevance was decided by Investigator. |
| Part C: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | up to Safety follow-up (Week 31.1) | ECG parameters included PR interval, RR interval, QT interval, QRS duration, QTc intervals (derived using Fridericia's correction method) and heart rate. A 12-lead ECG was recorded with the participant in a supine position after a rest of at least 5 minutes using an ECG machine. Clinical significance was determined by investigator. Number of participants with clinically significant abnormalities in 12-lead ECGs were reported. |
| Part C: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by the Investigator | Time from first dose of study treatment up to 6.4 years | OR is defined as the confirmed assessment of best overall response of complete response (CR) or partial response (PR). CR is defined as disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A2: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 (each cycle is of 21 days) | Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf\*Lambda Z), where AUC0-inf = (AUC0-t + Clast pred/Lambda Z). Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. |
| Part A2: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | Accumulation ratio of Cmax was calculated as Cmax, after dosing on Day 8 divided by Cmax, after dosing on Day 1 of Cycle 1. |
| Part A2: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344 | Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 (in BID arms), 24 hours post-dose (in QD arms) on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | Accumulation ratio of AUC0-t was calculated as AUC0-t, after dosing on Day 8 divided by AUC0-t, after dosing on Day 1 of Cycle 1. |
| Part A2: Accumulation Ratio for Area Under the Plasma Concentration Time Curve (Racc [AUC]) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | Accumulation ratio of AUC was calculated as AUC, after dosing on Day 8 divided by AUC, after dosing on Day 1 of Cycle 1. |
| Part A2: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose. Cmax/dose was measured in nanogram per milliliter per milligram (ng/mL/mg). |
| Part A2: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 (each cycle is of 21 days) | AUC0-inf/Dose was defined as AUC extrapolated to infinity divided by dose. AUC0-inf/Dose was measured in nanogram\*hour per milliliter per milligram (ng\*h/mL/mg). |
| Part A2: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 (in BID arms), 24 hours post-dose (in QD arms) on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | AUC0-t/Dose was defined as AUC from time of dosing to the time of the last measurable concentration divided by dose. |
| Part A2: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Time from first dose of study treatment up to 6.2 years | SD is defined as neither sufficient increase to qualify for progression disease (PD) nor sufficient shrinkage to qualify for partial response (PR). PR: at least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions. PD: at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. |
| Part A2: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Time from first dose of study treatment up to 6.2 years | The OR was defined as the confirmed assessment of best overall response (BOR) of partial response (PR),or complete response (CR) according to RECIST v1.1. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions. |
| Part B1: Maximum Observed Plasma Concentration (Cmax) of M4344 | Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days) | Cmax was obtained directly from the plasma concentration versus time curve. |
| Part B1: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days) | Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule. |
| Part B1: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days) | AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. |
| Part B1:Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days) | Tmax was obtained directly from the plasma concentration versus time curve. |
| Part B1: Terminal Elimination Half-Life (T1/2) of M4344 | Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days) | Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. |
| Part B1: Apparent Clearance (CL/f) of M4344 | Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days) | CL/f was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-t + Clast pred/Lambda Z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLQ) and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. |
| Part C: Maximum Observed Plasma Concentration (Cmax) of M4344 | Pre-dose up to 2 hours post-dose on Cycle 1 Day 1; Pre-dose up to 1 hours post-dose on Cycle 1 Day 8 and Cycle 1 Day 15 (each cycle is of 21 days) | Cmax was obtained directly from the plasma concentration versus time curve. |
| Part B1: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days) | Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf\*Lambda Z), where AUC0-inf = (AUC0-t + Clast pred/Lambda Z). Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. |
| Part B1: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days) | Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose. |
| Part C: Overall Survival (OS) | Time from first dose of study treatment up to 6.4 years | OS was defined as the time from treatment start to the date of death due to any cause. The participants who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date. OS was measured using Kaplan-Meier (KM) estimates. |
| Part B1: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days) | AUC0-t/Dose was defined as AUC from time of dosing to the time of the last measurable concentration divided by dose. |
| Part B1: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days) | AUC0-inf/Dose was defined as AUC extrapolated to infinity divided by dose. |
| Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | Cmax was obtained directly from the plasma concentration versus time curve. |
| Part C: Number of Participants With Confirmed Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 | Time from first dose of study treatment up to 6.4 years | Confirmed BOR is defined as best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the treatment start date until documented disease progression. CR: Disappearance of all evidence of target/non-target lesions. PR: At least 30%reduction from baseline in sum of longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD: at least a 20% increase in SLD, taking as reference smallest SLD recorded from baseline/appearance of 1or more new lesions and unequivocal progression of non-target lesions. |
| Part C: Progression-Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 as Assessed by Investigator | Time from first dose of study treatment up to 6.4 years | PFS is defined as the time from start of study treatment to progression disease (PD) or death. PD: at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier (KM) estimates. |
| Part C: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator | Time from first documentation of objective response, assessed up to 6.4 years | DOR was defined for participants with confirmed response, as the time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. |
| Part C: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Pre-dose up to 2 hours post-dose on Cycle 1 Day 1; Pre-dose up to 1 hours post-dose on Cycle 1 Day 8 and Cycle 1 Day 15 (each cycle is of 21 days) | Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule. |
| Part C: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Pre-dose up to 2 hours post-dose on Cycle 1 Day 1; Pre-dose up to 1 hours post-dose on Cycle 1 Day 8 and Cycle 1 Day 15 (each cycle is of 21 days) | Tmax was obtained directly from the plasma concentration versus time curve. |
| Part B1: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Time from first dose of study treatment up to 5.2 years | The OR was defined as the confirmed assessment of best overall response (BOR) of partial response (PR),or complete response (CR) according to RECIST v1.1. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions. |
| Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule. |
| Part A: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 1 (each cycle is of 21 days) | AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. |
| Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | Tmax was obtained directly from the plasma concentration versus time curve. |
| Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. |
| Part A: Apparent Clearance (CL/f) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | CL/f was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-t + Clast pred/Lambda Z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLQ) and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. |
| Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf\*Lambda Z), where AUC0-inf = (AUC0-t + Clast pred/Lambda Z). Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. |
| Part A: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | Accumulation ratio of Cmax was calculated as Cmax, after dosing on Day 8 divided by Cmax, after dosing on Day 1 of Cycle 1. |
| Part A: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | Accumulation ratio of AUC0-t was calculated as AUC0-t, after dosing on Day 8 divided by AUC0-t, after dosing on Day 1 of Cycle 1. |
| Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose. Cmax/dose was measured in nanogram per milliliter per milligram (ng/mL/mg). |
| Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | AUC0-t/Dose was defined as AUC from time of dosing to the time of the last measurable concentration divided by dose. AUC0-t/dose was measured in nanogram\*hour per milliliter per milligram (ng\*h/mL/mg). |
| Part A: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8, and 24 hours post-dose on Cycle 1 Day 1 (each cycle is of 21 days) | AUC0-inf/Dose was defined as AUC extrapolated to infinity divided by dose. |
| Part A: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Time from first dose of study treatment up to 4.3 years | The OR was defined as the confirmed assessment of best overall response (BOR) of partial response (PR),or complete response (CR) according to RECIST v1.1. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions. |
| Part A: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Time from first dose of study treatment up to 4.3 years | SD is defined as neither sufficient increase to qualify for progression disease (PD) nor sufficient shrinkage to qualify for partial response (PR). PR: at least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions. PD: at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. |
| Part A2: Maximum Observed Plasma Concentration (Cmax) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | Cmax was obtained directly from the plasma concentration versus time curve. |
| Part A2: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 (each cycle is of 21 days) | AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. |
| Part A2: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 (in BID arms), 24 hours post-dose (in QD arms) on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule. |
| Part A2: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | Tmax was obtained directly from the plasma concentration versus time curve. |
| Part A2: Terminal Elimination Half-Life (T1/2) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. |
| Part A2: Apparent Clearance (CL/f) of M4344 | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days) | CL/f was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-t + Clast pred/Lambda Z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLQ) and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. |
Countries
Netherlands, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
This study was planned to be conducted in multiple parts; Part A, Part A2, Part B1, Part A3 (Dose escalation), Part C1, Part C2, Part C3, Part C4, Part C5 and Part C6 (Dose expansion). On 10 December 2020, the Sponsor decided to discontinue the development of M4344 and stop enrollment of any new participants. Due to the low number of cohorts and participants, data were not summarized per Part (Part C1, C2 and C3). Also, optional Parts A3, C4, C5, and C6 were not conducted.
Participants by arm
| Arm | Count |
|---|---|
| Part A: M4344 10 mg BIW Participants received M4344 at a dose of 10 milligrams (mg) orally twice weekly (BIW) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. | 2 |
| Part A: M4344 20 mg BIW Participants received M4344 at a dose of 20 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. | 1 |
| Part A: M4344 40 mg BIW Participants received M4344 at a dose of 40 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. | 2 |
| Part A: M4344 80 mg BIW Participants received M4344 at a dose of 80 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. | 1 |
| Part A: M4344 160 mg BIW Participants received M4344 at a dose of 160 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. | 1 |
| Part A: M4344 300 mg BIW Participants received M4344 at a dose of 300 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. | 2 |
| Part A: M4344 450 mg BIW Participants received M4344 at a dose of 450 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. | 4 |
| Part A: M4344 700 mg BIW Participants received M4344 at a dose of 700 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. | 12 |
| Part A: M4344 1050 mg BIW Participants received M4344 at a dose of 1050 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. | 10 |
| Part A: M4344 1200 mg BIW Participants received M4344 at a dose of 1200 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. | 7 |
| Part A2: M4344 100 mg BID Participants received M4344 at a dose of 100 mg orally twice daily (BID) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. | 7 |
| Part A2: M4344 150 mg QD Participants received M4344 at a dose of 150 mg orally once daily (QD) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. | 5 |
| Part A2: M4344 250 mg QD Participants received M4344 at a dose of 250 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. | 7 |
| Part A2: M4344 350 mg QD Participants received M4344 at a dose of 350 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. | 7 |
| Part B1: M4344 350 mg + Carboplatin Participants received M4344 at a dose of 350 mg orally on Day 2 and Day 9 in combination with intravenous infusion of Carboplatin at a dose of Area under the concentration versus time curve 5 (AUC5) on Day 1 of 21-day cycle until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. | 3 |
| Part B1: M4344 400 mg + Carboplatin Participants received M4344 at a dose of 400 mg orally on Day 2 and Day 9 in combination with intravenous infusion of Carboplatin at a dose of AUC5 on Day 1 of 21-day cycle until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. | 7 |
| Part B1: M4344 500 mg + Carboplatin Participants received M4344 at a dose of 500 mg orally on Day 2 and Day 9 in combination with intravenous infusion of Carboplatin at a dose of AUC5 on Day 1 of 21-day cycle until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. | 6 |
| Part C: M4344 250 mg QD Participants received M4344 at a dose of 250 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. | 13 |
| Total | 97 |
Baseline characteristics
| Characteristic | Total | Part A: M4344 20 mg BIW | Part A: M4344 40 mg BIW | Part A: M4344 80 mg BIW | Part A: M4344 10 mg BIW | Part A: M4344 160 mg BIW | Part A: M4344 300 mg BIW | Part A: M4344 450 mg BIW | Part A: M4344 700 mg BIW | Part A: M4344 1050 mg BIW | Part A: M4344 1200 mg BIW | Part A2: M4344 100 mg BID | Part A2: M4344 150 mg QD | Part A2: M4344 250 mg QD | Part A2: M4344 350 mg QD | Part B1: M4344 350 mg + Carboplatin | Part B1: M4344 400 mg + Carboplatin | Part B1: M4344 500 mg + Carboplatin | Part C: M4344 250 mg QD |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 33 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 4 Participants | 3 Participants | 1 Participants | 2 Participants | 3 Participants | 2 Participants | 3 Participants | 1 Participants | 4 Participants | 1 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 64 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 8 Participants | 7 Participants | 6 Participants | 5 Participants | 2 Participants | 5 Participants | 4 Participants | 2 Participants | 3 Participants | 5 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 85 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 4 Participants | 12 Participants | 9 Participants | 5 Participants | 6 Participants | 4 Participants | 7 Participants | 6 Participants | 2 Participants | 4 Participants | 5 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 12 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 17 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 3 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 77 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 4 Participants | 12 Participants | 8 Participants | 5 Participants | 4 Participants | 2 Participants | 7 Participants | 6 Participants | 2 Participants | 4 Participants | 3 Participants | 12 Participants |
| Sex: Female, Male Female | 45 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 8 Participants | 6 Participants | 4 Participants | 3 Participants | 2 Participants | 4 Participants | 2 Participants | 0 Participants | 2 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 52 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 4 Participants | 4 Participants | 4 Participants | 3 Participants | 4 Participants | 3 Participants | 3 Participants | 5 Participants | 3 Participants | 5 Participants | 3 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 1 | 1 / 2 | 0 / 1 | 1 / 1 | 1 / 2 | 1 / 4 | 8 / 12 | 3 / 10 | 1 / 7 | 5 / 7 | 3 / 5 | 2 / 7 | 3 / 7 | 1 / 3 | 4 / 7 | 2 / 6 | 6 / 13 |
| other Total, other adverse events | 2 / 2 | 1 / 1 | 1 / 2 | 1 / 1 | 1 / 1 | 2 / 2 | 4 / 4 | 12 / 12 | 10 / 10 | 7 / 7 | 7 / 7 | 5 / 5 | 7 / 7 | 7 / 7 | 3 / 3 | 7 / 7 | 6 / 6 | 13 / 13 |
| serious Total, serious adverse events | 1 / 2 | 0 / 1 | 1 / 2 | 0 / 1 | 1 / 1 | 0 / 2 | 2 / 4 | 6 / 12 | 6 / 10 | 4 / 7 | 5 / 7 | 1 / 5 | 2 / 7 | 5 / 7 | 1 / 3 | 4 / 7 | 3 / 6 | 7 / 13 |
Outcome results
Primary
Part A2: Maximum Tolerated Dose (MTD) of M4344 Administered With a Dose Dense Schedule
MTD as per NCI-CTCAE v5.0 is defined as highest dose for a given schedule at which there is no more than 1 dose- limiting toxicity (DLT) in 6 participants. DLT: as related/possibly drug-related: Neutropenia Grade (Gr)4 for \> 7 days duration/requiring hemopoietic growth factors; Febrile neutropenia; Infection with Gr3/4 neutropenia; Thrombocytopenia Gr3; Thrombocytopenia Gr4 for \> 7 days duration/requiring hemopoietic growth factors; Gr3/4 toxicity to organs other than bone marrow; Gr3/4 increase in bilirubin unless increase is due to inhibition of bilirubin glucuronidation; Death due to drug-related complications; Cardiac: QTc prolongation, Gr2/greater ventricular arrhythmia, severe sustained/symptomatic sinus bradycardia, persistent supraventricular arrhythmia, Symptoms suggestive of congestive heart failure, Troponin-T level consistent with myocardial infarction; drug-related toxicity causes interruption of treatment for \> 2 weeks.
Time frame: up to Cycle 1 (each cycle is of 21 days)
Population: DLT evaluable set included all enrolled participants who received at least one dose of M4344 and either: Experienced a DLT before the end of Cycle 1 or Received at least 80% of scheduled M4344 doses through the end of Cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Maximum Tolerated Dose (MTD) of M4344 Administered With a Dose Dense Schedule | 250 mg |
Primary
Part A2: Number of Participants With Clinically Relevant Findings in Vital Signs
Vital signs included body temperature, heart rate, systolic and diastolic blood pressure and respiration rate. Number of participants with clinically relevant findings were reported. Clinical relevance was decided by Investigator.
Time frame: up to safety follow-up visit (Week 39)
Population: The SAF included all enrolled participants who received at least 1 dose of study drug (either M4344 or carboplatin (Part B1 only) with the actual amount \> 0 mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Number of Participants With Clinically Relevant Findings in Vital Signs | 0 Participants |
| Part A: M4344 20 mg BIW | Part A2: Number of Participants With Clinically Relevant Findings in Vital Signs | 0 Participants |
| Part A: M4344 40 mg BIW | Part A2: Number of Participants With Clinically Relevant Findings in Vital Signs | 0 Participants |
| Part A: M4344 80 mg BIW | Part A2: Number of Participants With Clinically Relevant Findings in Vital Signs | 0 Participants |
Primary
Part A2: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs)
ECG parameters included PR interval, RR interval, QT interval, QRS duration, QTc intervals (derived using Fridericia's correction method) and heart rate. A 12-lead ECG was recorded with the participant in a supine position after a rest of at least 5 minutes using an ECG machine. Clinical Significance was determined by investigator. Number of participants with clinically significant abnormalities in 12-lead ECGs were reported.
Time frame: up to safety follow-up visit (Week 39)
Population: The SAF included all enrolled participants who received at least 1 dose of study drug (either M4344 or carboplatin (Part B1 only) with the actual amount \> 0 mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | 0 Participants |
| Part A: M4344 20 mg BIW | Part A2: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | 0 Participants |
| Part A: M4344 40 mg BIW | Part A2: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | 0 Participants |
| Part A: M4344 80 mg BIW | Part A2: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | 0 Participants |
Primary
Part A2: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0)
Laboratory parameters: hematology and chemistry. Blood samples were collected for analysis of following hematology parameters: Hemoglobin, Erythrocytes, mean corpuscular hemoglobin (MCH), MCH concentration, Mean corpuscular volume, Reticulocytes, Platelets, Leukocytes, Eosinophils, Basophils, Neutrophils, Lymphocytes, Monocytes. Blood samples were collected for analysis of following chemistry parameters: Glucose, Blood urea nitrogen/Urea, Creatinine, Sodium, Potassium, Calcium, Chloride, Magnesium, Bicarbonate, Inorganic phosphate, Total bilirubin, Direct bilirubin, Total protein, Albumin, Creatine kinase, Alkaline phosphatase, Aspartate aminotransferase, Alanine aminotransferase, Lactate dehydrogenase, Uric acid, Thyroid stimulating hormone. Number of participants with Grade 3 or 4 (\>20% of total) in laboratory parameters were reported as per NCI-CTCAE v5.0 graded from Grade 1 to 5. Grade 1: Mild, Grade 2: Moderate; Grade 3: Severe. Grade 4: Life-threatening and Grade 5: Death.
Time frame: up to safety follow-up visit (Week 39)
Population: The SAF included all enrolled participants who received at least 1 dose of study drug (either M4344 or carboplatin (Part B1 only) with the actual amount \> 0 mg.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Total Bilirubin | 3 Participants |
| Part A: M4344 10 mg BIW | Part A2: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Aspartate Aminotransferase | 2 Participants |
| Part A: M4344 10 mg BIW | Part A2: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Alanine Aminotransferase | 2 Participants |
| Part A: M4344 10 mg BIW | Part A2: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Low lymphocytes | 1 Participants |
| Part A: M4344 20 mg BIW | Part A2: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Aspartate Aminotransferase | 1 Participants |
| Part A: M4344 20 mg BIW | Part A2: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Alanine Aminotransferase | 2 Participants |
| Part A: M4344 20 mg BIW | Part A2: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Low lymphocytes | 1 Participants |
| Part A: M4344 20 mg BIW | Part A2: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Total Bilirubin | 2 Participants |
| Part A: M4344 40 mg BIW | Part A2: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Alanine Aminotransferase | 0 Participants |
| Part A: M4344 40 mg BIW | Part A2: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Aspartate Aminotransferase | 0 Participants |
| Part A: M4344 40 mg BIW | Part A2: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Low lymphocytes | 2 Participants |
| Part A: M4344 40 mg BIW | Part A2: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Total Bilirubin | 3 Participants |
| Part A: M4344 80 mg BIW | Part A2: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Low lymphocytes | 3 Participants |
| Part A: M4344 80 mg BIW | Part A2: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Aspartate Aminotransferase | 4 Participants |
| Part A: M4344 80 mg BIW | Part A2: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Total Bilirubin | 3 Participants |
| Part A: M4344 80 mg BIW | Part A2: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Alanine Aminotransferase | 3 Participants |
Primary
Part A2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. Serious AE: AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs are defined as AEs that were reported or worsened on or after start of study drug dosing through the Safety Follow-up Visit. TEAEs included both serious TEAEs and non-serious TEAEs.
Time frame: up to safety follow-up visit (Week 39)
Population: The SAF included all enrolled participants who received at least 1 dose of study drug (either M4344 or carboplatin (Part B1 only) with the actual amount \> 0 mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 7 Participants |
| Part A: M4344 20 mg BIW | Part A2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 5 Participants |
| Part A: M4344 40 mg BIW | Part A2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 7 Participants |
| Part A: M4344 80 mg BIW | Part A2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 7 Participants |
Primary
Part A: Maximum Tolerated Dose (MTD) of M4344 Administered Twice Weekly (BIW)
MTD as per NCI-CTCAE v4.0 is defined as highest dose for a given schedule at which there is no more than 1 dose- limiting toxicity (DLT) in 6 participants. DLT: as related/possibly drug-related: Neutropenia Grade (Gr)4 for \> 7 days duration/requiring hemopoietic growth factors; Febrile neutropenia; Infection with Gr3/4 neutropenia; Thrombocytopenia Gr3; Thrombocytopenia Gr4 for \> 7 days duration/requiring hemopoietic growth factors; Gr3/4 toxicity to organs other than bone marrow; Gr3/4 increase in bilirubin unless increase is due to inhibition of bilirubin glucuronidation; Death due to drug-related complications; Cardiac: QTc prolongation, Gr2/greater ventricular arrhythmia, severe sustained/symptomatic sinus bradycardia, persistent supraventricular arrhythmia, Symptoms suggestive of congestive heart failure, Troponin-T level consistent with myocardial infarction; drug-related toxicity causes interruption of treatment for \> 2 weeks.
Time frame: up to Cycle 1 (each cycle is of 21 days)
Population: Dose Limiting Toxicity (DLT) Evaluable Set: included all enrolled participants who received at least 1 dose of M4344 and either: Experienced a DLT before the end of Cycle 1 or Received at least 80% of scheduled M4344 doses through the end of Cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part A: Maximum Tolerated Dose (MTD) of M4344 Administered Twice Weekly (BIW) | NA milligrams (mg) |
Primary
Part A: Number of Participants With Clinically Relevant Findings in Vital Signs
Vital signs included body temperature, heart rate, systolic and diastolic blood pressure and respiration rate. Number of participants with clinically relevant findings in vital signs were reported. Clinical relevance was decided by Investigator.
Time frame: up to safety follow-up visit (Week 124.9)
Population: The safety analysis set (SAF) included all enrolled participants who received at least 1 dose of study drug (either M4344 or carboplatin (Part B1 only) with the actual amount \> 0 mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part A: Number of Participants With Clinically Relevant Findings in Vital Signs | 0 Participants |
| Part A: M4344 20 mg BIW | Part A: Number of Participants With Clinically Relevant Findings in Vital Signs | 0 Participants |
| Part A: M4344 40 mg BIW | Part A: Number of Participants With Clinically Relevant Findings in Vital Signs | 0 Participants |
| Part A: M4344 80 mg BIW | Part A: Number of Participants With Clinically Relevant Findings in Vital Signs | 0 Participants |
| Part A: M4344 160 mg BIW | Part A: Number of Participants With Clinically Relevant Findings in Vital Signs | 0 Participants |
| Part A: M4344 300 mg BIW | Part A: Number of Participants With Clinically Relevant Findings in Vital Signs | 0 Participants |
| Part A: M4344 450 mg BIW | Part A: Number of Participants With Clinically Relevant Findings in Vital Signs | 0 Participants |
| Part A: M4344 700 mg BIW | Part A: Number of Participants With Clinically Relevant Findings in Vital Signs | 0 Participants |
| Part A: M4344 1050 mg BIW | Part A: Number of Participants With Clinically Relevant Findings in Vital Signs | 0 Participants |
| Part A: M4344 1200 mg BIW | Part A: Number of Participants With Clinically Relevant Findings in Vital Signs | 0 Participants |
Primary
Part A: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs)
ECG parameters included PR interval, RR interval, QT interval, QRS duration, QTc intervals (derived using Fridericia's correction method) and heart rate. A 12-lead ECG was recorded with the participant in a supine position after a rest of at least 5 minutes using an ECG machine. Clinical significance was decided by investigator. Number of participants with clinically significant abnormalities in 12-Lead ECGs were reported.
Time frame: up to safety follow-up visit (Week 124.9)
Population: The safety analysis set (SAF) included all enrolled participants who received at least 1 dose of study drug (either M4344 or carboplatin (Part B1 only) with the actual amount \> 0 mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part A: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | 0 Participants |
| Part A: M4344 20 mg BIW | Part A: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | 0 Participants |
| Part A: M4344 40 mg BIW | Part A: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | 0 Participants |
| Part A: M4344 80 mg BIW | Part A: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | 0 Participants |
| Part A: M4344 160 mg BIW | Part A: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | 0 Participants |
| Part A: M4344 300 mg BIW | Part A: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | 0 Participants |
| Part A: M4344 450 mg BIW | Part A: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | 0 Participants |
| Part A: M4344 700 mg BIW | Part A: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | 1 Participants |
| Part A: M4344 1050 mg BIW | Part A: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | 0 Participants |
| Part A: M4344 1200 mg BIW | Part A: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | 1 Participants |
Primary
Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0)
Laboratory parameters: hematology and chemistry. Blood samples were collected for analysis of following hematology parameters: Hemoglobin, Erythrocytes, mean corpuscular hemoglobin (MCH), MCH concentration, Mean corpuscular volume, Reticulocytes, Platelets, Leukocytes, Eosinophils, Basophils, Neutrophils, Lymphocytes, Monocytes. Blood samples were collected for analysis of following chemistry parameters: Glucose, Blood urea nitrogen/Urea, Creatinine, Sodium, Potassium, Calcium, Chloride, Magnesium, Bicarbonate, Inorganic phosphate, Total bilirubin, Direct bilirubin, Total protein, Albumin, Creatine kinase, Alkaline phosphatase, Aspartate aminotransferase, Alanine aminotransferase, Lactate dehydrogenase, Uric acid, Thyroid stimulating hormone. Number of participants with Grade 3 or 4 (\>20% of total) in laboratory parameters were reported as per NCI-CTCAE v4.0 graded from Grade 1 to 5. Grade 1: Mild, Grade 2: Moderate; Grade 3: Severe. Grade 4: Life-threatening and Grade 5: Death.
Time frame: up to safety follow-up visit (Week 124.9)
Population: The safety analysis set (SAF) included all enrolled participants who received at least 1 dose of study drug (either M4344 or carboplatin (Part B1 only) with the actual amount \> 0 mg.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Hematology | 0 Participants |
| Part A: M4344 10 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Total Bilirubin | 0 Participants |
| Part A: M4344 20 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Hematology | 0 Participants |
| Part A: M4344 20 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Total Bilirubin | 0 Participants |
| Part A: M4344 40 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Hematology | 0 Participants |
| Part A: M4344 40 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Total Bilirubin | 0 Participants |
| Part A: M4344 80 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Hematology | 0 Participants |
| Part A: M4344 80 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Total Bilirubin | 0 Participants |
| Part A: M4344 160 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Total Bilirubin | 0 Participants |
| Part A: M4344 160 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Hematology | 0 Participants |
| Part A: M4344 300 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Total Bilirubin | 0 Participants |
| Part A: M4344 300 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Hematology | 0 Participants |
| Part A: M4344 450 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Total Bilirubin | 0 Participants |
| Part A: M4344 450 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Hematology | 0 Participants |
| Part A: M4344 700 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Hematology | 0 Participants |
| Part A: M4344 700 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Total Bilirubin | 5 Participants |
| Part A: M4344 1050 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Hematology | 0 Participants |
| Part A: M4344 1050 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Total Bilirubin | 6 Participants |
| Part A: M4344 1200 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Hematology | 0 Participants |
| Part A: M4344 1200 mg BIW | Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Total Bilirubin | 4 Participants |
Primary
Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. Serious AE: AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs are defined as AEs that were reported or worsened on or after start of study drug dosing through the Safety Follow-up Visit. TEAEs included both serious TEAEs and non-serious TEAEs.
Time frame: up to safety follow-up visit (Week 124.9)
Population: The safety analysis set (SAF) included all enrolled participants who received at least 1 dose of study drug (either M4344 or carboplatin (Part B1 only) with the actual amount \> 0 mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 2 Participants |
| Part A: M4344 20 mg BIW | Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 1 Participants |
| Part A: M4344 40 mg BIW | Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 2 Participants |
| Part A: M4344 80 mg BIW | Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 1 Participants |
| Part A: M4344 160 mg BIW | Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 1 Participants |
| Part A: M4344 300 mg BIW | Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 2 Participants |
| Part A: M4344 450 mg BIW | Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 4 Participants |
| Part A: M4344 700 mg BIW | Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 12 Participants |
| Part A: M4344 1050 mg BIW | Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 10 Participants |
| Part A: M4344 1200 mg BIW | Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 7 Participants |
Primary
Part B1: Maximum Tolerated Dose (MTD) of M4344 (Monotherapy) Administered in Combination With Carboplatin
MTD as per NCI-CTCAE v4.0 is defined as highest dose for a given schedule at which there is no more than 1 dose- limiting toxicity (DLT) in 6 participants. DLT: as related/possibly drug-related: Neutropenia Grade (Gr)4 for \> 7 days duration/requiring hemopoietic growth factors; Febrile neutropenia; Infection with Gr3/4 neutropenia; Thrombocytopenia Gr3; Thrombocytopenia Gr4 for \> 7 days duration/requiring hemopoietic growth factors; Gr3/4 toxicity to organs other than bone marrow; Gr3/4 increase in bilirubin unless increase is due to inhibition of bilirubin glucuronidation; Death due to drug-related complications; Cardiac: QTc prolongation, Gr2/greater ventricular arrhythmia, severe sustained/symptomatic sinus bradycardia, persistent supraventricular arrhythmia, Symptoms suggestive of congestive heart failure, Troponin-T level consistent with myocardial infarction; drug-related toxicity causes interruption of treatment for \> 2 weeks.
Time frame: up to Cycle 1 (each cycle is of 21 days)
Population: DLT evaluable set included all enrolled participants who received at least one dose of M4344 and either: Experienced a DLT before the end of Cycle 1 or Received Carboplatin dose on Day 1 and M4344 dose on Days 2 and 9.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part B1: Maximum Tolerated Dose (MTD) of M4344 (Monotherapy) Administered in Combination With Carboplatin | NA mg |
Primary
Part B1: Number of Participants With Clinically Relevant Findings in Vital Signs
Vital signs included body temperature, heart rate, systolic and diastolic blood pressure and respiration rate. Number of participants with clinically relevant findings in vital signs were reported. Clinical relevance was decided by Investigator.
Time frame: up to Safety follow-up (Week 92.3)
Population: The SAF included all enrolled participants who received at least 1 dose of study drug (either M4344 or carboplatin (Part B1 only) with the actual amount \> 0 mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part B1: Number of Participants With Clinically Relevant Findings in Vital Signs | 0 Participants |
| Part A: M4344 20 mg BIW | Part B1: Number of Participants With Clinically Relevant Findings in Vital Signs | 0 Participants |
| Part A: M4344 40 mg BIW | Part B1: Number of Participants With Clinically Relevant Findings in Vital Signs | 0 Participants |
Primary
Part B1: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs)
ECG parameters included PR interval, RR interval, QT interval, QRS duration, QTc intervals (derived using Fridericia's correction method) and heart rate. A 12-lead ECG was recorded with the participant in a supine position after a rest of at least 5 minutes using an ECG machine. Clinical significance was determined by Investigator. Number of participants with clinically significant abnormalities in 12-lead ECGs were reported.
Time frame: up to Safety follow-up (Week 92.3)
Population: The SAF included all enrolled participants who received at least 1 dose of study drug (either M4344 or carboplatin (Part B1 only) with the actual amount \> 0 mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part B1: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | 0 Participants |
| Part A: M4344 20 mg BIW | Part B1: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | 0 Participants |
| Part A: M4344 40 mg BIW | Part B1: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | 0 Participants |
Primary
Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0)
Laboratory parameters: hematology and chemistry. Blood samples were collected for analysis of following hematology parameters: Hemoglobin, Erythrocytes, mean corpuscular hemoglobin (MCH), MCH concentration, Mean corpuscular volume, Reticulocytes, Platelets, Leukocytes, Eosinophils, Basophils, Neutrophils, Lymphocytes, Monocytes. Blood samples were collected for analysis of following chemistry parameters: Glucose, Blood urea nitrogen/Urea, Creatinine, Sodium, Potassium, Calcium, Chloride, Magnesium, Bicarbonate, Inorganic phosphate, Total bilirubin, Direct bilirubin, Total protein, Albumin, Creatine kinase, Alkaline phosphatase, Aspartate aminotransferase, Alanine aminotransferase, Lactate dehydrogenase, Uric acid, Thyroid stimulating hormone. Number of participants with Grade 3 or 4 (\>20% of total) in laboratory parameters were reported as per NCI-CTCAE v4.0 graded from Grade 1 to 5. Grade 1: Mild, Grade 2: Moderate; Grade 3: Severe. Grade 4: Life-threatening and Grade 5: Death.
Time frame: up to Safety follow-up (Week 92.3)
Population: The SAF included all enrolled participants who received at least 1 dose of study drug (either M4344 or carboplatin (Part B1 only) with the actual amount \> 0 mg.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Neutrophils | 1 Participants |
| Part A: M4344 10 mg BIW | Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Platelets | 1 Participants |
| Part A: M4344 10 mg BIW | Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Low hemoglobin | 1 Participants |
| Part A: M4344 10 mg BIW | Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Low Leukocytes | 0 Participants |
| Part A: M4344 10 mg BIW | Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Low lymphocytes | 1 Participants |
| Part A: M4344 10 mg BIW | Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Chemistry | 0 Participants |
| Part A: M4344 20 mg BIW | Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Chemistry | 0 Participants |
| Part A: M4344 20 mg BIW | Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Neutrophils | 1 Participants |
| Part A: M4344 20 mg BIW | Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Low Leukocytes | 1 Participants |
| Part A: M4344 20 mg BIW | Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Low lymphocytes | 3 Participants |
| Part A: M4344 20 mg BIW | Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Platelets | 3 Participants |
| Part A: M4344 20 mg BIW | Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Low hemoglobin | 4 Participants |
| Part A: M4344 40 mg BIW | Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Platelets | 3 Participants |
| Part A: M4344 40 mg BIW | Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Low hemoglobin | 1 Participants |
| Part A: M4344 40 mg BIW | Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Chemistry | 0 Participants |
| Part A: M4344 40 mg BIW | Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Low Leukocytes | 4 Participants |
| Part A: M4344 40 mg BIW | Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Neutrophils | 5 Participants |
| Part A: M4344 40 mg BIW | Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0) | Low lymphocytes | 1 Participants |
Primary
Part B1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. Serious AE: AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs are defined as AEs that were reported or worsened on or after start of study drug dosing through the Safety Follow-up Visit. TEAEs included both serious TEAEs and non-serious TEAEs.
Time frame: up to Safety follow-up (Week 92.3)
Population: The SAF included all enrolled participants who received at least 1 dose of study drug (either M4344 or carboplatin (Part B1 only) with the actual amount \> 0 mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part B1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 3 Participants |
| Part A: M4344 20 mg BIW | Part B1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 7 Participants |
| Part A: M4344 40 mg BIW | Part B1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 6 Participants |
Primary
Part C: Number of Participants With Clinically Relevant Findings in Vital Signs
Vital signs included body temperature, heart rate, systolic and diastolic blood pressure and respiration rate. Number of participants with clinically relevant findings in vital signs were reported. Clinical relevance was decided by Investigator.
Time frame: up to Safety follow-up (Week 31.1)
Population: The SAF included all participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part C: Number of Participants With Clinically Relevant Findings in Vital Signs | 0 Participants |
Primary
Part C: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs)
ECG parameters included PR interval, RR interval, QT interval, QRS duration, QTc intervals (derived using Fridericia's correction method) and heart rate. A 12-lead ECG was recorded with the participant in a supine position after a rest of at least 5 minutes using an ECG machine. Clinical significance was determined by investigator. Number of participants with clinically significant abnormalities in 12-lead ECGs were reported.
Time frame: up to Safety follow-up (Week 31.1)
Population: The SAF included all participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part C: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) | 6 Participants |
Primary
Part C: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0)
Laboratory parameters: hematology and chemistry. Blood samples were collected for analysis of following hematology parameters: Hemoglobin, Erythrocytes, mean corpuscular hemoglobin (MCH), MCH concentration, Mean corpuscular volume, Reticulocytes, Platelets, Leukocytes, Eosinophils, Basophils, Neutrophils, Lymphocytes, Monocytes. Blood samples were collected for analysis of following chemistry parameters: Glucose, Blood urea nitrogen/Urea, Creatinine, Sodium, Potassium, Calcium, Chloride, Magnesium, Bicarbonate, Inorganic phosphate, Total bilirubin, Direct bilirubin, Total protein, Albumin, Creatine kinase, Alkaline phosphatase, Aspartate aminotransferase, Alanine aminotransferase, Lactate dehydrogenase, Uric acid, Thyroid stimulating hormone. Number of participants with Grade 3 or 4 (\>20% of total) in laboratory parameters were reported as per NCI-CTCAE v5.0 graded from Grade 1 to 5. Grade 1: Mild, Grade 2: Moderate; Grade 3: Severe. Grade 4: Life-threatening and Grade 5: Death.
Time frame: up to Safety follow-up (Week 31.1)
Population: The SAF included all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part C: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Low lymphocytes | 8 Participants |
| Part A: M4344 10 mg BIW | Part C: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Low hemoglobin | 6 Participants |
| Part A: M4344 10 mg BIW | Part C: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Total Bilirubin | 7 Participants |
| Part A: M4344 10 mg BIW | Part C: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Aspartate Aminotransferase | 4 Participants |
| Part A: M4344 10 mg BIW | Part C: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) | Alanine Aminotransferase | 3 Participants |
Primary
Part C: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related AEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0
AE: any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with use of a medicinal product, regardless if it is considered related to medicinal product. Serious AE: AE that resulted in any of following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs: AEs that were reported/worsened on/after start of study drug dosing through the Safety Follow-up Visit. TEAEs included both serious TEAEs and non-serious TEAEs. Treatment related AEs: reasonably related to the study drug/study treatment. AE could medically (pharmacologically/clinically) be attributed to the study drug/study treatment under study in this clinical study protocol.
Time frame: up to Safety follow-up (Week 31.1)
Population: The SAF included all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part C: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related AEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Participants with TEAEs | 13 Participants |
| Part A: M4344 10 mg BIW | Part C: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related AEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Participants with Treatment related AEs | 13 Participants |
Primary
Part C: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by the Investigator
OR is defined as the confirmed assessment of best overall response of complete response (CR) or partial response (PR). CR is defined as disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions.
Time frame: Time from first dose of study treatment up to 6.4 years
Population: Full Analysis Set (FAS) included all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part C: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by the Investigator | 0.0 percentage of participants |
Secondary
Part A2: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344
Accumulation ratio of AUC0-t was calculated as AUC0-t, after dosing on Day 8 divided by AUC0-t, after dosing on Day 1 of Cycle 1.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 (in BID arms), 24 hours post-dose (in QD arms) on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344 | 1.00 ratio | Geometric Coefficient of Variation 55.3 |
| Part A: M4344 20 mg BIW | Part A2: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344 | 1.42 ratio | Geometric Coefficient of Variation 142.4 |
| Part A: M4344 40 mg BIW | Part A2: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344 | 0.672 ratio | Geometric Coefficient of Variation 90.7 |
| Part A: M4344 80 mg BIW | Part A2: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344 | NA ratio | — |
Secondary
Part A2: Accumulation Ratio for Area Under the Plasma Concentration Time Curve (Racc [AUC]) of M4344
Accumulation ratio of AUC was calculated as AUC, after dosing on Day 8 divided by AUC, after dosing on Day 1 of Cycle 1.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Accumulation Ratio for Area Under the Plasma Concentration Time Curve (Racc [AUC]) of M4344 | 0.997 ratio | Geometric Coefficient of Variation 55.7 |
| Part A: M4344 20 mg BIW | Part A2: Accumulation Ratio for Area Under the Plasma Concentration Time Curve (Racc [AUC]) of M4344 | 1.32 ratio | Geometric Coefficient of Variation 133.5 |
| Part A: M4344 40 mg BIW | Part A2: Accumulation Ratio for Area Under the Plasma Concentration Time Curve (Racc [AUC]) of M4344 | 0.676 ratio | Geometric Coefficient of Variation 88.4 |
| Part A: M4344 80 mg BIW | Part A2: Accumulation Ratio for Area Under the Plasma Concentration Time Curve (Racc [AUC]) of M4344 | NA ratio | — |
Secondary
Part A2: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344
Accumulation ratio of Cmax was calculated as Cmax, after dosing on Day 8 divided by Cmax, after dosing on Day 1 of Cycle 1.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344 | 1.08 ratio | Geometric Coefficient of Variation 47.5 |
| Part A: M4344 20 mg BIW | Part A2: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344 | 2.26 ratio | Geometric Coefficient of Variation 245.2 |
| Part A: M4344 40 mg BIW | Part A2: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344 | 0.733 ratio | Geometric Coefficient of Variation 92.1 |
| Part A: M4344 80 mg BIW | Part A2: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344 | NA ratio | — |
Secondary
Part A2: Apparent Clearance (CL/f) of M4344
CL/f was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-t + Clast pred/Lambda Z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLQ) and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 1 | 461 liter per hour | Geometric Coefficient of Variation 44.2 |
| Part A: M4344 10 mg BIW | Part A2: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 8 | 424 liter per hour | Geometric Coefficient of Variation 55.4 |
| Part A: M4344 20 mg BIW | Part A2: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 8 | 239 liter per hour | Geometric Coefficient of Variation 58.9 |
| Part A: M4344 20 mg BIW | Part A2: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 1 | 344 liter per hour | Geometric Coefficient of Variation 127.4 |
| Part A: M4344 40 mg BIW | Part A2: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 1 | 207 liter per hour | Geometric Coefficient of Variation 95 |
| Part A: M4344 40 mg BIW | Part A2: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 8 | 302 liter per hour | Geometric Coefficient of Variation 101.4 |
| Part A: M4344 80 mg BIW | Part A2: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 1 | 515 liter per hour | Geometric Coefficient of Variation 144.1 |
| Part A: M4344 80 mg BIW | Part A2: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 8 | NA liter per hour | — |
Secondary
Part A2: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344
Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf\*Lambda Z), where AUC0-inf = (AUC0-t + Clast pred/Lambda Z). Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | 876 liters | Geometric Coefficient of Variation 36.3 |
| Part A: M4344 20 mg BIW | Part A2: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | 1220 liters | Geometric Coefficient of Variation 661.7 |
| Part A: M4344 40 mg BIW | Part A2: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | 519 liters | Geometric Coefficient of Variation 191.1 |
| Part A: M4344 80 mg BIW | Part A2: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | 1760 liters | Geometric Coefficient of Variation 214.7 |
Secondary
Part A2: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344
AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | 217 ng*h/mL | Geometric Coefficient of Variation 44.2 |
| Part A: M4344 20 mg BIW | Part A2: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | 436 ng*h/mL | Geometric Coefficient of Variation 127.4 |
| Part A: M4344 40 mg BIW | Part A2: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | 1210 ng*h/mL | Geometric Coefficient of Variation 95 |
| Part A: M4344 80 mg BIW | Part A2: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | 680 ng*h/mL | Geometric Coefficient of Variation 144.1 |
Secondary
Part A2: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344
Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 (in BID arms), 24 hours post-dose (in QD arms) on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 1 | 216 ng*h/mL | Geometric Coefficient of Variation 43.2 |
| Part A: M4344 10 mg BIW | Part A2: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 8 | 236 ng*h/mL | Geometric Coefficient of Variation 55.4 |
| Part A: M4344 20 mg BIW | Part A2: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 8 | 627 ng*h/mL | Geometric Coefficient of Variation 58.9 |
| Part A: M4344 20 mg BIW | Part A2: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 1 | 414 ng*h/mL | Geometric Coefficient of Variation 142.9 |
| Part A: M4344 40 mg BIW | Part A2: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 1 | 1230 ng*h/mL | Geometric Coefficient of Variation 86.1 |
| Part A: M4344 40 mg BIW | Part A2: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 8 | 829 ng*h/mL | Geometric Coefficient of Variation 101.4 |
| Part A: M4344 80 mg BIW | Part A2: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 1 | 703 ng*h/mL | Geometric Coefficient of Variation 142.7 |
| Part A: M4344 80 mg BIW | Part A2: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 8 | NA ng*h/mL | — |
Secondary
Part A2: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344
AUC0-inf/Dose was defined as AUC extrapolated to infinity divided by dose. AUC0-inf/Dose was measured in nanogram\*hour per milliliter per milligram (ng\*h/mL/mg).
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | 2.17 ng*h/mL/mg | Geometric Coefficient of Variation 44.2 |
| Part A: M4344 20 mg BIW | Part A2: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | 2.91 ng*h/mL/mg | Geometric Coefficient of Variation 127.4 |
| Part A: M4344 40 mg BIW | Part A2: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | 4.84 ng*h/mL/mg | Geometric Coefficient of Variation 95 |
| Part A: M4344 80 mg BIW | Part A2: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | 1.94 ng*h/mL/mg | Geometric Coefficient of Variation 144.1 |
Secondary
Part A2: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344
AUC0-t/Dose was defined as AUC from time of dosing to the time of the last measurable concentration divided by dose.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 (in BID arms), 24 hours post-dose (in QD arms) on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 1 | 2.16 ng*h/mL/mg | Geometric Coefficient of Variation 43.2 |
| Part A: M4344 10 mg BIW | Part A2: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 8 | 2.36 ng*h/mL/mg | Geometric Coefficient of Variation 55.4 |
| Part A: M4344 20 mg BIW | Part A2: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 8 | 4.18 ng*h/mL/mg | Geometric Coefficient of Variation 58.9 |
| Part A: M4344 20 mg BIW | Part A2: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 1 | 2.76 ng*h/mL/mg | Geometric Coefficient of Variation 142.9 |
| Part A: M4344 40 mg BIW | Part A2: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 1 | 4.93 ng*h/mL/mg | Geometric Coefficient of Variation 86.1 |
| Part A: M4344 40 mg BIW | Part A2: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 8 | 3.32 ng*h/mL/mg | Geometric Coefficient of Variation 101.4 |
| Part A: M4344 80 mg BIW | Part A2: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 1 | 2.01 ng*h/mL/mg | Geometric Coefficient of Variation 142.7 |
| Part A: M4344 80 mg BIW | Part A2: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 8 | NA ng*h/mL/mg | — |
Secondary
Part A2: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344
Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose. Cmax/dose was measured in nanogram per milliliter per milligram (ng/mL/mg).
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 1 | 1.11 ng/mL/mg | Geometric Coefficient of Variation 40.3 |
| Part A: M4344 10 mg BIW | Part A2: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 8 | 1.14 ng/mL/mg | Geometric Coefficient of Variation 32.3 |
| Part A: M4344 20 mg BIW | Part A2: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 8 | 1.63 ng/mL/mg | Geometric Coefficient of Variation 59.3 |
| Part A: M4344 20 mg BIW | Part A2: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 1 | 0.829 ng/mL/mg | Geometric Coefficient of Variation 392.2 |
| Part A: M4344 40 mg BIW | Part A2: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 1 | 2.07 ng/mL/mg | Geometric Coefficient of Variation 78.3 |
| Part A: M4344 40 mg BIW | Part A2: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 8 | 1.52 ng/mL/mg | Geometric Coefficient of Variation 88.9 |
| Part A: M4344 80 mg BIW | Part A2: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 1 | 0.758 ng/mL/mg | Geometric Coefficient of Variation 152.7 |
| Part A: M4344 80 mg BIW | Part A2: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 8 | NA ng/mL/mg | — |
Secondary
Part A2: Maximum Observed Plasma Concentration (Cmax) of M4344
Cmax was obtained directly from the plasma concentration versus time curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signifies those participants who were evaluable at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 1 | 111 ng/mL | Geometric Coefficient of Variation 40.3 |
| Part A: M4344 10 mg BIW | Part A2: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 8 | 114 ng/mL | Geometric Coefficient of Variation 32.3 |
| Part A: M4344 20 mg BIW | Part A2: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 8 | 244 ng/mL | Geometric Coefficient of Variation 59.3 |
| Part A: M4344 20 mg BIW | Part A2: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 1 | 124 ng/mL | Geometric Coefficient of Variation 392.2 |
| Part A: M4344 40 mg BIW | Part A2: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 1 | 517 ng/mL | Geometric Coefficient of Variation 78.3 |
| Part A: M4344 40 mg BIW | Part A2: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 8 | 379 ng/mL | Geometric Coefficient of Variation 88.9 |
| Part A: M4344 80 mg BIW | Part A2: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 1 | 265 ng/mL | Geometric Coefficient of Variation 152.7 |
| Part A: M4344 80 mg BIW | Part A2: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 8 | NA ng/mL | — |
Secondary
Part A2: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
SD is defined as neither sufficient increase to qualify for progression disease (PD) nor sufficient shrinkage to qualify for partial response (PR). PR: at least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions. PD: at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Time frame: Time from first dose of study treatment up to 6.2 years
Population: FAS is defined as all enrolled participants who received at least 1 dose of study drug, have a baseline scan, and received at least one disease assessment while on treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 1 Participants |
| Part A: M4344 20 mg BIW | Part A2: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 1 Participants |
| Part A: M4344 40 mg BIW | Part A2: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 4 Participants |
| Part A: M4344 80 mg BIW | Part A2: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 2 Participants |
Secondary
Part A2: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
The OR was defined as the confirmed assessment of best overall response (BOR) of partial response (PR),or complete response (CR) according to RECIST v1.1. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions.
Time frame: Time from first dose of study treatment up to 6.2 years
Population: FAS is defined as all enrolled participants who received at least 1 dose of study drug, have a baseline scan, and received at least one disease assessment while on treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0.0 percentage of participants |
| Part A: M4344 20 mg BIW | Part A2: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0.0 percentage of participants |
| Part A: M4344 40 mg BIW | Part A2: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0.0 percentage of participants |
| Part A: M4344 80 mg BIW | Part A2: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0.0 percentage of participants |
Secondary
Part A2: Terminal Elimination Half-Life (T1/2) of M4344
Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 1 | 1.32 hours | Geometric Coefficient of Variation 27.1 |
| Part A: M4344 10 mg BIW | Part A2: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 8 | 1.36 hours | Geometric Coefficient of Variation 58.7 |
| Part A: M4344 20 mg BIW | Part A2: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 8 | 1.31 hours | Geometric Coefficient of Variation 28.9 |
| Part A: M4344 20 mg BIW | Part A2: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 1 | 2.47 hours | Geometric Coefficient of Variation 165.9 |
| Part A: M4344 40 mg BIW | Part A2: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 1 | 1.74 hours | Geometric Coefficient of Variation 58.8 |
| Part A: M4344 40 mg BIW | Part A2: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 8 | 1.31 hours | Geometric Coefficient of Variation 18.7 |
| Part A: M4344 80 mg BIW | Part A2: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 1 | 2.37 hours | Geometric Coefficient of Variation 60.9 |
| Part A: M4344 80 mg BIW | Part A2: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 8 | NA hours | — |
Secondary
Part A2: Time to Reach Maximum Plasma Concentration (Tmax) of M4344
Tmax was obtained directly from the plasma concentration versus time curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A2: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 1 | 1.45 hours |
| Part A: M4344 10 mg BIW | Part A2: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 8 | 1.03 hours |
| Part A: M4344 20 mg BIW | Part A2: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 1 | 1.62 hours |
| Part A: M4344 20 mg BIW | Part A2: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 8 | 1.28 hours |
| Part A: M4344 40 mg BIW | Part A2: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 8 | 1.50 hours |
| Part A: M4344 40 mg BIW | Part A2: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 1 | 1.50 hours |
| Part A: M4344 80 mg BIW | Part A2: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 8 | NA hours |
| Part A: M4344 80 mg BIW | Part A2: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 1 | 1.10 hours |
Secondary
Part A: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344
Accumulation ratio of AUC0-t was calculated as AUC0-t, after dosing on Day 8 divided by AUC0-t, after dosing on Day 1 of Cycle 1.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344 | NA ratio | — |
| Part A: M4344 20 mg BIW | Part A: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344 | NA ratio | — |
| Part A: M4344 40 mg BIW | Part A: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344 | NA ratio | — |
| Part A: M4344 80 mg BIW | Part A: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344 | NA ratio | — |
| Part A: M4344 160 mg BIW | Part A: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344 | NA ratio | — |
| Part A: M4344 300 mg BIW | Part A: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344 | NA ratio | — |
| Part A: M4344 450 mg BIW | Part A: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344 | 0.955 ratio | Geometric Coefficient of Variation 23.7 |
| Part A: M4344 700 mg BIW | Part A: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344 | 1.46 ratio | Geometric Coefficient of Variation 77.8 |
| Part A: M4344 1050 mg BIW | Part A: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344 | 1.36 ratio | Geometric Coefficient of Variation 163.7 |
| Part A: M4344 1200 mg BIW | Part A: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344 | 1.89 ratio | Geometric Coefficient of Variation 33.6 |
Secondary
Part A: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344
Accumulation ratio of Cmax was calculated as Cmax, after dosing on Day 8 divided by Cmax, after dosing on Day 1 of Cycle 1.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344 | NA ratio | — |
| Part A: M4344 20 mg BIW | Part A: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344 | NA ratio | — |
| Part A: M4344 40 mg BIW | Part A: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344 | NA ratio | — |
| Part A: M4344 80 mg BIW | Part A: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344 | NA ratio | — |
| Part A: M4344 160 mg BIW | Part A: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344 | NA ratio | — |
| Part A: M4344 300 mg BIW | Part A: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344 | NA ratio | — |
| Part A: M4344 450 mg BIW | Part A: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344 | 0.988 ratio | Geometric Coefficient of Variation 37.9 |
| Part A: M4344 700 mg BIW | Part A: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344 | 1.19 ratio | Geometric Coefficient of Variation 67.5 |
| Part A: M4344 1050 mg BIW | Part A: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344 | 1.01 ratio | Geometric Coefficient of Variation 163.2 |
| Part A: M4344 1200 mg BIW | Part A: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344 | 1.55 ratio | Geometric Coefficient of Variation 17.4 |
Secondary
Part A: Apparent Clearance (CL/f) of M4344
CL/f was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-t + Clast pred/Lambda Z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLQ) and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 8 | NA liter per hour | — |
| Part A: M4344 10 mg BIW | Part A: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 1 | NA liter per hour | — |
| Part A: M4344 20 mg BIW | Part A: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 1 | NA liter per hour | — |
| Part A: M4344 20 mg BIW | Part A: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 8 | NA liter per hour | — |
| Part A: M4344 40 mg BIW | Part A: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 1 | NA liter per hour | — |
| Part A: M4344 40 mg BIW | Part A: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 8 | NA liter per hour | — |
| Part A: M4344 80 mg BIW | Part A: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 8 | NA liter per hour | — |
| Part A: M4344 80 mg BIW | Part A: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 1 | NA liter per hour | — |
| Part A: M4344 160 mg BIW | Part A: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 1 | NA liter per hour | — |
| Part A: M4344 160 mg BIW | Part A: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 8 | NA liter per hour | — |
| Part A: M4344 300 mg BIW | Part A: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 8 | NA liter per hour | — |
| Part A: M4344 300 mg BIW | Part A: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 1 | NA liter per hour | — |
| Part A: M4344 450 mg BIW | Part A: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 1 | 464 liter per hour | Geometric Coefficient of Variation 53.6 |
| Part A: M4344 450 mg BIW | Part A: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 8 | 513 liter per hour | Geometric Coefficient of Variation 78.2 |
| Part A: M4344 700 mg BIW | Part A: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 1 | 409 liter per hour | Geometric Coefficient of Variation 92.5 |
| Part A: M4344 700 mg BIW | Part A: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 8 | 221 liter per hour | Geometric Coefficient of Variation 114.3 |
| Part A: M4344 1050 mg BIW | Part A: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 8 | NA liter per hour | — |
| Part A: M4344 1050 mg BIW | Part A: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 1 | 597 liter per hour | Geometric Coefficient of Variation 122.3 |
| Part A: M4344 1200 mg BIW | Part A: Apparent Clearance (CL/f) of M4344 | Cycle 1 Day 1 | 781 liter per hour | Geometric Coefficient of Variation 128.9 |
Secondary
Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344
Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf\*Lambda Z), where AUC0-inf = (AUC0-t + Clast pred/Lambda Z). Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Cycle 1 Day 8 | NA liters | — |
| Part A: M4344 10 mg BIW | Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Cycle 1 Day 1 | NA liters | — |
| Part A: M4344 20 mg BIW | Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Cycle 1 Day 1 | NA liters | — |
| Part A: M4344 20 mg BIW | Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Cycle 1 Day 8 | NA liters | — |
| Part A: M4344 40 mg BIW | Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Cycle 1 Day 1 | NA liters | — |
| Part A: M4344 40 mg BIW | Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Cycle 1 Day 8 | NA liters | — |
| Part A: M4344 80 mg BIW | Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Cycle 1 Day 8 | NA liters | — |
| Part A: M4344 80 mg BIW | Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Cycle 1 Day 1 | NA liters | — |
| Part A: M4344 160 mg BIW | Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Cycle 1 Day 1 | NA liters | — |
| Part A: M4344 160 mg BIW | Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Cycle 1 Day 8 | NA liters | — |
| Part A: M4344 300 mg BIW | Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Cycle 1 Day 8 | NA liters | — |
| Part A: M4344 300 mg BIW | Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Cycle 1 Day 1 | NA liters | — |
| Part A: M4344 450 mg BIW | Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Cycle 1 Day 1 | 1480 liters | Geometric Coefficient of Variation 187.9 |
| Part A: M4344 450 mg BIW | Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Cycle 1 Day 8 | 1620 liters | Geometric Coefficient of Variation 716.8 |
| Part A: M4344 700 mg BIW | Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Cycle 1 Day 1 | 1960 liters | Geometric Coefficient of Variation 116 |
| Part A: M4344 700 mg BIW | Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Cycle 1 Day 8 | 993 liters | Geometric Coefficient of Variation 59.6 |
| Part A: M4344 1050 mg BIW | Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Cycle 1 Day 8 | NA liters | — |
| Part A: M4344 1050 mg BIW | Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Cycle 1 Day 1 | 3970 liters | Geometric Coefficient of Variation 95.8 |
| Part A: M4344 1200 mg BIW | Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | Cycle 1 Day 1 | 4060 liters | Geometric Coefficient of Variation 211.6 |
Secondary
Part A: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344
AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 1 (each cycle is of 21 days)
Population: The Pharmacokinetic Analysis Set (PAS) included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | NA ng*h/mL | — |
| Part A: M4344 20 mg BIW | Part A: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | NA ng*h/mL | — |
| Part A: M4344 40 mg BIW | Part A: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | NA ng*h/mL | — |
| Part A: M4344 80 mg BIW | Part A: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | NA ng*h/mL | — |
| Part A: M4344 160 mg BIW | Part A: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | NA ng*h/mL | — |
| Part A: M4344 300 mg BIW | Part A: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | NA ng*h/mL | — |
| Part A: M4344 450 mg BIW | Part A: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | 971 ng*h/mL | Geometric Coefficient of Variation 53.6 |
| Part A: M4344 700 mg BIW | Part A: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | 1710 ng*h/mL | Geometric Coefficient of Variation 92.5 |
| Part A: M4344 1050 mg BIW | Part A: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | 1760 ng*h/mL | Geometric Coefficient of Variation 122.3 |
| Part A: M4344 1200 mg BIW | Part A: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | 1540 ng*h/mL | Geometric Coefficient of Variation 128.9 |
Secondary
Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344
Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 8 | NA nanogram*hour per milliliter (ng*h/mL) | — |
| Part A: M4344 10 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 1 | NA nanogram*hour per milliliter (ng*h/mL) | — |
| Part A: M4344 20 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 8 | NA nanogram*hour per milliliter (ng*h/mL) | — |
| Part A: M4344 20 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 1 | NA nanogram*hour per milliliter (ng*h/mL) | — |
| Part A: M4344 40 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 8 | NA nanogram*hour per milliliter (ng*h/mL) | — |
| Part A: M4344 40 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 1 | NA nanogram*hour per milliliter (ng*h/mL) | — |
| Part A: M4344 80 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 8 | NA nanogram*hour per milliliter (ng*h/mL) | — |
| Part A: M4344 80 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 1 | NA nanogram*hour per milliliter (ng*h/mL) | — |
| Part A: M4344 160 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 8 | NA nanogram*hour per milliliter (ng*h/mL) | — |
| Part A: M4344 160 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 1 | NA nanogram*hour per milliliter (ng*h/mL) | — |
| Part A: M4344 300 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 1 | NA nanogram*hour per milliliter (ng*h/mL) | — |
| Part A: M4344 300 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 8 | NA nanogram*hour per milliliter (ng*h/mL) | — |
| Part A: M4344 450 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 1 | 948 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 56.4 |
| Part A: M4344 450 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 8 | 809 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 96.6 |
| Part A: M4344 700 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 1 | 1830 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 102 |
| Part A: M4344 700 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 8 | 2670 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 91.2 |
| Part A: M4344 1050 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 1 | 1390 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 64.5 |
| Part A: M4344 1050 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 8 | 1550 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 295.1 |
| Part A: M4344 1200 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 8 | 1880 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 74 |
| Part A: M4344 1200 mg BIW | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | Cycle 1 Day 1 | 2220 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 105.9 |
Secondary
Part A: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344
AUC0-inf/Dose was defined as AUC extrapolated to infinity divided by dose.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8, and 24 hours post-dose on Cycle 1 Day 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | NA ng*h/mL/mg | — |
| Part A: M4344 20 mg BIW | Part A: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | NA ng*h/mL/mg | — |
| Part A: M4344 40 mg BIW | Part A: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | NA ng*h/mL/mg | — |
| Part A: M4344 80 mg BIW | Part A: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | NA ng*h/mL/mg | — |
| Part A: M4344 160 mg BIW | Part A: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | NA ng*h/mL/mg | — |
| Part A: M4344 300 mg BIW | Part A: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | NA ng*h/mL/mg | — |
| Part A: M4344 450 mg BIW | Part A: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | 2.16 ng*h/mL/mg | Geometric Coefficient of Variation 53.6 |
| Part A: M4344 700 mg BIW | Part A: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | 2.45 ng*h/mL/mg | Geometric Coefficient of Variation 92.5 |
| Part A: M4344 1050 mg BIW | Part A: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | 1.68 ng*h/mL/mg | Geometric Coefficient of Variation 122.3 |
| Part A: M4344 1200 mg BIW | Part A: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | 1.28 ng*h/mL/mg | Geometric Coefficient of Variation 128.9 |
Secondary
Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344
AUC0-t/Dose was defined as AUC from time of dosing to the time of the last measurable concentration divided by dose. AUC0-t/dose was measured in nanogram\*hour per milliliter per milligram (ng\*h/mL/mg).
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 1 | NA ng*h/mL/mg | — |
| Part A: M4344 10 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 8 | NA ng*h/mL/mg | — |
| Part A: M4344 20 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 1 | NA ng*h/mL/mg | — |
| Part A: M4344 20 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 8 | NA ng*h/mL/mg | — |
| Part A: M4344 40 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 1 | NA ng*h/mL/mg | — |
| Part A: M4344 40 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 8 | NA ng*h/mL/mg | — |
| Part A: M4344 80 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 1 | NA ng*h/mL/mg | — |
| Part A: M4344 80 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 8 | NA ng*h/mL/mg | — |
| Part A: M4344 160 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 8 | NA ng*h/mL/mg | — |
| Part A: M4344 160 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 1 | NA ng*h/mL/mg | — |
| Part A: M4344 300 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 8 | NA ng*h/mL/mg | — |
| Part A: M4344 300 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 1 | NA ng*h/mL/mg | — |
| Part A: M4344 450 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 8 | 1.80 ng*h/mL/mg | Geometric Coefficient of Variation 96.6 |
| Part A: M4344 450 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 1 | 2.11 ng*h/mL/mg | Geometric Coefficient of Variation 56.4 |
| Part A: M4344 700 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 1 | 2.61 ng*h/mL/mg | Geometric Coefficient of Variation 102 |
| Part A: M4344 700 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 8 | 3.82 ng*h/mL/mg | Geometric Coefficient of Variation 91.2 |
| Part A: M4344 1050 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 1 | 1.32 ng*h/mL/mg | Geometric Coefficient of Variation 64.5 |
| Part A: M4344 1050 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 8 | 1.47 ng*h/mL/mg | Geometric Coefficient of Variation 295.1 |
| Part A: M4344 1200 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 1 | 1.85 ng*h/mL/mg | Geometric Coefficient of Variation 105.9 |
| Part A: M4344 1200 mg BIW | Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | Cycle 1 Day 8 | 1.57 ng*h/mL/mg | Geometric Coefficient of Variation 74 |
Secondary
Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344
Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose. Cmax/dose was measured in nanogram per milliliter per milligram (ng/mL/mg).
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 1 | NA ng/mL/mg | — |
| Part A: M4344 10 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 8 | NA ng/mL/mg | — |
| Part A: M4344 20 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 1 | NA ng/mL/mg | — |
| Part A: M4344 20 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 8 | NA ng/mL/mg | — |
| Part A: M4344 40 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 1 | NA ng/mL/mg | — |
| Part A: M4344 40 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 8 | NA ng/mL/mg | — |
| Part A: M4344 80 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 1 | NA ng/mL/mg | — |
| Part A: M4344 80 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 8 | NA ng/mL/mg | — |
| Part A: M4344 160 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 8 | NA ng/mL/mg | — |
| Part A: M4344 160 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 1 | NA ng/mL/mg | — |
| Part A: M4344 300 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 8 | NA ng/mL/mg | — |
| Part A: M4344 300 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 1 | NA ng/mL/mg | — |
| Part A: M4344 450 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 8 | 0.760 ng/mL/mg | Geometric Coefficient of Variation 136.6 |
| Part A: M4344 450 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 1 | 0.835 ng/mL/mg | Geometric Coefficient of Variation 64.2 |
| Part A: M4344 700 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 1 | 0.738 ng/mL/mg | Geometric Coefficient of Variation 83.6 |
| Part A: M4344 700 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 8 | 0.964 ng/mL/mg | Geometric Coefficient of Variation 65.7 |
| Part A: M4344 1050 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 1 | 0.376 ng/mL/mg | Geometric Coefficient of Variation 73.2 |
| Part A: M4344 1050 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 8 | 0.312 ng/mL/mg | Geometric Coefficient of Variation 313.1 |
| Part A: M4344 1200 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 1 | 0.480 ng/mL/mg | Geometric Coefficient of Variation 79.9 |
| Part A: M4344 1200 mg BIW | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | Cycle 1 Day 8 | 0.405 ng/mL/mg | Geometric Coefficient of Variation 23.8 |
Secondary
Part A: Maximum Observed Plasma Concentration (Cmax) of M4344
Cmax was obtained directly from the plasma concentration versus time curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The Pharmacokinetic Analysis Set (PAS) included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 8 | NA nanogram per milliliter (ng/mL) | — |
| Part A: M4344 10 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 1 | NA nanogram per milliliter (ng/mL) | — |
| Part A: M4344 20 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 8 | NA nanogram per milliliter (ng/mL) | — |
| Part A: M4344 20 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 1 | NA nanogram per milliliter (ng/mL) | — |
| Part A: M4344 40 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 8 | NA nanogram per milliliter (ng/mL) | — |
| Part A: M4344 40 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 1 | NA nanogram per milliliter (ng/mL) | — |
| Part A: M4344 80 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 8 | NA nanogram per milliliter (ng/mL) | — |
| Part A: M4344 80 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 1 | NA nanogram per milliliter (ng/mL) | — |
| Part A: M4344 160 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 8 | NA nanogram per milliliter (ng/mL) | — |
| Part A: M4344 160 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 1 | NA nanogram per milliliter (ng/mL) | — |
| Part A: M4344 300 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 1 | NA nanogram per milliliter (ng/mL) | — |
| Part A: M4344 300 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 8 | NA nanogram per milliliter (ng/mL) | — |
| Part A: M4344 450 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 1 | 376 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 64.2 |
| Part A: M4344 450 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 8 | 342 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 136.6 |
| Part A: M4344 700 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 1 | 516 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 83.6 |
| Part A: M4344 700 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 8 | 675 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 65.7 |
| Part A: M4344 1050 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 1 | 395 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 73.2 |
| Part A: M4344 1050 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 8 | 328 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 313.1 |
| Part A: M4344 1200 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 8 | 486 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 23.8 |
| Part A: M4344 1200 mg BIW | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 | Cycle 1 Day 1 | 576 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 79.9 |
Secondary
Part A: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
SD is defined as neither sufficient increase to qualify for progression disease (PD) nor sufficient shrinkage to qualify for partial response (PR). PR: at least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions. PD: at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Time frame: Time from first dose of study treatment up to 4.3 years
Population: FAS: all enrolled participants who satisfy all of the following criteria: received at least 1 dose of study drug with the actual amount \> 0 mg; have a baseline scan with a measurable target lesion (sum of diameters of all target lesions \> 0 mm) and have at least 1 disease assessment on treatment with a measurable target lesion (sum of diameters of all target lesions \>= 0 mm); or subjects who have discontinued the study due to either progressive disease or death.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part A: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0 Participants |
| Part A: M4344 20 mg BIW | Part A: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 1 Participants |
| Part A: M4344 40 mg BIW | Part A: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0 Participants |
| Part A: M4344 80 mg BIW | Part A: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0 Participants |
| Part A: M4344 160 mg BIW | Part A: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0 Participants |
| Part A: M4344 300 mg BIW | Part A: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0 Participants |
| Part A: M4344 450 mg BIW | Part A: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 2 Participants |
| Part A: M4344 700 mg BIW | Part A: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 2 Participants |
| Part A: M4344 1050 mg BIW | Part A: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 1 Participants |
| Part A: M4344 1200 mg BIW | Part A: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 1 Participants |
Secondary
Part A: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
The OR was defined as the confirmed assessment of best overall response (BOR) of partial response (PR),or complete response (CR) according to RECIST v1.1. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions.
Time frame: Time from first dose of study treatment up to 4.3 years
Population: Full analysis set (FAS): all enrolled participants who satisfy all of the following criteria: received at least 1 dose of study drug with the actual amount \> 0 mg; have a baseline scan with a measurable target lesion (sum of diameters of all target lesions \> 0 mm) and have at least 1 disease assessment on treatment with a measurable target lesion (sum of diameters of all target lesions \>= 0 mm); or subjects who have discontinued the study due to either progressive disease or death.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part A: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0.0 percentage of participants |
| Part A: M4344 20 mg BIW | Part A: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0.0 percentage of participants |
| Part A: M4344 40 mg BIW | Part A: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0.0 percentage of participants |
| Part A: M4344 80 mg BIW | Part A: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0.0 percentage of participants |
| Part A: M4344 160 mg BIW | Part A: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0.0 percentage of participants |
| Part A: M4344 300 mg BIW | Part A: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0.0 percentage of participants |
| Part A: M4344 450 mg BIW | Part A: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0.0 percentage of participants |
| Part A: M4344 700 mg BIW | Part A: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0.0 percentage of participants |
| Part A: M4344 1050 mg BIW | Part A: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0.0 percentage of participants |
| Part A: M4344 1200 mg BIW | Part A: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0.0 percentage of participants |
Secondary
Part A: Terminal Elimination Half-Life (T1/2) of M4344
Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 8 | NA hours | — |
| Part A: M4344 10 mg BIW | Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 1 | NA hours | — |
| Part A: M4344 20 mg BIW | Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 1 | NA hours | — |
| Part A: M4344 20 mg BIW | Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 8 | NA hours | — |
| Part A: M4344 40 mg BIW | Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 1 | NA hours | — |
| Part A: M4344 40 mg BIW | Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 8 | NA hours | — |
| Part A: M4344 80 mg BIW | Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 8 | NA hours | — |
| Part A: M4344 80 mg BIW | Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 1 | NA hours | — |
| Part A: M4344 160 mg BIW | Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 1 | NA hours | — |
| Part A: M4344 160 mg BIW | Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 8 | NA hours | — |
| Part A: M4344 300 mg BIW | Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 8 | NA hours | — |
| Part A: M4344 300 mg BIW | Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 1 | NA hours | — |
| Part A: M4344 450 mg BIW | Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 1 | 2.22 hours | Geometric Coefficient of Variation 99 |
| Part A: M4344 450 mg BIW | Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 8 | 2.19 hours | Geometric Coefficient of Variation 220.1 |
| Part A: M4344 700 mg BIW | Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 1 | 3.33 hours | Geometric Coefficient of Variation 42.3 |
| Part A: M4344 700 mg BIW | Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 8 | 3.11 hours | Geometric Coefficient of Variation 64.2 |
| Part A: M4344 1050 mg BIW | Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 8 | NA hours | — |
| Part A: M4344 1050 mg BIW | Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 1 | 4.61 hours | Geometric Coefficient of Variation 65.2 |
| Part A: M4344 1200 mg BIW | Part A: Terminal Elimination Half-Life (T1/2) of M4344 | Cycle 1 Day 1 | 3.60 hours | Geometric Coefficient of Variation 39.9 |
Secondary
Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344
Tmax was obtained directly from the plasma concentration versus time curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 1 | NA hours |
| Part A: M4344 10 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 8 | NA hours |
| Part A: M4344 20 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 8 | NA hours |
| Part A: M4344 20 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 1 | NA hours |
| Part A: M4344 40 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 8 | NA hours |
| Part A: M4344 40 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 1 | NA hours |
| Part A: M4344 80 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 8 | NA hours |
| Part A: M4344 80 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 1 | NA hours |
| Part A: M4344 160 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 8 | NA hours |
| Part A: M4344 160 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 1 | NA hours |
| Part A: M4344 300 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 8 | NA hours |
| Part A: M4344 300 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 1 | NA hours |
| Part A: M4344 450 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 1 | 1.51 hours |
| Part A: M4344 450 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 8 | 1.22 hours |
| Part A: M4344 700 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 1 | 2.00 hours |
| Part A: M4344 700 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 8 | 2.00 hours |
| Part A: M4344 1050 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 1 | 2.06 hours |
| Part A: M4344 1050 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 8 | 4.00 hours |
| Part A: M4344 1200 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 8 | 3.95 hours |
| Part A: M4344 1200 mg BIW | Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | Cycle 1 Day 1 | 3.07 hours |
Secondary
Part B1: Apparent Clearance (CL/f) of M4344
CL/f was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-t + Clast pred/Lambda Z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLQ) and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part B1: Apparent Clearance (CL/f) of M4344 | NA liter per hour | — |
| Part A: M4344 20 mg BIW | Part B1: Apparent Clearance (CL/f) of M4344 | 1090 liter per hour | Geometric Coefficient of Variation 147.3 |
| Part A: M4344 40 mg BIW | Part B1: Apparent Clearance (CL/f) of M4344 | 194 liter per hour | Geometric Coefficient of Variation 124.3 |
Secondary
Part B1: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344
Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf\*Lambda Z), where AUC0-inf = (AUC0-t + Clast pred/Lambda Z). Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part B1: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | NA liters | — |
| Part A: M4344 20 mg BIW | Part B1: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | 1620 liters | Geometric Coefficient of Variation 155.5 |
| Part A: M4344 40 mg BIW | Part B1: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 | 1060 liters | Geometric Coefficient of Variation 45.1 |
Secondary
Part B1: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344
AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part B1: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | NA ng*h/mL | — |
| Part A: M4344 20 mg BIW | Part B1: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | 368 ng*h/mL | Geometric Coefficient of Variation 147.3 |
| Part A: M4344 40 mg BIW | Part B1: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 | 2570 ng*h/mL | Geometric Coefficient of Variation 124.3 |
Secondary
Part B1: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344
Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part B1: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | 392 ng*h/mL | Geometric Coefficient of Variation 101.8 |
| Part A: M4344 20 mg BIW | Part B1: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | 268 ng*h/mL | Geometric Coefficient of Variation 179.6 |
| Part A: M4344 40 mg BIW | Part B1: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 | 1450 ng*h/mL | Geometric Coefficient of Variation 115.6 |
Secondary
Part B1: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344
AUC0-inf/Dose was defined as AUC extrapolated to infinity divided by dose.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part B1: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | NA ng*h/mL/mg | — |
| Part A: M4344 20 mg BIW | Part B1: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | 0.920 ng*h/mL/mg | Geometric Coefficient of Variation 147.3 |
| Part A: M4344 40 mg BIW | Part B1: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344 | 5.15 ng*h/mL/mg | Geometric Coefficient of Variation 124.3 |
Secondary
Part B1: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344
AUC0-t/Dose was defined as AUC from time of dosing to the time of the last measurable concentration divided by dose.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part B1: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | 1.12 ng*h/mL/mg | Geometric Coefficient of Variation 101.8 |
| Part A: M4344 20 mg BIW | Part B1: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | 0.669 ng*h/mL/mg | Geometric Coefficient of Variation 179.6 |
| Part A: M4344 40 mg BIW | Part B1: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 | 2.90 ng*h/mL/mg | Geometric Coefficient of Variation 115.6 |
Secondary
Part B1: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344
Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part B1: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | 0.884 ng/mL/mg | Geometric Coefficient of Variation 78.1 |
| Part A: M4344 20 mg BIW | Part B1: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | 0.286 ng/mL/mg | Geometric Coefficient of Variation 191.6 |
| Part A: M4344 40 mg BIW | Part B1: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 | 0.735 ng/mL/mg | Geometric Coefficient of Variation 89.8 |
Secondary
Part B1: Maximum Observed Plasma Concentration (Cmax) of M4344
Cmax was obtained directly from the plasma concentration versus time curve.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part B1: Maximum Observed Plasma Concentration (Cmax) of M4344 | 309 ng/mL | Geometric Coefficient of Variation 78.1 |
| Part A: M4344 20 mg BIW | Part B1: Maximum Observed Plasma Concentration (Cmax) of M4344 | 114 ng/mL | Geometric Coefficient of Variation 191.6 |
| Part A: M4344 40 mg BIW | Part B1: Maximum Observed Plasma Concentration (Cmax) of M4344 | 367 ng/mL | Geometric Coefficient of Variation 89.8 |
Secondary
Part B1: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
The OR was defined as the confirmed assessment of best overall response (BOR) of partial response (PR),or complete response (CR) according to RECIST v1.1. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions.
Time frame: Time from first dose of study treatment up to 5.2 years
Population: FAS is defined as all enrolled participants who received at least 1 dose of study treatment, have a baseline scan with a measurable target lesion, and at least one on-treatment disease assessment or have discontinued the study due to either progressive disease or death.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part B1: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0.0 percentage of participants |
| Part A: M4344 20 mg BIW | Part B1: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 14.3 percentage of participants |
| Part A: M4344 40 mg BIW | Part B1: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0.0 percentage of participants |
Secondary
Part B1: Terminal Elimination Half-Life (T1/2) of M4344
Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part B1: Terminal Elimination Half-Life (T1/2) of M4344 | NA hours | — |
| Part A: M4344 20 mg BIW | Part B1: Terminal Elimination Half-Life (T1/2) of M4344 | 1.03 hours | Geometric Coefficient of Variation 23.6 |
| Part A: M4344 40 mg BIW | Part B1: Terminal Elimination Half-Life (T1/2) of M4344 | 3.77 hours | Geometric Coefficient of Variation 59.1 |
Secondary
Part B1:Time to Reach Maximum Plasma Concentration (Tmax) of M4344
Tmax was obtained directly from the plasma concentration versus time curve.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Population: The PAS included all enrolled participants who received at least one dose of M4344 with the actual amount \> 0 mg and provide at least one measurable post-dose concentration. Participants were analyzed according to the actual treatment they received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part B1:Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | 1.52 hours |
| Part A: M4344 20 mg BIW | Part B1:Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | 1.50 hours |
| Part A: M4344 40 mg BIW | Part B1:Time to Reach Maximum Plasma Concentration (Tmax) of M4344 | 1.96 hours |
Secondary
Part C: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344
Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule.
Time frame: Pre-dose up to 2 hours post-dose on Cycle 1 Day 1; Pre-dose up to 1 hours post-dose on Cycle 1 Day 8 and Cycle 1 Day 15 (each cycle is of 21 days)
Population: As per changes in planned analysis, the outcome measures related to pharmacokinetic parameters were not assessed for Part C.
Secondary
Part C: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator
DOR was defined for participants with confirmed response, as the time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Time frame: Time from first documentation of objective response, assessed up to 6.4 years
Population: As per planned analysis, DoR was not analyzed due to the small number of participants and the low likelihood that any participant would experience an objective response.
Secondary
Part C: Maximum Observed Plasma Concentration (Cmax) of M4344
Cmax was obtained directly from the plasma concentration versus time curve.
Time frame: Pre-dose up to 2 hours post-dose on Cycle 1 Day 1; Pre-dose up to 1 hours post-dose on Cycle 1 Day 8 and Cycle 1 Day 15 (each cycle is of 21 days)
Population: As per changes in planned analysis, the outcome measures related to pharmacokinetic parameters were not assessed for Part C.
Secondary
Part C: Number of Participants With Confirmed Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1
Confirmed BOR is defined as best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the treatment start date until documented disease progression. CR: Disappearance of all evidence of target/non-target lesions. PR: At least 30%reduction from baseline in sum of longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD: at least a 20% increase in SLD, taking as reference smallest SLD recorded from baseline/appearance of 1or more new lesions and unequivocal progression of non-target lesions.
Time frame: Time from first dose of study treatment up to 6.4 years
Population: FAS included all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part C: Number of Participants With Confirmed Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 | Complete response (CR) | 0 Participants |
| Part A: M4344 10 mg BIW | Part C: Number of Participants With Confirmed Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 | Partial response (PR) | 0 Participants |
| Part A: M4344 10 mg BIW | Part C: Number of Participants With Confirmed Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 | Stable disease (SD) | 3 Participants |
| Part A: M4344 10 mg BIW | Part C: Number of Participants With Confirmed Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 | Progressive disease (PD) | 8 Participants |
| Part A: M4344 10 mg BIW | Part C: Number of Participants With Confirmed Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 | Non-CR/Non-PD | 0 Participants |
| Part A: M4344 10 mg BIW | Part C: Number of Participants With Confirmed Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 | Non-evaluable | 2 Participants |
Secondary
Part C: Overall Survival (OS)
OS was defined as the time from treatment start to the date of death due to any cause. The participants who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date. OS was measured using Kaplan-Meier (KM) estimates.
Time frame: Time from first dose of study treatment up to 6.4 years
Population: FAS included all participants who received at least one dose of study drug. The summarized data was not available for these arms therefore individual data was presented. Here, Overall Number of Participants signifies those participants who were evaluable for this outcome measure and number analyzed = specific participants evaluated in the arm.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: M4344 10 mg BIW | Part C: Overall Survival (OS) | Participant 1 | 1.91 months |
| Part A: M4344 10 mg BIW | Part C: Overall Survival (OS) | Participant 2 | 0.79 months |
| Part A: M4344 10 mg BIW | Part C: Overall Survival (OS) | Participant 3 | 1.61 months |
| Part A: M4344 10 mg BIW | Part C: Overall Survival (OS) | Participant 4 | 3.98 months |
| Part A: M4344 10 mg BIW | Part C: Overall Survival (OS) | Participant 5 | 2.53 months |
| Part A: M4344 10 mg BIW | Part C: Overall Survival (OS) | Participant 6 | 2.63 months |
Secondary
Part C: Progression-Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 as Assessed by Investigator
PFS is defined as the time from start of study treatment to progression disease (PD) or death. PD: at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier (KM) estimates.
Time frame: Time from first dose of study treatment up to 6.4 years
Population: FAS included all participants who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: M4344 10 mg BIW | Part C: Progression-Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 as Assessed by Investigator | 1.6 months |
Secondary
Part C: Time to Reach Maximum Plasma Concentration (Tmax) of M4344
Tmax was obtained directly from the plasma concentration versus time curve.
Time frame: Pre-dose up to 2 hours post-dose on Cycle 1 Day 1; Pre-dose up to 1 hours post-dose on Cycle 1 Day 8 and Cycle 1 Day 15 (each cycle is of 21 days)
Population: As per changes in planned analysis, the outcome measures related to pharmacokinetic parameters were not assessed for Part C.