Advanced Solid Tumors
Conditions
Keywords
M4076, Maximum tolerated dose, Pharmacokinetics, Pharmacodynamics
Brief summary
The purpose of this study was to determine the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) (if reached) and early signs of efficacy of M4076 monotherapy in participants with solid tumors in dose escalation (Part 1A). Once the recommended dose for expansion (RDE) was declared in Part 1A, a preliminary food effect cohort, Part 1B, will follow at the RDE determined from Part 1A.
Interventions
DRUGM4076
M4076 was administered orally.
Sponsors
Merck KGaA, Darmstadt, Germany
EMD Serono Research & Development Institute, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with advanced solid tumors, for whom no standard of care therapy exists or for whom is not considered sufficiently effective, or who cannot tolerate standard of care * Participants with Eastern Cooperative Oncology Group Performance status 0 or 1 * Adequate hematological, hepatic, and renal function as defined in the protocol * Participants in Part 1B (the preliminary food effect assessment) must agree to provide paired tumor biopsies if not contraindicated for medical reasons * Other protocol defined inclusion criteria could apply
Exclusion criteria
* Clinically significant (i.e., active) uncontrolled intercurrent illness including, but not limited to: 1. Active infection (i.e., requiring systemic antibiotics or antifungals) 2. Uncontrolled arterial hypertension 3. Severe cardiac arrhythmia requiring medication 4. Cerebral vascular accident/stroke * Has known ataxia telangiectasia * Participants with tumors harboring previously identified ATM mutations * Participants with hypersensitivity to the active substance or to any of the excipients of M4076 * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0 | Day 1 to Day 21 of Cycle 1 (21-day cycle) | A DLT was defined as the occurrence of any of following events that were judged by the study investigator, received at least 80% of the planned cumulative dose during the DLT period of each study intervention and completed the DLT period or additionally, participants who did not receive 80% of the planned total dose of study intervention, but at least 80% dosing of a different dose cohort and finished the DLT period are eligible for the DLT analysis set to be analyzed in the highest dose cohort for which they received 80% of dosing. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Related TEAEs | From the first dose of study drug administration until 30 days after the last dose of study drug administration (up to 603 days) | An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious TEAEs and non-serious TEAEs. |
| Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days) | Vital sign assessments included assessments of heart rate, diastolic blood pressure, systolic blood pressure, weight, respiratory rate and temperature. Clinical significance was assessed by the investigator. Number of participants who with clinically significant changes from baseline in vital signs were reported. |
| Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days) | The laboratory measurements included hematology and biochemistry values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). Number of participants with change from baseline to grade 3 or higher values for the hematology and biochemistry were reported. |
| Number of Participants With Clinically Significant Changes From Baseline in Electrocardiogram (ECG) Values | Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days) | ECG parameters included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, QT intervals, and corrected QT(QTc) intervals. Clinical significance was determined by the investigator. Number of participants with clinically significant change from baseline in 12-lead ECG were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of M4076 | Day 1 and Day 8 | Cmax was obtained directly from the concentration versus time curve. |
| Absolute Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-ATM | Baseline up to Day 23 | Phosphorylated ataxia-telangiectasia mutated (p-ATM) is measured by flow cytometry and immunohistochemistry. Absolute change from baseline was to be reported. |
| Absolute Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-CHK2 | Baseline up to Day 23 | p-CHK2 is measured by flow cytometry and immunohistochemistry. Absolute change from baseline was to be reported. |
| Number of Participants With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator | Time from first study treatment up to 603 days | Confirmed objective response was defined as the number of participants with a confirmed objective response of complete response (CR) or partial response (PR). CR: 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. Confirmed CR = at least 2 determinations of CR at least 4 weeks apart and before progression. Confirmed PR = at least 2 determinations of PR at least 4 weeks apart and before progression (and not qualifying for a CR). |
| Relative Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-CHK2 | Baseline up to Day 23 | p-CHK2 is measured by flow cytometry and immunohistochemistry. Relative change from baseline was to be reported. |
| Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Baseline up to Day 23 | gamma-H2AX is measured by flow cytometry and immunohistochemistry. Absolute values were reported for each participant as descriptive data for this outcome measure was not calculated. P= Part, D=Day, H=Hour in the below mentioned categories. Mean Fluorescent Intensity (MFI) is a number generated by the flow cytometer; an instrument that measures the fluorescent signal emitted by a sample. The stronger the fluorescent signal, the higher the MFI value detected by the instrument's acquisition software. The values displayed in the system represent each MFI measurement at different time points, with the MFI value for the blank sample subtracted. |
| Relative Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-ATM | Baseline up to Day 23 | Phosphorylated ataxia-telangiectasia mutated (p-ATM) is measured by flow cytometry and immunohistochemistry. Relative change from baseline was to be reported. |
| 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 to the date of first documentation of PD or death due to any cause, assessed up to 603 days | 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 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. |
| Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigators | Time from the first dose of study intervention until occurrence of PD, death due to any cause or last tumor assessment (assessed up to 603 days) | PFS is defined as the time (in months) from date of first administration of study intervention to the date of the first documentation of progressive disease (PD) or death due to any cause, whichever occurs first. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was to be estimated using Kaplan-Meier (KM) plots. |
| Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUClast) of M4076 | Day 1 and Day 8 | Area under the plasma concentration vs 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-tlast was to be calculated according to the mixed log-linear trapezoidal rule. |
| Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4076 | Day 1 and Day 8 | The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination. AUC0-inf = AUC0-tlast +Clast pred/ lambda z (single dose only) |
Countries
Canada, United States
Participant flow
Recruitment details
A total of 31 participants were screened, of which 22 participants received the study drug.
Pre-assignment details
This study was to be conducted in 2 parts; Part 1A was the dose escalation phase and Part 1B was the expansion phase. However, the sponsor decided not to conduct the expansion phase (Part 2).
Participants by arm
| Arm | Count |
|---|---|
| Part 1A Dose Escalation: M4076 100 mg Participants received M4076 film coated tablets at a dose of 100 milligrams (mg), orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study | 2 |
| Part 1A Dose Escalation: M4076 200 mg Participants received M4076 film coated tablets at a dose of 200 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. | 7 |
| Part 1A Dose Escalation: M4076 300 mg Participants received M4076 film coated tablets at a dose of 300 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. | 9 |
| Part 1A Dose Escalation: M4076 400 mg Participants received M4076 film coated tablets at a dose of 400 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. | 4 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 2 | 2 |
| Overall Study | COVID-19-related and COVID-19-non-related | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | Part 1A Dose Escalation: M4076 100 mg | Total | Part 1A Dose Escalation: M4076 400 mg | Part 1A Dose Escalation: M4076 300 mg | Part 1A Dose Escalation: M4076 200 mg |
|---|---|---|---|---|---|
| Age, Continuous | 74 Years STANDARD_DEVIATION 6.4 | 58 Years STANDARD_DEVIATION 8.8 | 57 Years STANDARD_DEVIATION 5.7 | 60 Years STANDARD_DEVIATION 7.9 | 53 Years STANDARD_DEVIATION 7 |
| Race/Ethnicity, Customized Ethnicity-Hispanic or Latino | 1 Participants | 4 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Ethnicity-Not Hispanic or Latino | 1 Participants | 18 Participants | 4 Participants | 8 Participants | 5 Participants |
| Race/Ethnicity, Customized Race-Asian | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race-Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race-Other | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race-White | 2 Participants | 17 Participants | 3 Participants | 7 Participants | 5 Participants |
| Sex: Female, Male Female | 1 Participants | 13 Participants | 3 Participants | 4 Participants | 5 Participants |
| Sex: Female, Male Male | 1 Participants | 9 Participants | 1 Participants | 5 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 4 / 7 | 1 / 9 | 0 / 4 |
| other Total, other adverse events | 2 / 2 | 7 / 7 | 9 / 9 | 4 / 4 |
| serious Total, serious adverse events | 0 / 2 | 4 / 7 | 2 / 9 | 3 / 4 |
Outcome results
Primary
Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0
A DLT was defined as the occurrence of any of following events that were judged by the study investigator, received at least 80% of the planned cumulative dose during the DLT period of each study intervention and completed the DLT period or additionally, participants who did not receive 80% of the planned total dose of study intervention, but at least 80% dosing of a different dose cohort and finished the DLT period are eligible for the DLT analysis set to be analyzed in the highest dose cohort for which they received 80% of dosing.
Time frame: Day 1 to Day 21 of Cycle 1 (21-day cycle)
Population: Dose escalation set included all participants who received at least 80 percent (%) of the planned cumulative dose during the DLT period (Period 1) and have completed the DLT Period or experienced at least one DLT during the DLT period, regardless of administered number of doses of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1A Dose Escalation: M4076 100 mg | Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0 | 0 Participants |
| Part 1A Dose Escalation: M4076 200 mg | Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0 | 1 Participants |
| Part 1A Dose Escalation: M4076 300 mg | Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0 | 1 Participants |
| Part 1A Dose Escalation: M4076 400 mg | Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0 | 2 Participants |
Primary
Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0
The laboratory measurements included hematology and biochemistry values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). Number of participants with change from baseline to grade 3 or higher values for the hematology and biochemistry were reported.
Time frame: Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days)
Population: Safety analysis set included all participants who were administered at least one dose of any study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1A Dose Escalation: M4076 100 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Sodium Low | 0 Participants |
| Part 1A Dose Escalation: M4076 100 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Gamma Glutamyl Transferase High | 0 Participants |
| Part 1A Dose Escalation: M4076 100 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Hemoglobin Low | 0 Participants |
| Part 1A Dose Escalation: M4076 100 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Lipase High | 0 Participants |
| Part 1A Dose Escalation: M4076 100 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Bilirubin High | 0 Participants |
| Part 1A Dose Escalation: M4076 100 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Aspartate Aminotransferase High | 0 Participants |
| Part 1A Dose Escalation: M4076 100 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Alanine Aminotransferase High | 0 Participants |
| Part 1A Dose Escalation: M4076 100 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Calcium High | 0 Participants |
| Part 1A Dose Escalation: M4076 100 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Potassium Low | 0 Participants |
| Part 1A Dose Escalation: M4076 100 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Alkaline Phosphatase High | 0 Participants |
| Part 1A Dose Escalation: M4076 100 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Lymphocytes Low | 0 Participants |
| Part 1A Dose Escalation: M4076 100 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Potassium High | 0 Participants |
| Part 1A Dose Escalation: M4076 200 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Potassium Low | 1 Participants |
| Part 1A Dose Escalation: M4076 200 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Alanine Aminotransferase High | 0 Participants |
| Part 1A Dose Escalation: M4076 200 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Aspartate Aminotransferase High | 0 Participants |
| Part 1A Dose Escalation: M4076 200 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Alkaline Phosphatase High | 0 Participants |
| Part 1A Dose Escalation: M4076 200 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Gamma Glutamyl Transferase High | 0 Participants |
| Part 1A Dose Escalation: M4076 200 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Bilirubin High | 1 Participants |
| Part 1A Dose Escalation: M4076 200 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Lipase High | 1 Participants |
| Part 1A Dose Escalation: M4076 200 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Sodium Low | 0 Participants |
| Part 1A Dose Escalation: M4076 200 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Potassium High | 1 Participants |
| Part 1A Dose Escalation: M4076 200 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Calcium High | 1 Participants |
| Part 1A Dose Escalation: M4076 200 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Hemoglobin Low | 1 Participants |
| Part 1A Dose Escalation: M4076 200 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Lymphocytes Low | 3 Participants |
| Part 1A Dose Escalation: M4076 300 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Lipase High | 0 Participants |
| Part 1A Dose Escalation: M4076 300 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Sodium Low | 1 Participants |
| Part 1A Dose Escalation: M4076 300 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Alkaline Phosphatase High | 0 Participants |
| Part 1A Dose Escalation: M4076 300 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Alanine Aminotransferase High | 0 Participants |
| Part 1A Dose Escalation: M4076 300 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Potassium High | 0 Participants |
| Part 1A Dose Escalation: M4076 300 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Potassium Low | 0 Participants |
| Part 1A Dose Escalation: M4076 300 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Aspartate Aminotransferase High | 0 Participants |
| Part 1A Dose Escalation: M4076 300 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Calcium High | 0 Participants |
| Part 1A Dose Escalation: M4076 300 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Lymphocytes Low | 3 Participants |
| Part 1A Dose Escalation: M4076 300 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Bilirubin High | 0 Participants |
| Part 1A Dose Escalation: M4076 300 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Gamma Glutamyl Transferase High | 0 Participants |
| Part 1A Dose Escalation: M4076 300 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Hemoglobin Low | 2 Participants |
| Part 1A Dose Escalation: M4076 400 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Bilirubin High | 0 Participants |
| Part 1A Dose Escalation: M4076 400 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Alkaline Phosphatase High | 1 Participants |
| Part 1A Dose Escalation: M4076 400 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Hemoglobin Low | 1 Participants |
| Part 1A Dose Escalation: M4076 400 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Lymphocytes Low | 2 Participants |
| Part 1A Dose Escalation: M4076 400 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Sodium Low | 0 Participants |
| Part 1A Dose Escalation: M4076 400 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Lipase High | 0 Participants |
| Part 1A Dose Escalation: M4076 400 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Calcium High | 0 Participants |
| Part 1A Dose Escalation: M4076 400 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Alanine Aminotransferase High | 1 Participants |
| Part 1A Dose Escalation: M4076 400 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Potassium High | 0 Participants |
| Part 1A Dose Escalation: M4076 400 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Aspartate Aminotransferase High | 1 Participants |
| Part 1A Dose Escalation: M4076 400 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Gamma Glutamyl Transferase High | 1 Participants |
| Part 1A Dose Escalation: M4076 400 mg | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | Grade>=3 Potassium Low | 0 Participants |
Primary
Number of Participants With Clinically Significant Changes From Baseline in Electrocardiogram (ECG) Values
ECG parameters included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, QT intervals, and corrected QT(QTc) intervals. Clinical significance was determined by the investigator. Number of participants with clinically significant change from baseline in 12-lead ECG were reported.
Time frame: Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days)
Population: Safety analysis set included all participants who were administered at least one dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1A Dose Escalation: M4076 100 mg | Number of Participants With Clinically Significant Changes From Baseline in Electrocardiogram (ECG) Values | 0 Participants |
| Part 1A Dose Escalation: M4076 200 mg | Number of Participants With Clinically Significant Changes From Baseline in Electrocardiogram (ECG) Values | 0 Participants |
| Part 1A Dose Escalation: M4076 300 mg | Number of Participants With Clinically Significant Changes From Baseline in Electrocardiogram (ECG) Values | 0 Participants |
| Part 1A Dose Escalation: M4076 400 mg | Number of Participants With Clinically Significant Changes From Baseline in Electrocardiogram (ECG) Values | 0 Participants |
Primary
Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
Vital sign assessments included assessments of heart rate, diastolic blood pressure, systolic blood pressure, weight, respiratory rate and temperature. Clinical significance was assessed by the investigator. Number of participants who with clinically significant changes from baseline in vital signs were reported.
Time frame: Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days)
Population: Safety analysis set included all participants who were administered at least one dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1A Dose Escalation: M4076 100 mg | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
| Part 1A Dose Escalation: M4076 200 mg | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
| Part 1A Dose Escalation: M4076 300 mg | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
| Part 1A Dose Escalation: M4076 400 mg | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Related TEAEs
An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious TEAEs and non-serious TEAEs.
Time frame: From the first dose of study drug administration until 30 days after the last dose of study drug administration (up to 603 days)
Population: Safety analysis set included all participants who were administered at least one dose of any study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1A Dose Escalation: M4076 100 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Related TEAEs | TEAEs | 2 Participants |
| Part 1A Dose Escalation: M4076 100 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Related TEAEs | Treatment Related TEAEs | 1 Participants |
| Part 1A Dose Escalation: M4076 200 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Related TEAEs | Treatment Related TEAEs | 2 Participants |
| Part 1A Dose Escalation: M4076 200 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Related TEAEs | TEAEs | 7 Participants |
| Part 1A Dose Escalation: M4076 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Related TEAEs | TEAEs | 9 Participants |
| Part 1A Dose Escalation: M4076 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Related TEAEs | Treatment Related TEAEs | 8 Participants |
| Part 1A Dose Escalation: M4076 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Related TEAEs | TEAEs | 4 Participants |
| Part 1A Dose Escalation: M4076 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Related TEAEs | Treatment Related TEAEs | 4 Participants |
Secondary
Absolute Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-ATM
Phosphorylated ataxia-telangiectasia mutated (p-ATM) is measured by flow cytometry and immunohistochemistry. Absolute change from baseline was to be reported.
Time frame: Baseline up to Day 23
Population: Data for p-ATM was not generated due to insufficient samples as all Peripheral Blood Mononuclear Cells (PBMC) samples were exhausted in gamma-H2AX analysis. Hence no data was collected.
Secondary
Absolute Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-CHK2
p-CHK2 is measured by flow cytometry and immunohistochemistry. Absolute change from baseline was to be reported.
Time frame: Baseline up to Day 23
Population: Data for p-CHK2 was not generated as no fresh tumor biopsies were collected. Hence no data was collected.
Secondary
Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX
gamma-H2AX is measured by flow cytometry and immunohistochemistry. Absolute values were reported for each participant as descriptive data for this outcome measure was not calculated. P= Part, D=Day, H=Hour in the below mentioned categories. Mean Fluorescent Intensity (MFI) is a number generated by the flow cytometer; an instrument that measures the fluorescent signal emitted by a sample. The stronger the fluorescent signal, the higher the MFI value detected by the instrument's acquisition software. The values displayed in the system represent each MFI measurement at different time points, with the MFI value for the blank sample subtracted.
Time frame: Baseline up to Day 23
Population: The pharmacodynamics (Pd) Analysis Set consisted of all participants, who received at least one dose of study intervention, had no clinically important protocol deviations or important events affecting Pd, and provide the baseline and at least one measurable Pd endpoint postdose. Participants will be analyzed per the actual study intervention they received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant15(P1AD1-6H Postdose) | 596 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant21(P1AD1-6H Postdose) | 787 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant21(P1AD1 Predose) | 2280 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant21(P1AD2-2H-4H Postdose) | -128 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant21(P1AD2 Predose) | 1389 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant1(P1AD1-2H Postdose) | 1316 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant1(P1AD1-4H Postdose) | 1037 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant1(P1AD1-6H Postdose) | 3127 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant1(P1AD1-Predose) | 1612 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant1(P1AD2-2-4H Postdose) | 347 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant1(P1AD2-Predose) | 1925 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant1(P1A/1BD22-2H Postdose | 1030 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant1(P1A/1BD22-4H Postdose) | 1023 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant1(P1A/1BD22-Predose) | 1461 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant2(P1AD1-6H Postdose) | 896 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant2(P1AD2-2-4H Postdose) | 143 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant2(P1A/1BD22-2H Postdose) | 753 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant2(P1A/1BD22-Predose) | 1441 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant3(P1AD1-2H Postdose) | 5555 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant3(P1AD1-4H Postdose) | 4432 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant3(P1AD2-2H-4H Postdose) | 1504 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant3(P1AD2-4H Predose) | 2649 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant4(P1AD1-2H Postdose) | 879 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant4(P1AD1-4H Potdose) | 395 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant4(P1AD1-6H Postdose) | 702 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant4(P1AD1-Predose) | -34 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant4(P1AD2-2H-4H Postdose) | 1045 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant4(P1AD2-Predose) | 1057 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant5(P1AD1-2H Postdose) | 195 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant5(P1AD1-4H Postdose) | 171 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant5(P1AD1-6H Postdose) | 75 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant5(P1AD1-Predose) | 144 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant5(P1AD2-2H-4H Postdose) | 0 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant5(P1AD2-Predose) | 22 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant6(P1AD1-2H Postdose) | 57 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant6(P1AD1-4H Postdose) | 138 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant6(P1AD1-6H Postdose) | 116 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant6(P1AD1-4H Predose) | 206 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant6(P1AD2-2H-4H Postdose) | 1 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant6(P1AD2- Predose) | 29 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant6(P1A/1BD22-2H Postdose) | 994 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant6(P1A/1BD22-4H Postdose) | 786 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant6(P1A/1BD22-Predose) | 2371 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant7(P1A/1BD22-4H Postdose) | 5397 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant7(P1A/1BD22-2H-4H Postdose) | 770 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant7(P1AD2-Predose) | 1103 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant8(P1AD1-2H Postdose) | 1775 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant8(P1AD1-4H Postdose) | 1504 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant8(P1AD1-6H Postdose) | 854 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant8(P1AD1-Predose) | 2294 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant8(P1AD1-2H-4H Postdose) | 381 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant8(Part1AD2-Predose) | 910 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant9(P1AD1-2H Postdose) | 2836 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant9(P1AD1-4H Postdose) | 1499 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant9(P1AD1-6H Postdose) | 1901 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant9(P1AD1-Predose) | -4092 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant9(P1AD2-2H-4H Postdose) | 2392 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant9(P1A/1BD22-2H Postdose) | 2795 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant9(P1A/1BD22-4H Postdose) | 3375 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant9(P1A/1BD22-Predose) | 3412 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant10(P1A/1BD22-2H Postdose) | 747 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant10(P1A/1BD22-4H Postdose) | 1186 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant10(P1A/1BD22-Predose) | 1608 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant10(P1AD1-2H Postdose) | 2014 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant10(P1AD1-4H Postdose) | 1522 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant10(P1AD1-2H-4H Postdose) | 2363 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant10(P1AD2-Predose) | 1018 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant11(P1AD1-2H Postdose) | 2432 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant11(P1AD1-4H Postdose) | 1282 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant11(P1A/1BD22-2H Postdose) | -802 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant11(P1A/1BD22- Predose) | -904 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant11(P1A/1BD22-4H Postdose) | -1708 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant12(P1AD1-2H Postdose) | 3613 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant12(P1AD1-Predose) | 5007 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant12(P1AD2-2H-4H Postdose) | 4438 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant12(P1AD2-Predose) | 4088 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant13(P1AD2-2H-4H Postdose) | 2650 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant13(P1AD2-Predose) | 2342 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant13(P1A/1BD22-2H Postdose) | 1194 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant13(P1A/1BD22-4H Postdose) | -70 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant13(P1A/1BD22 Predose) | 2532 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant14(P1AD1-2H Postdose) | 329 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant14(P1AD1-4H Postdose) | 139 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant14(P1AD1-6H Postdose) | 194 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant14(P1AD1-Predose) | 704 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant14(P1AD2-2H-4H Postdose) | 208 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant14(P1AD2-Predose) | 115 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant14(P1A/1BD22-Predose) | 210 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant15(P1AD1-2H Postdose) | 829 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant15(P1AD1-4H Postdose) | 1006 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant15(P1AD1-Predose) | 1808 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant15(P1AD2-2H-4H Postdose) | 1742 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant15(P1AD2-2H Predose) | 2074 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant16(P1AD1-2H Postdose) | 562 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant16(P1AD1-4H Postdose) | 416 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant16(P1AD1-6H Postdose) | 554 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant16(P1AD1-Predose) | 644 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant16(P1AD2-2H-4H Postdose) | 704 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant17(P1AD1-2H Postdose) | 2200 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant17(P1AD1-4H Postdose) | 799 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant17(P1AD2-2H-4H Postdose) | 729 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant17(P1AD2-Predose) | 3157 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant18(P1AD1-6H Postdose) | 845 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant18(P1AD1-Presdose) | 1261 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant18(P1AD2-2H-4H Postdose) | 2257 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant19(P1AD1-2H Postdose) | 2182 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant19(P1AD1-4H Postdose) | 1831 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant19(P1AD1-6H Postdose) | 1871 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant19(P1AD1-Predose) | -2466 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant19(P1AD2-2H-4H Postdose) | 1677 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant19(P1AD2-Predose) | 4862 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant20(P1A/1BD22-2H Postdose) | 11119 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant20(P1AD1-2H Postdose | 1967 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant20(P1AD1-4H Postdose | -593 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant20(P1AD1-6H Postdose | 2977 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant20(P1AD1-Predose) | 262 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant20(P1AD2-2H-4H Postdose) | 1860 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant20(P1AD2-Predose) | 3150 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant21(P1AD1-2H Postdose) | 660 Mean fluorescence intensity |
| Part 1A Dose Escalation: M4076 100 mg | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | Participant21(P1AD1-4H Postdose) | 1392 Mean fluorescence intensity |
Secondary
Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4076
The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination. AUC0-inf = AUC0-tlast +Clast pred/ lambda z (single dose only)
Time frame: Day 1 and Day 8
Population: Pharmacokinetic Analysis Set included all participants who were administered at least one dose of study intervention. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1A Dose Escalation: M4076 100 mg | Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4076 | Day 1 | NA h*ng/mL | — |
| Part 1A Dose Escalation: M4076 200 mg | Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4076 | Day 1 | 39200 h*ng/mL | Geometric Coefficient of Variation 40.3 |
| Part 1A Dose Escalation: M4076 300 mg | Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4076 | Day 1 | 44900 h*ng/mL | Geometric Coefficient of Variation 49.9 |
| Part 1A Dose Escalation: M4076 400 mg | Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4076 | Day 1 | 69800 h*ng/mL | Geometric Coefficient of Variation 20.4 |
Secondary
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUClast) of M4076
Area under the plasma concentration vs 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-tlast was to be calculated according to the mixed log-linear trapezoidal rule.
Time frame: Day 1 and Day 8
Population: Pharmacokinetic Analysis Set included all participants who were administered at least one dose of study intervention. Here, Number analyzed signifies those participants who were evaluable for this outcome measure at specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1A Dose Escalation: M4076 100 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUClast) of M4076 | Day 1 | NA hour*nanograms per milliliter | — |
| Part 1A Dose Escalation: M4076 100 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUClast) of M4076 | Day 8 | NA hour*nanograms per milliliter | — |
| Part 1A Dose Escalation: M4076 200 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUClast) of M4076 | Day 8 | 36500 hour*nanograms per milliliter | Geometric Coefficient of Variation 109.2 |
| Part 1A Dose Escalation: M4076 200 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUClast) of M4076 | Day 1 | 37000 hour*nanograms per milliliter | Geometric Coefficient of Variation 34.1 |
| Part 1A Dose Escalation: M4076 300 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUClast) of M4076 | Day 1 | 50500 hour*nanograms per milliliter | Geometric Coefficient of Variation 45.1 |
| Part 1A Dose Escalation: M4076 300 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUClast) of M4076 | Day 8 | 56500 hour*nanograms per milliliter | Geometric Coefficient of Variation 67.6 |
| Part 1A Dose Escalation: M4076 400 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUClast) of M4076 | Day 1 | 76600 hour*nanograms per milliliter | Geometric Coefficient of Variation 44.3 |
| Part 1A Dose Escalation: M4076 400 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUClast) of M4076 | Day 8 | 85900 hour*nanograms per milliliter | Geometric Coefficient of Variation 40.8 |
Secondary
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 percent (%) 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 to the date of first documentation of PD or death due to any cause, assessed up to 603 days
Population: None of the participants showed objective response.
Secondary
Maximum Observed Plasma Concentration (Cmax) of M4076
Cmax was obtained directly from the concentration versus time curve.
Time frame: Day 1 and Day 8
Population: Pharmacokinetic Analysis Set included all participants who were administered at least one dose of study intervention, have no clinically important protocol deviations or important events affecting pharmacodynamics, and provide the baseline and at least one measurable pharmacodynamics endpoint post dose. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1A Dose Escalation: M4076 100 mg | Maximum Observed Plasma Concentration (Cmax) of M4076 | Day 1 | NA nanogram per milliliter (ng/mL) | — |
| Part 1A Dose Escalation: M4076 100 mg | Maximum Observed Plasma Concentration (Cmax) of M4076 | Day 8 | NA nanogram per milliliter (ng/mL) | — |
| Part 1A Dose Escalation: M4076 200 mg | Maximum Observed Plasma Concentration (Cmax) of M4076 | Day 8 | 4690 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 52.5 |
| Part 1A Dose Escalation: M4076 200 mg | Maximum Observed Plasma Concentration (Cmax) of M4076 | Day 1 | 4080 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 26.5 |
| Part 1A Dose Escalation: M4076 300 mg | Maximum Observed Plasma Concentration (Cmax) of M4076 | Day 1 | 6270 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 20.3 |
| Part 1A Dose Escalation: M4076 300 mg | Maximum Observed Plasma Concentration (Cmax) of M4076 | Day 8 | 6730 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 26.3 |
| Part 1A Dose Escalation: M4076 400 mg | Maximum Observed Plasma Concentration (Cmax) of M4076 | Day 1 | 8510 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 30.1 |
| Part 1A Dose Escalation: M4076 400 mg | Maximum Observed Plasma Concentration (Cmax) of M4076 | Day 8 | 9600 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 22.8 |
Secondary
Number of Participants With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator
Confirmed objective response was defined as the number of participants with a confirmed objective response of complete response (CR) or partial response (PR). CR: 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. Confirmed CR = at least 2 determinations of CR at least 4 weeks apart and before progression. Confirmed PR = at least 2 determinations of PR at least 4 weeks apart and before progression (and not qualifying for a CR).
Time frame: Time from first study treatment up to 603 days
Population: Full analysis set included all participants who were administered at least one dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1A Dose Escalation: M4076 100 mg | Number of Participants With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator | 0 Participants |
| Part 1A Dose Escalation: M4076 200 mg | Number of Participants With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator | 0 Participants |
| Part 1A Dose Escalation: M4076 300 mg | Number of Participants With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator | 0 Participants |
| Part 1A Dose Escalation: M4076 400 mg | Number of Participants With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator | 0 Participants |
Secondary
Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigators
PFS is defined as the time (in months) from date of first administration of study intervention to the date of the first documentation of progressive disease (PD) or death due to any cause, whichever occurs first. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was to be estimated using Kaplan-Meier (KM) plots.
Time frame: Time from the first dose of study intervention until occurrence of PD, death due to any cause or last tumor assessment (assessed up to 603 days)
Population: Full analysis set included all participants who were administered at least one dose of any study intervention.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1A Dose Escalation: M4076 100 mg | Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigators | NA months |
| Part 1A Dose Escalation: M4076 200 mg | Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigators | 1.1 months |
| Part 1A Dose Escalation: M4076 300 mg | Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigators | 1.3 months |
| Part 1A Dose Escalation: M4076 400 mg | Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigators | NA months |
Secondary
Relative Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-ATM
Phosphorylated ataxia-telangiectasia mutated (p-ATM) is measured by flow cytometry and immunohistochemistry. Relative change from baseline was to be reported.
Time frame: Baseline up to Day 23
Population: Data for p-ATM was not generated due to insufficient samples as all Peripheral Blood Mononuclear Cells (PBMC) samples were exhausted in gamma-H2AX analysis. Hence no data was collected.
Secondary
Relative Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-CHK2
p-CHK2 is measured by flow cytometry and immunohistochemistry. Relative change from baseline was to be reported.
Time frame: Baseline up to Day 23
Population: Data for p-CHK2 was not generated as no fresh tumor biopsies were collected. Hence no data was collected.