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

Study Overview
=================
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.

Official Title
-----------------
A Multicentre, Open Label, Phase I Trial in Japan of the MEK Inhibitor Pimasertib Given Orally to Subjects With Solid Tumors as Monotherapy

Conditions
-----------------
Advanced Solid Tumors, Hepatocellular Carcinoma

Intervention / Treatment
-----------------
* Drug: Pimasertib
* Drug: Pimasertib
* Drug: Pimasertib
* Drug: Pimasertib
* Drug: Pimasertib


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Pimasertib 30mg in Solid Tumor<br> | Drug: Pimasertib<br>* 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.<br>|
| Experimental: Part 1: Pimasertib 45 mg in Solid Tumor<br> | Drug: Pimasertib<br>* Subjects with solid tumor will be 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.<br>|
| Experimental: Part 1: Pimasertib 60 mg in Solid Tumor<br> | Drug: Pimasertib<br>* Subjects with solid tumor will be 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.<br>|
| Experimental: Part 1: Pimasertib 30 mg in Hepatocellular Carcinoma (HCC)<br> | Drug: Pimasertib<br>* Subjects with HCC will be 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.<br>|
| Experimental: Part 1: Pimasertib 45 mg in HCC<br> | Drug: Pimasertib<br>* Subjects with HCC will be 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | During Treatment Cycle 1 (Day 1 to 21) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to 30 days post last dose of study drug; assessed maximum up to 39.4 weeks | 
| 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 | The summarized data was not available for this arm therefore individual data was presented. | 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 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. | 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 | 
| 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. | 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 | 
| 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 | The summarized data was not available for this arm therefore individual data was presented. | 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) 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. | 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 | 
| 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. | 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 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 | The summarized data was not available for this arm therefore individual data was presented. | 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 (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). | 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 (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. | 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 (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. | 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 (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. | 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 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. | 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 | 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. | 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 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. | 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 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. | 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 (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. | 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 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. | 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 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. | 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 (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. | 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 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. | 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 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. | 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 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. | 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 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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). | 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 | 
| 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. | 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 | 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. | 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 | 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. | Day 1 of Cycle 3 and Day 1 of every alternate until end of treatment (up to a maximum of 35.4 weeks) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Advanced solid tumors, Hepatocellular carcinoma, cancer, liver