A Multicentre, Open Label, Phase 1 Trial in Japan of the Mitogen Activated Protein Extracellular Signal Regulated Kinase (MEK) Inhibitor Pimasertib Given Orally to Subjects With Solid Tumors as Monotherapy

Phase 1

Terminated

Conditions: Hepatocellular Carcinoma
Advanced Solid Tumors

Interventions: Drug: Pimasertib

Registration Number: NCT01668017

Lead Sponsor: Merck KGaA, Darmstadt, Germany

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 26

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part 1: Pimasertib 45 mg in Solid Tumor	Pimasertib	-
Part 1: Pimasertib 60 mg in Solid Tumor	Pimasertib	-
Part 1: Pimasertib 30mg in Solid Tumor	Pimasertib	-
Part 1: Pimasertib 30 mg in Hepatocellular Carcinoma (HCC)	Pimasertib	-
Part 1: Pimasertib 45 mg in HCC	Pimasertib	-

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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 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.
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.
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 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
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
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.
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.
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 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 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 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.
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.