Advanced Solid Tumors, Hepatocellular Carcinoma
Conditions
Keywords
Advanced solid tumors, Hepatocellular carcinoma, cancer, liver
Brief summary
This is a two-part trial. Solid tumor in this protocol means solid tumor excluding hepatocellular carcinoma (HCC). Part 1: Dose Escalation Phase in subjects with solid tumor (Cohort A) and HCC (Cohort B). The dose will be increased from 45 mg twice a day (BID) with 3+3 cohort method up to the recommended phase 2 dose (RP2D) of pimasertib established as single agent in the global studies for each arm independently. Part 2: The Maximum Tolerated Dose (MTD) defined in Part 1 will be confirmed in more subjects in Cohort A (N=18) and Cohort B (N=6) separately. Following the recommendation by the Safety Monitoring Committee, Cohort B was discontinued due to hepatocellular carcinoma (HCC) and there will be no further enrollment of subjects to this cohort. This decision is based upon review of safety and efficacy information.
Interventions
DRUGPimasertib
Subjects with solid tumor will be administered with Pimasertib 30 mg twice a day (BID) in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.
Sponsors
Merck Serono Co., Ltd., Japan
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Cohort A: A histologically or cytologically confirmed diagnosis of advanced solid tumors which is either refractory after standard therapy for the disease or for which no effective standard therapy is available. Archived tumor tissue available or biopsy of tumor tissue needs to be performed. Cohort B: A histologically or cytologically confirmed diagnosis of advanced hepatocellular carcinoma (HCC) which is either refractory after standard therapy for the disease or for which no effective standard therapy is available. Archived tumor tissue available or biopsy of tumor tissue needs to be performed. Subjects with Child Pugh A. * Male or female Japanese, age greater than or equal to (\>=) 18 years. * Subject has read and understands the informed consent form and is willing and able to give informed consent. The subject fully understands requirements of the trial and is willing to comply with all trial visits and assessments. * Women of childbearing potential must have a negative blood pregnancy test at the screening visit. * Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 2 weeks prior to, during and four weeks after the last dose investigational medicinal product (IMP). * Life expectancy of at least 3 months
Exclusion criteria
Hematological abnormality Cohort A: Hematological test abnormalities of Hemoglobin \< 9.0 g/dL, Neutrophil count \< 1.0\*10\^9/L and Platelet count \< 100\*10\^9/L. Cohort B: Hematological test abnormalities of Hemoglobin \< 9.0 g/dL, Neutrophil count \< 1.0\*10\^9/L, Platelet count \< 75\*10\^9/L, subjects with hepatic encephalopathy * Renal impairment as evidenced by serum creatinine \> 1.5\*upper limit of normal (ULN), and calculated creatinine clearance \< 60 mL/min by Cockcroft-Gault formula. * Liver function abnormality of Total Bilirubin \> 1.5\*ULN, or aspartate transaminase 9AST) or alkaline phosphatase (ALT)\> 2.5\*ULN. For subjects with HCC or liver involvement AST/ALT \> 5\*ULN. * History of central nervous system (CNS) metastases, unless subject has been previously treated for CNS metastases * History of difficulty swallowing, malabsorption or other chronic gastro-intestinal disease or conditions * Eastern Cooperative Oncology Group Performance status (ECOG PS) greater than 1. * Has received chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or any other anticancer therapy (including any investigational agent) or surgical intervention within 28 days or 5 half lives for non-cytotoxics of registration. * Baseline corrected QT interval on screening ECG (QTc) \>= 480 ms or left ventricular ejection fraction (LVEF) \< 40% on screening echocardiogram * Cohort B: Subjects with hepatic encephalopathy, remarkable ascites and subjects with history of esophageal varices rupture within 6 months (subjects with symptom improvement after treatment are eligible) * Other serious illness or medical conditions. * Retinal degenerative disease. * Previous treatment with MEK inhibitors. * Legal incapacity or limited legal capacity.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Experienced at Least One Dose Limiting Toxicity (DLT) | During Treatment Cycle 1 (Day 1 to 21) | DLT defined using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 3.0 (NCI CTCAE v3.0): any of following toxicities possibly/probably related to study drug: Any non-hematological toxicity of Grade 3 or higher (excluding Grade 3 asymptomatic rise in liver function tests (aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\], alkaline phosphatase \[ALP\], gamma-glutamyl transferase \[GGT\] reversible in 7 days for subjects with solid tumor and without liver involvement, or Grade 4 for subjects with HCC or with liver involvement; Grade 3 or 4 asymptomatic rise in creatinine phosphokinase (CPK) reversible in 7 days, deniable for myocardial infarction and rhabdomyolysis; Grade 3 vomiting/diarrhea encountered without optimal therapy). Any Grade 4 neutropenia \>5 days duration, any Grade 3 or above febrile neutropenia. Grade 4 thrombocytopenia \>1 day or Grade 3 with bleeding. Any treatment delay \>2 weeks due to drug-related adverse effects. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Experienced Treatment-Emergent Adverse Events (TEAEs) or Serious TEAEs | Baseline up to 30 days post last dose of study drug; assessed maximum up to 39.4 weeks | An adverse event (AE) was defined as any untoward medical occurrence which does not necessarily have a causal relationship with this the study drug. An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 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. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. TEAEs include both Serious TEAEs and non-serious TEAEs. |
| Maximum Observed Concentration (Cmax) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 | The summarized data was not available for this arm therefore individual data was presented. |
| Maximum Observed Concentration (Cmax) of Pimasertib on Cycle 1 Day 15 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15 | Data were not reported for Part 1: Pimasertib 45 mg in HCC arm as there were no PK samples collected for this arm. |
| Maximum Observed Concentration (Cmax) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15 | The summarized data was not available for this arm therefore individual data was presented. |
| Time to Reach Maximum Concentration (Tmax) on Cycle 1 Day 1 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 | — |
| Time to Reach Maximum Concentration (Tmax) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 | The summarized data was not available for this arm therefore individual data was presented. |
| Time to Reach Maximum Concentration (Tmax) on Cycle 1 Day 15 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15 | Data were not reported for Part 1: Pimasertib 45 mg In HCC arm as there were no PK samples collected for this arm. |
| Time to Reach Maximum Concentration (Tmax) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15 | The summarized data was not available for this arm therefore individual data was presented. |
| Area Under the Concentration Over Time (AUCt) at Cycle 1 Day 1 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 | — |
| Area Under the Concentration Over Time (AUCt) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 | The summarized data was not available for this arm therefore individual data was presented. |
| Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib at Cycle 1 Day 1 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 | Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (12 hours). |
| Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib of 1 Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 | Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (12 hours). The summarized data was not available for this arm therefore individual data was presented. |
| Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib at Cycle 1 Day 15 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15 | Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (12 hours). Data were not reported for Part 1: Pimasertib 45 mg In HCC arm as there were no PK samples collected for this arm. |
| Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15 | Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (12 hours). The summarized data was not available for this arm therefore individual data was presented. |
| Apparent Terminal Half-life (t1/2) of Pimasertib on Cycle 1 Day 1 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 | The apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. |
| Apparent Terminal Half-life (t1/2) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 | The apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. The summarized data was not available for this arm therefore individual data was presented. |
| Maximum Observed Concentration (Cmax) of Pimasertib on Cycle 1 Day 1 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 | — |
| Apparent Terminal Half-life (t1/2) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15 | The apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. The summarized data was not available for this arm therefore individual data was presented. |
| Apparent Clearance (CL/f) of Pimasertib on Cycle 1 Day 1 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 | Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed. |
| Apparent Clearance (CL/f) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 | Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed. The summarized data was not available for this arm therefore individual data was presented. |
| Apparent Clearance at Steady-state (CLss/f) of Pimasertib on Cycle 1 Day 15 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15 | Apparent clearance at steady state was reported. Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Data were not reported for Part 1: Pimasertib 45 mg In HCC arm as there were no PK samples collected for this arm. |
| Apparent Clearance at Steady-state (CLss/f) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15 | Apparent clearance at steady state was reported. Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. The summarized data was not available for this arm therefore individual data was presented. |
| Apparent Volume of Distribution at Terminal Phase (Vz/f) of Pimasertib on Cycle 1 Day 1 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. |
| Apparent Volume of Distribution at Terminal Phase (Vz/f) Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. The summarized data was not available for this arm therefore individual data was presented. |
| Apparent Volume of Distribution at Terminal Phase (Vz/f) of Pimasertib on Cycle 1 Day 15 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15 | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. Data were not reported for Part 1: Pimasertib 45 mg In HCC arm as there were no PK samples collected for this arm. |
| Apparent Volume of Distribution at Terminal Phase (Vz/f) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15 | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. The summarized data was not available for this arm therefore individual data was presented. |
| Accumulation Ratio for AUC Racc(AUC) of Pimasertib | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 and Day 15 | Racc (AUC) was calculated as, area under the curve from time zero to end of dosing interval on Day 1 divided by area under the curve from time zero to end of dosing interval on Day 15. Data were not reported for Part 1: Pimasertib 45 mg In HCC arm as there were no PK samples collected for this arm. |
| Accumulation Ratio for AUC Racc(AUC) of Part 1: Pimasertib 30 mg In HCC Arm | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 and Day 15 | Racc (AUC) was calculated as, area under the curve from time zero to end of dosing interval on Day 1 divided by area under the curve from time zero to end of dosing interval on Day 15. |
| Accumulation Ratio for Cmax Racc(Cmax) of Pimasertib | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 and Day 15 | Racc (Cmax) was calculated as, maximum observed plasma concentration on Day 1 (Cmax) divided by maximum observed plasma concentration on Day 15 (Cmax). Data were not reported for Part 1: Pimasertib 45 mg In HCC arm as there were no PK samples collected for this arm. |
| Accumulation Ratio for Cmax Racc(Cmax) of Part 1: Pimasertib 30 mg In HCC Arm | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 and Day 15 | Racc (Cmax) was calculated as, maximum observed plasma concentration on Day 1 (Cmax) divided by maximum observed plasma concentration on Day 15 (Cmax). |
| Percentage of Subjects With Best Overall Response | Day 1 of Cycle 3 and Day 1 of every alternate until end of treatment (up to a maximum of 35.4 weeks) | Percentage of subjects with best overall response in each category (complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\]) according to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) was reported. CR was defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) or unequivocal progression of existing non-target lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
| Percentage of Subjects With Objective Response | Day 1 of Cycle 3 and Day 1 of every alternate until end of treatment (up to a maximum of 35.4 weeks) | Percentage of subjects with objective response (CR plus PR) according to RECIST Version 1.1 was reported. CR was defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Percentage of Subjects With Disease Control | Day 1 of Cycle 3 and Day 1 of every alternate until end of treatment (up to a maximum of 35.4 weeks) | Percentage of subjects with disease control (CR plus PR plus greater than 12 weeks SD) according to RECIST Version 1.1 was reported CR was defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) or unequivocal progression of existing non-target lesions. |
| Apparent Terminal Half-life (t1/2) of Pimasertib on Cycle 1 Day 15 | Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15 | The apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. Data were not reported for Part 1: Pimasertib 45 mg In HCC arm as there were no PK samples collected for this arm. |
Countries
Japan
Participant flow
Recruitment details
First/last subject (informed consent): September 2012/April 2015. Last subject completed: April 2015.
Pre-assignment details
This study was to be conducted in 2 parts; Part 1 was the dose escalation phase and Part 2 was the expansion phase. However, due to early termination of the study, the sponsor decided not to conduct the expansion phase (Part 2).
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor Subjects with solid tumor were administered with Pimasertib 30 mg BID in 21- day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject. | 4 |
| Part 1: Pimasertib 45 mg in Solid Tumor Subjects with solid tumor were administered with Pimasertib 45 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject. | 9 |
| Part 1: Pimasertib 60 mg in Solid Tumor Subjects with solid tumor were administered with Pimasertib 60 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject. | 6 |
| Part 1: Pimasertib 30 mg in HCC Subjects with HCC were administered with Pimasertib 30 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject. | 5 |
| Part 1: Pimasertib 45 mg in HCC Subjects with HCC were administered with Pimasertib 45 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject. | 2 |
| Total | 26 |
Baseline characteristics
| Characteristic | Part 1: Pimasertib 30 mg in Solid Tumor | Part 1: Pimasertib 45 mg in Solid Tumor | Part 1: Pimasertib 60 mg in Solid Tumor | Part 1: Pimasertib 30 mg in HCC | Part 1: Pimasertib 45 mg in HCC | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 62.3 years STANDARD_DEVIATION 12.2 | 61.4 years STANDARD_DEVIATION 10.63 | 61.5 years STANDARD_DEVIATION 9.29 | 58.8 years STANDARD_DEVIATION 13.63 | 56.5 years STANDARD_DEVIATION 20.51 | 60.7 years STANDARD_DEVIATION 11 |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 4 Participants | 2 Participants | 1 Participants | 13 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 2 Participants | 3 Participants | 1 Participants | 13 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 9 / 9 | 6 / 6 | 5 / 5 | 2 / 2 |
| serious Total, serious adverse events | 2 / 4 | 2 / 9 | 2 / 6 | 2 / 5 | 0 / 2 |
Outcome results
Primary
Number of Subjects Who Experienced at Least One Dose Limiting Toxicity (DLT)
DLT defined using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 3.0 (NCI CTCAE v3.0): any of following toxicities possibly/probably related to study drug: Any non-hematological toxicity of Grade 3 or higher (excluding Grade 3 asymptomatic rise in liver function tests (aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\], alkaline phosphatase \[ALP\], gamma-glutamyl transferase \[GGT\] reversible in 7 days for subjects with solid tumor and without liver involvement, or Grade 4 for subjects with HCC or with liver involvement; Grade 3 or 4 asymptomatic rise in creatinine phosphokinase (CPK) reversible in 7 days, deniable for myocardial infarction and rhabdomyolysis; Grade 3 vomiting/diarrhea encountered without optimal therapy). Any Grade 4 neutropenia \>5 days duration, any Grade 3 or above febrile neutropenia. Grade 4 thrombocytopenia \>1 day or Grade 3 with bleeding. Any treatment delay \>2 weeks due to drug-related adverse effects.
Time frame: During Treatment Cycle 1 (Day 1 to 21)
Population: DLT analysis set included all subjects who experienced any DLT during Cycle 1 and who received above 85% of all planned doses of pimasertib during Cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Number of Subjects Who Experienced at Least One Dose Limiting Toxicity (DLT) | 0 subjects |
| Part 1: Pimasertib 45 mg in Solid Tumor | Number of Subjects Who Experienced at Least One Dose Limiting Toxicity (DLT) | 0 subjects |
| Part 1: Pimasertib 60 mg in Solid Tumor | Number of Subjects Who Experienced at Least One Dose Limiting Toxicity (DLT) | 2 subjects |
| Part 1: Pimasertib 30 mg in HCC | Number of Subjects Who Experienced at Least One Dose Limiting Toxicity (DLT) | 1 subjects |
| Part 1: Pimasertib 45 mg in HCC | Number of Subjects Who Experienced at Least One Dose Limiting Toxicity (DLT) | 1 subjects |
Secondary
Accumulation Ratio for AUC Racc(AUC) of Part 1: Pimasertib 30 mg In HCC Arm
Racc (AUC) was calculated as, area under the curve from time zero to end of dosing interval on Day 1 divided by area under the curve from time zero to end of dosing interval on Day 15.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 and Day 15
Population: PK analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Accumulation Ratio for AUC Racc(AUC) of Part 1: Pimasertib 30 mg In HCC Arm | Subject 1 | 2.43 ratio |
| Part 1: Pimasertib 30 mg in Solid Tumor | Accumulation Ratio for AUC Racc(AUC) of Part 1: Pimasertib 30 mg In HCC Arm | Subject 2 | 1.83 ratio |
Secondary
Accumulation Ratio for AUC Racc(AUC) of Pimasertib
Racc (AUC) was calculated as, area under the curve from time zero to end of dosing interval on Day 1 divided by area under the curve from time zero to end of dosing interval on Day 15. Data were not reported for Part 1: Pimasertib 45 mg In HCC arm as there were no PK samples collected for this arm.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 and Day 15
Population: PK analysis set. Here Overall Number of Participants Analyzed signifies the overall number of subjects who were evaluable for this outcome measure for each arm, respectively.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Accumulation Ratio for AUC Racc(AUC) of Pimasertib | 1.782 ratio | Geometric Coefficient of Variation 4.2 |
| Part 1: Pimasertib 45 mg in Solid Tumor | Accumulation Ratio for AUC Racc(AUC) of Pimasertib | 1.382 ratio | Geometric Coefficient of Variation 30.2 |
| Part 1: Pimasertib 60 mg in Solid Tumor | Accumulation Ratio for AUC Racc(AUC) of Pimasertib | 1.311 ratio | Geometric Coefficient of Variation 51.5 |
Secondary
Accumulation Ratio for Cmax Racc(Cmax) of Part 1: Pimasertib 30 mg In HCC Arm
Racc (Cmax) was calculated as, maximum observed plasma concentration on Day 1 (Cmax) divided by maximum observed plasma concentration on Day 15 (Cmax).
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 and Day 15
Population: PK analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Accumulation Ratio for Cmax Racc(Cmax) of Part 1: Pimasertib 30 mg In HCC Arm | Subject 1 | 1.50 ratio |
| Part 1: Pimasertib 30 mg in Solid Tumor | Accumulation Ratio for Cmax Racc(Cmax) of Part 1: Pimasertib 30 mg In HCC Arm | Subject 2 | 2.31 ratio |
Secondary
Accumulation Ratio for Cmax Racc(Cmax) of Pimasertib
Racc (Cmax) was calculated as, maximum observed plasma concentration on Day 1 (Cmax) divided by maximum observed plasma concentration on Day 15 (Cmax). Data were not reported for Part 1: Pimasertib 45 mg In HCC arm as there were no PK samples collected for this arm.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1 and Day 15
Population: PK analysis set. Here Overall Number of Participants Analyzed signifies the overall number of subjects who were evaluable for this outcome measure for each arm, respectively.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Accumulation Ratio for Cmax Racc(Cmax) of Pimasertib | 1.227 ratio | Geometric Coefficient of Variation 38.3 |
| Part 1: Pimasertib 45 mg in Solid Tumor | Accumulation Ratio for Cmax Racc(Cmax) of Pimasertib | 0.8281 ratio | Geometric Coefficient of Variation 65.5 |
| Part 1: Pimasertib 60 mg in Solid Tumor | Accumulation Ratio for Cmax Racc(Cmax) of Pimasertib | 1.215 ratio | Geometric Coefficient of Variation 61.3 |
Secondary
Apparent Clearance at Steady-state (CLss/f) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15
Apparent clearance at steady state was reported. Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. The summarized data was not available for this arm therefore individual data was presented.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15
Population: PK analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Apparent Clearance at Steady-state (CLss/f) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15 | Subject 1 | 13.3 L/h |
| Part 1: Pimasertib 30 mg in Solid Tumor | Apparent Clearance at Steady-state (CLss/f) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15 | Subject 2 | 17.8 L/h |
Secondary
Apparent Clearance at Steady-state (CLss/f) of Pimasertib on Cycle 1 Day 15
Apparent clearance at steady state was reported. Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Data were not reported for Part 1: Pimasertib 45 mg In HCC arm as there were no PK samples collected for this arm.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15
Population: PK analysis set. Here Overall Number of Participants Analyzed signifies the overall number of subjects who were evaluable for this outcome measure for each arm, respectively.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Apparent Clearance at Steady-state (CLss/f) of Pimasertib on Cycle 1 Day 15 | 25.24 L/h | Geometric Coefficient of Variation 73.6 |
| Part 1: Pimasertib 45 mg in Solid Tumor | Apparent Clearance at Steady-state (CLss/f) of Pimasertib on Cycle 1 Day 15 | 40.00 L/h | Geometric Coefficient of Variation 62.1 |
| Part 1: Pimasertib 60 mg in Solid Tumor | Apparent Clearance at Steady-state (CLss/f) of Pimasertib on Cycle 1 Day 15 | 28.02 L/h | Geometric Coefficient of Variation 37.6 |
Secondary
Apparent Clearance (CL/f) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1
Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed. The summarized data was not available for this arm therefore individual data was presented.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1
Population: PK analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Apparent Clearance (CL/f) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Subject 1 | 18.5 L/h |
| Part 1: Pimasertib 30 mg in Solid Tumor | Apparent Clearance (CL/f) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Subject 2 | 23.7 L/h |
Secondary
Apparent Clearance (CL/f) of Pimasertib on Cycle 1 Day 1
Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1
Population: PK analysis set. Here Overall Number of Participants Analyzed signifies the overall number of subjects who were evaluable for this outcome measure for each arm, respectively.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Apparent Clearance (CL/f) of Pimasertib on Cycle 1 Day 1 | 41.67 liter/hour (L/h) | Geometric Coefficient of Variation 80.5 |
| Part 1: Pimasertib 45 mg in Solid Tumor | Apparent Clearance (CL/f) of Pimasertib on Cycle 1 Day 1 | 48.17 liter/hour (L/h) | Geometric Coefficient of Variation 52.8 |
| Part 1: Pimasertib 60 mg in Solid Tumor | Apparent Clearance (CL/f) of Pimasertib on Cycle 1 Day 1 | 32.62 liter/hour (L/h) | Geometric Coefficient of Variation 54.6 |
| Part 1: Pimasertib 30 mg in HCC | Apparent Clearance (CL/f) of Pimasertib on Cycle 1 Day 1 | 32.19 liter/hour (L/h) | Geometric Coefficient of Variation 27.3 |
Secondary
Apparent Terminal Half-life (t1/2) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15
The apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. The summarized data was not available for this arm therefore individual data was presented.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15
Population: PK analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Apparent Terminal Half-life (t1/2) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15 | Subject 1 | 15.4 hours |
| Part 1: Pimasertib 30 mg in Solid Tumor | Apparent Terminal Half-life (t1/2) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15 | Subject 2 | 5.41 hours |
Secondary
Apparent Terminal Half-life (t1/2) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1
The apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. The summarized data was not available for this arm therefore individual data was presented.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1
Population: PK analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Apparent Terminal Half-life (t1/2) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Subject 2 | 5.46 hours |
| Part 1: Pimasertib 30 mg in Solid Tumor | Apparent Terminal Half-life (t1/2) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Subject 1 | 5.68 hours |
Secondary
Apparent Terminal Half-life (t1/2) of Pimasertib on Cycle 1 Day 1
The apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1
Population: PK analysis set. Here Overall Number of Participants Analyzed signifies the overall number of subjects who were evaluable for this outcome measure for each arm, respectively.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Apparent Terminal Half-life (t1/2) of Pimasertib on Cycle 1 Day 1 | 3.480 hours |
| Part 1: Pimasertib 45 mg in Solid Tumor | Apparent Terminal Half-life (t1/2) of Pimasertib on Cycle 1 Day 1 | 3.545 hours |
| Part 1: Pimasertib 60 mg in Solid Tumor | Apparent Terminal Half-life (t1/2) of Pimasertib on Cycle 1 Day 1 | 3.935 hours |
| Part 1: Pimasertib 30 mg in HCC | Apparent Terminal Half-life (t1/2) of Pimasertib on Cycle 1 Day 1 | 4.560 hours |
Secondary
Apparent Terminal Half-life (t1/2) of Pimasertib on Cycle 1 Day 15
The apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. Data were not reported for Part 1: Pimasertib 45 mg In HCC arm as there were no PK samples collected for this arm.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15
Population: PK analysis set. Here Overall Number of Participants Analyzed signifies the overall number of subjects who were evaluable for this outcome measure for each arm, respectively.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Apparent Terminal Half-life (t1/2) of Pimasertib on Cycle 1 Day 15 | 4.235 hours |
| Part 1: Pimasertib 45 mg in Solid Tumor | Apparent Terminal Half-life (t1/2) of Pimasertib on Cycle 1 Day 15 | 4.000 hours |
| Part 1: Pimasertib 60 mg in Solid Tumor | Apparent Terminal Half-life (t1/2) of Pimasertib on Cycle 1 Day 15 | 5.530 hours |
Secondary
Apparent Volume of Distribution at Terminal Phase (Vz/f) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. The summarized data was not available for this arm therefore individual data was presented.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15
Population: PK analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Apparent Volume of Distribution at Terminal Phase (Vz/f) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15 | Subject 1 | 297 liters |
| Part 1: Pimasertib 30 mg in Solid Tumor | Apparent Volume of Distribution at Terminal Phase (Vz/f) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15 | Subject 2 | 139 liters |
Secondary
Apparent Volume of Distribution at Terminal Phase (Vz/f) of Pimasertib on Cycle 1 Day 1
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1
Population: PK analysis set. Here Overall Number of Participants Analyzed signifies the overall number of subjects who were evaluable for this outcome measure for each arm, respectively.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Apparent Volume of Distribution at Terminal Phase (Vz/f) of Pimasertib on Cycle 1 Day 1 | 231.2 liters | Geometric Coefficient of Variation 71.6 |
| Part 1: Pimasertib 45 mg in Solid Tumor | Apparent Volume of Distribution at Terminal Phase (Vz/f) of Pimasertib on Cycle 1 Day 1 | 238.1 liters | Geometric Coefficient of Variation 46.7 |
| Part 1: Pimasertib 60 mg in Solid Tumor | Apparent Volume of Distribution at Terminal Phase (Vz/f) of Pimasertib on Cycle 1 Day 1 | 169.8 liters | Geometric Coefficient of Variation 29.7 |
| Part 1: Pimasertib 30 mg in HCC | Apparent Volume of Distribution at Terminal Phase (Vz/f) of Pimasertib on Cycle 1 Day 1 | 177.2 liters | Geometric Coefficient of Variation 15.9 |
Secondary
Apparent Volume of Distribution at Terminal Phase (Vz/f) of Pimasertib on Cycle 1 Day 15
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. Data were not reported for Part 1: Pimasertib 45 mg In HCC arm as there were no PK samples collected for this arm.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15
Population: PK analysis set. Here Overall Number of Participants Analyzed signifies the overall number of subjects who were evaluable for this outcome measure for each arm, respectively.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Apparent Volume of Distribution at Terminal Phase (Vz/f) of Pimasertib on Cycle 1 Day 15 | 105.0 liters | Geometric Coefficient of Variation 161.1 |
| Part 1: Pimasertib 45 mg in Solid Tumor | Apparent Volume of Distribution at Terminal Phase (Vz/f) of Pimasertib on Cycle 1 Day 15 | 233.9 liters | Geometric Coefficient of Variation 46.4 |
| Part 1: Pimasertib 60 mg in Solid Tumor | Apparent Volume of Distribution at Terminal Phase (Vz/f) of Pimasertib on Cycle 1 Day 15 | 209.1 liters | Geometric Coefficient of Variation 10.6 |
Secondary
Apparent Volume of Distribution at Terminal Phase (Vz/f) Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. The summarized data was not available for this arm therefore individual data was presented.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1
Population: PK analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Apparent Volume of Distribution at Terminal Phase (Vz/f) Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Subject 1 | 152 liters |
| Part 1: Pimasertib 30 mg in Solid Tumor | Apparent Volume of Distribution at Terminal Phase (Vz/f) Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Subject 2 | 187 liters |
Secondary
Area Under the Concentration Over Time (AUCt) at Cycle 1 Day 1
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1
Population: PK analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Area Under the Concentration Over Time (AUCt) at Cycle 1 Day 1 | 703.0 h*ng/mL | Geometric Coefficient of Variation 73.8 |
| Part 1: Pimasertib 45 mg in Solid Tumor | Area Under the Concentration Over Time (AUCt) at Cycle 1 Day 1 | 862.4 h*ng/mL | Geometric Coefficient of Variation 42.8 |
| Part 1: Pimasertib 60 mg in Solid Tumor | Area Under the Concentration Over Time (AUCt) at Cycle 1 Day 1 | 1626.9 h*ng/mL | Geometric Coefficient of Variation 43.6 |
| Part 1: Pimasertib 30 mg in HCC | Area Under the Concentration Over Time (AUCt) at Cycle 1 Day 1 | 911.4 h*ng/mL | Geometric Coefficient of Variation 27.3 |
Secondary
Area Under the Concentration Over Time (AUCt) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1
The summarized data was not available for this arm therefore individual data was presented.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1
Population: PK analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Area Under the Concentration Over Time (AUCt) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Subject 1 | 1754 h*ng/mL |
| Part 1: Pimasertib 30 mg in Solid Tumor | Area Under the Concentration Over Time (AUCt) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Subject 2 | 1430 h*ng/mL |
Secondary
Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15
Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (12 hours). The summarized data was not available for this arm therefore individual data was presented.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15
Population: PK analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15 | Subject 1 | 2250 h*ng/mL |
| Part 1: Pimasertib 30 mg in Solid Tumor | Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15 | Subject 2 | 1687 h*ng/mL |
Secondary
Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib at Cycle 1 Day 1
Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (12 hours).
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1
Population: PK analysis set. Here Overall Number of Participants Analyzed signifies the overall number of subjects who were evaluable for this outcome measure for each arm, respectively.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib at Cycle 1 Day 1 | 618.3 h*ng/mL | Geometric Coefficient of Variation 86.1 |
| Part 1: Pimasertib 45 mg in Solid Tumor | Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib at Cycle 1 Day 1 | 857.4 h*ng/mL | Geometric Coefficient of Variation 46 |
| Part 1: Pimasertib 60 mg in Solid Tumor | Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib at Cycle 1 Day 1 | 1629.3 h*ng/mL | Geometric Coefficient of Variation 43.7 |
| Part 1: Pimasertib 30 mg in HCC | Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib at Cycle 1 Day 1 | 911.7 h*ng/mL | Geometric Coefficient of Variation 27.2 |
Secondary
Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib at Cycle 1 Day 15
Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (12 hours). Data were not reported for Part 1: Pimasertib 45 mg In HCC arm as there were no PK samples collected for this arm.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15
Population: PK analysis set. Here Overall Number of Participants Analyzed signifies the overall number of subjects who were evaluable for this outcome measure for each arm, respectively.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib at Cycle 1 Day 15 | 1189.3 h*ng/mL | Geometric Coefficient of Variation 73.6 |
| Part 1: Pimasertib 45 mg in Solid Tumor | Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib at Cycle 1 Day 15 | 1125.0 h*ng/mL | Geometric Coefficient of Variation 62.1 |
| Part 1: Pimasertib 60 mg in Solid Tumor | Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib at Cycle 1 Day 15 | 2140.7 h*ng/mL | Geometric Coefficient of Variation 37.6 |
Secondary
Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib of 1 Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1
Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (12 hours). The summarized data was not available for this arm therefore individual data was presented.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1
Population: PK analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib of 1 Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Subject 1 | 1761 h*ng/mL |
| Part 1: Pimasertib 30 mg in Solid Tumor | Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib of 1 Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Subject 2 | 1431 h*ng/mL |
Secondary
Maximum Observed Concentration (Cmax) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15
The summarized data was not available for this arm therefore individual data was presented.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15
Population: PK analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Maximum Observed Concentration (Cmax) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15 | Subject 1 | 320 ng/mL |
| Part 1: Pimasertib 30 mg in Solid Tumor | Maximum Observed Concentration (Cmax) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15 | Subject 2 | 419 ng/mL |
Secondary
Maximum Observed Concentration (Cmax) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1
The summarized data was not available for this arm therefore individual data was presented.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1
Population: PK analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Maximum Observed Concentration (Cmax) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Subject 1 | 225 ng/mL |
| Part 1: Pimasertib 30 mg in Solid Tumor | Maximum Observed Concentration (Cmax) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Subject 2 | 281 ng/mL |
Secondary
Maximum Observed Concentration (Cmax) of Pimasertib on Cycle 1 Day 1
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1
Population: Pharmacokinetic (PK) analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Maximum Observed Concentration (Cmax) of Pimasertib on Cycle 1 Day 1 | 162.4 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 113.1 |
| Part 1: Pimasertib 45 mg in Solid Tumor | Maximum Observed Concentration (Cmax) of Pimasertib on Cycle 1 Day 1 | 222.1 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 45.2 |
| Part 1: Pimasertib 60 mg in Solid Tumor | Maximum Observed Concentration (Cmax) of Pimasertib on Cycle 1 Day 1 | 288.3 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 52.1 |
| Part 1: Pimasertib 30 mg in HCC | Maximum Observed Concentration (Cmax) of Pimasertib on Cycle 1 Day 1 | 167.6 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 26.3 |
Secondary
Maximum Observed Concentration (Cmax) of Pimasertib on Cycle 1 Day 15
Data were not reported for Part 1: Pimasertib 45 mg in HCC arm as there were no PK samples collected for this arm.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15
Population: PK analysis set. Here Overall Number of Participants Analyzed signifies the overall number of subjects who were evaluable for this outcome measure for each arm, respectively.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Maximum Observed Concentration (Cmax) of Pimasertib on Cycle 1 Day 15 | 199.5 ng/mL | Geometric Coefficient of Variation 58.9 |
| Part 1: Pimasertib 45 mg in Solid Tumor | Maximum Observed Concentration (Cmax) of Pimasertib on Cycle 1 Day 15 | 231.6 ng/mL | Geometric Coefficient of Variation 66.1 |
| Part 1: Pimasertib 60 mg in Solid Tumor | Maximum Observed Concentration (Cmax) of Pimasertib on Cycle 1 Day 15 | 336.3 ng/mL | Geometric Coefficient of Variation 30.8 |
Secondary
Number of Subjects Who Experienced Treatment-Emergent Adverse Events (TEAEs) or Serious TEAEs
An adverse event (AE) was defined as any untoward medical occurrence which does not necessarily have a causal relationship with this the study drug. An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 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. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. TEAEs include both Serious TEAEs and non-serious TEAEs.
Time frame: Baseline up to 30 days post last dose of study drug; assessed maximum up to 39.4 weeks
Population: Safety analysis set included all subjects who received at least one administration of pimasertib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Number of Subjects Who Experienced Treatment-Emergent Adverse Events (TEAEs) or Serious TEAEs | TEAEs | 4 subjects |
| Part 1: Pimasertib 30 mg in Solid Tumor | Number of Subjects Who Experienced Treatment-Emergent Adverse Events (TEAEs) or Serious TEAEs | Serious TEAEs | 2 subjects |
| Part 1: Pimasertib 45 mg in Solid Tumor | Number of Subjects Who Experienced Treatment-Emergent Adverse Events (TEAEs) or Serious TEAEs | TEAEs | 9 subjects |
| Part 1: Pimasertib 45 mg in Solid Tumor | Number of Subjects Who Experienced Treatment-Emergent Adverse Events (TEAEs) or Serious TEAEs | Serious TEAEs | 2 subjects |
| Part 1: Pimasertib 60 mg in Solid Tumor | Number of Subjects Who Experienced Treatment-Emergent Adverse Events (TEAEs) or Serious TEAEs | TEAEs | 6 subjects |
| Part 1: Pimasertib 60 mg in Solid Tumor | Number of Subjects Who Experienced Treatment-Emergent Adverse Events (TEAEs) or Serious TEAEs | Serious TEAEs | 2 subjects |
| Part 1: Pimasertib 30 mg in HCC | Number of Subjects Who Experienced Treatment-Emergent Adverse Events (TEAEs) or Serious TEAEs | Serious TEAEs | 2 subjects |
| Part 1: Pimasertib 30 mg in HCC | Number of Subjects Who Experienced Treatment-Emergent Adverse Events (TEAEs) or Serious TEAEs | TEAEs | 5 subjects |
| Part 1: Pimasertib 45 mg in HCC | Number of Subjects Who Experienced Treatment-Emergent Adverse Events (TEAEs) or Serious TEAEs | TEAEs | 2 subjects |
| Part 1: Pimasertib 45 mg in HCC | Number of Subjects Who Experienced Treatment-Emergent Adverse Events (TEAEs) or Serious TEAEs | Serious TEAEs | 0 subjects |
Secondary
Percentage of Subjects With Best Overall Response
Percentage of subjects with best overall response in each category (complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\]) according to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) was reported. CR was defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) or unequivocal progression of existing non-target lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: Day 1 of Cycle 3 and Day 1 of every alternate until end of treatment (up to a maximum of 35.4 weeks)
Population: Efficacy analysis set included all subjects who received at least one administration of planned dose of pimasertib and who have had at least one efficacy assessment after the first dose.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Percentage of Subjects With Best Overall Response | SD | 0 percentage of subjects |
| Part 1: Pimasertib 30 mg in Solid Tumor | Percentage of Subjects With Best Overall Response | Not evaluable | 33.3 percentage of subjects |
| Part 1: Pimasertib 30 mg in Solid Tumor | Percentage of Subjects With Best Overall Response | CR | 0 percentage of subjects |
| Part 1: Pimasertib 30 mg in Solid Tumor | Percentage of Subjects With Best Overall Response | PD | 66.7 percentage of subjects |
| Part 1: Pimasertib 30 mg in Solid Tumor | Percentage of Subjects With Best Overall Response | PR | 0 percentage of subjects |
| Part 1: Pimasertib 45 mg in Solid Tumor | Percentage of Subjects With Best Overall Response | CR | 0 percentage of subjects |
| Part 1: Pimasertib 45 mg in Solid Tumor | Percentage of Subjects With Best Overall Response | SD | 14.3 percentage of subjects |
| Part 1: Pimasertib 45 mg in Solid Tumor | Percentage of Subjects With Best Overall Response | Not evaluable | 0 percentage of subjects |
| Part 1: Pimasertib 45 mg in Solid Tumor | Percentage of Subjects With Best Overall Response | PR | 42.9 percentage of subjects |
| Part 1: Pimasertib 45 mg in Solid Tumor | Percentage of Subjects With Best Overall Response | PD | 42.9 percentage of subjects |
| Part 1: Pimasertib 60 mg in Solid Tumor | Percentage of Subjects With Best Overall Response | PR | 0 percentage of subjects |
| Part 1: Pimasertib 60 mg in Solid Tumor | Percentage of Subjects With Best Overall Response | CR | 0 percentage of subjects |
| Part 1: Pimasertib 60 mg in Solid Tumor | Percentage of Subjects With Best Overall Response | PD | 75.0 percentage of subjects |
| Part 1: Pimasertib 60 mg in Solid Tumor | Percentage of Subjects With Best Overall Response | Not evaluable | 25.0 percentage of subjects |
| Part 1: Pimasertib 60 mg in Solid Tumor | Percentage of Subjects With Best Overall Response | SD | 0 percentage of subjects |
| Part 1: Pimasertib 30 mg in HCC | Percentage of Subjects With Best Overall Response | CR | 0 percentage of subjects |
| Part 1: Pimasertib 30 mg in HCC | Percentage of Subjects With Best Overall Response | Not evaluable | 25.0 percentage of subjects |
| Part 1: Pimasertib 30 mg in HCC | Percentage of Subjects With Best Overall Response | PD | 75.0 percentage of subjects |
| Part 1: Pimasertib 30 mg in HCC | Percentage of Subjects With Best Overall Response | PR | 0 percentage of subjects |
| Part 1: Pimasertib 30 mg in HCC | Percentage of Subjects With Best Overall Response | SD | 0 percentage of subjects |
| Part 1: Pimasertib 45 mg in HCC | Percentage of Subjects With Best Overall Response | SD | 0 percentage of subjects |
| Part 1: Pimasertib 45 mg in HCC | Percentage of Subjects With Best Overall Response | Not evaluable | 50.0 percentage of subjects |
| Part 1: Pimasertib 45 mg in HCC | Percentage of Subjects With Best Overall Response | CR | 0 percentage of subjects |
| Part 1: Pimasertib 45 mg in HCC | Percentage of Subjects With Best Overall Response | PD | 50.0 percentage of subjects |
| Part 1: Pimasertib 45 mg in HCC | Percentage of Subjects With Best Overall Response | PR | 0 percentage of subjects |
Secondary
Percentage of Subjects With Disease Control
Percentage of subjects with disease control (CR plus PR plus greater than 12 weeks SD) according to RECIST Version 1.1 was reported CR was defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) or unequivocal progression of existing non-target lesions.
Time frame: Day 1 of Cycle 3 and Day 1 of every alternate until end of treatment (up to a maximum of 35.4 weeks)
Population: Efficacy analysis set included all subjects who received at least one administration of planned dose of pimasertib and who have had at least one efficacy assessment after the first dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Percentage of Subjects With Disease Control | 0 percentage of subjects |
| Part 1: Pimasertib 45 mg in Solid Tumor | Percentage of Subjects With Disease Control | 57.1 percentage of subjects |
| Part 1: Pimasertib 60 mg in Solid Tumor | Percentage of Subjects With Disease Control | 0 percentage of subjects |
| Part 1: Pimasertib 30 mg in HCC | Percentage of Subjects With Disease Control | 0 percentage of subjects |
| Part 1: Pimasertib 45 mg in HCC | Percentage of Subjects With Disease Control | 0 percentage of subjects |
Secondary
Percentage of Subjects With Objective Response
Percentage of subjects with objective response (CR plus PR) according to RECIST Version 1.1 was reported. CR was defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Day 1 of Cycle 3 and Day 1 of every alternate until end of treatment (up to a maximum of 35.4 weeks)
Population: Efficacy analysis set' included all subjects who received at least one administration of planned dose of pimasertib and who have had at least one efficacy assessment after the first dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Percentage of Subjects With Objective Response | 0 percentage of subjects |
| Part 1: Pimasertib 45 mg in Solid Tumor | Percentage of Subjects With Objective Response | 42.9 percentage of subjects |
| Part 1: Pimasertib 60 mg in Solid Tumor | Percentage of Subjects With Objective Response | 0 percentage of subjects |
| Part 1: Pimasertib 30 mg in HCC | Percentage of Subjects With Objective Response | 0 percentage of subjects |
| Part 1: Pimasertib 45 mg in HCC | Percentage of Subjects With Objective Response | 0 percentage of subjects |
Secondary
Time to Reach Maximum Concentration (Tmax) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15
The summarized data was not available for this arm therefore individual data was presented.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15
Population: PK analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Time to Reach Maximum Concentration (Tmax) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15 | Subject 1 | 0.98 hours |
| Part 1: Pimasertib 30 mg in Solid Tumor | Time to Reach Maximum Concentration (Tmax) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15 | Subject 2 | 0.95 hours |
Secondary
Time to Reach Maximum Concentration (Tmax) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1
The summarized data was not available for this arm therefore individual data was presented.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1
Population: PK analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Time to Reach Maximum Concentration (Tmax) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Subject 1 | 1.47 hours |
| Part 1: Pimasertib 30 mg in Solid Tumor | Time to Reach Maximum Concentration (Tmax) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1 | Subject 2 | 1.92 hours |
Secondary
Time to Reach Maximum Concentration (Tmax) on Cycle 1 Day 1
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 1
Population: PK analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Time to Reach Maximum Concentration (Tmax) on Cycle 1 Day 1 | 2.450 hours |
| Part 1: Pimasertib 45 mg in Solid Tumor | Time to Reach Maximum Concentration (Tmax) on Cycle 1 Day 1 | 1.480 hours |
| Part 1: Pimasertib 60 mg in Solid Tumor | Time to Reach Maximum Concentration (Tmax) on Cycle 1 Day 1 | 1.710 hours |
| Part 1: Pimasertib 30 mg in HCC | Time to Reach Maximum Concentration (Tmax) on Cycle 1 Day 1 | 1.000 hours |
Secondary
Time to Reach Maximum Concentration (Tmax) on Cycle 1 Day 15
Data were not reported for Part 1: Pimasertib 45 mg In HCC arm as there were no PK samples collected for this arm.
Time frame: Cycle 1: Pre-morning dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, hours post dose, pre-evening dose (Hour 12) at Day 15
Population: PK analysis set. Here Overall Number of Participants Analyzed signifies the overall number of subjects who were evaluable for this outcome measure for each arm, respectively.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Pimasertib 30 mg in Solid Tumor | Time to Reach Maximum Concentration (Tmax) on Cycle 1 Day 15 | 1.805 hours |
| Part 1: Pimasertib 45 mg in Solid Tumor | Time to Reach Maximum Concentration (Tmax) on Cycle 1 Day 15 | 1.910 hours |
| Part 1: Pimasertib 60 mg in Solid Tumor | Time to Reach Maximum Concentration (Tmax) on Cycle 1 Day 15 | 2.550 hours |