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

Hepatocellular Carcinoma Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01668017
• Other study ID #: EMR 200066-010
• Status: Terminated
• Phase: Phase 1
• First received: August 15, 2012
• Last updated: October 19, 2015
• Start date: September 2012
• Est. completion date: April 2015

Study information

• Verified date: October 2015
• Source: Merck KGaA
• Contact: n/a
• Is FDA regulated: No
• Health authority: Japan: Pharmaceuticals and Medical Devices Agency
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 26
• Est. completion date: April 2015
• Est. primary completion date: April 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 = 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

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Advanced Solid Tumors
• Carcinoma, Hepatocellular
• Hepatocellular Carcinoma

Intervention

Drug:
• Pimasertib
Pimasertib will be supplied as 15 and 30 mg hard gelatin capsules. Pimasertib will be taken orally twice a day continuously. Treatment will be administered in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject, whichever comes first.

Locations

Country	Name	City	State
Japan	Please contact	Merck Serono Co., Ltd for recruiting locations in

Sponsors (2)

Lead Sponsor	Collaborator
Merck KGaA	Merck Serono Co., Ltd., Japan

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of subjects Who Experienced at least one Dose Limiting Toxicity (DLT) During Treatment Cycle 1 (days 1-21) by arm and treatment level		Days 1-21	Yes
Secondary	Number of subjects who experienced treatment-emergent adverse events (TEAEs)		Day 1 up to approximately Day 84 (end of cycle 4)	Yes
Secondary	Maximum observed concentration (Cmax) of Pimasertib		Cycle 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12, and 24 hours post dose; Days 3 and 8: 30 minutes pre-dose, 1 and 4 hours post dose; Day 15: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6 and 8 hours post dose and Day 16:Pre-dose; Cycles 2-4:Pre-dose and at EoT	No
Secondary	Time to reach maximum concentration (Tmax)		Cycle 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12, and 24 hours post dose; Days 3 and 8: 30 minutes pre-dose, 1 and 4 hours post dose; Day 15: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6 and 8 hours post dose and Day 16:Pre-dose; Cycles 2-4:Pre-dose and at EoT	No
Secondary	Area under the concentration time curve from 0-24 hours (AUC0-24) of pimasertib		Cycle 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12, and 24 hours post dose; Days 3 and 8: 30 minutes pre-dose, 1 and 4 hours post dose; Day 15: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6 and 8 hours post dose and Day 16:Pre-dose; Cycles 2-4:Pre-dose and at EoT	No
Secondary	Area under the concentration over time (AUCt)		Cycle 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12, and 24 hours post dose; Days 3 and 8: 30 minutes pre-dose, 1 and 4 hours post dose; Day 15: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6 and 8 hours post dose and Day 16:Pre-dose; Cycles 2-4:Pre-dose and at EoT	No
Secondary	Apparent terminal half-life (t1/2) of pimasertib		Cycle 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12, and 24 hours post dose; Days 3 and 8: 30 minutes pre-dose, 1 and 4 hours post dose; Day 15: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6 and 8 hours post dose and Day 16:Pre-dose; Cycles 2-4:Pre-dose and at EoT	No
Secondary	Apparent clearance (CL/f) of pimasertib		Cycle 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12, and 24 hours post dose; Days 3 and 8: 30 minutes pre-dose, 1 and 4 hours post dose; Day 15: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6 and 8 hours post dose and Day 16:Pre-dose; Cycles 2-4:Pre-dose and at EoT	No
Secondary	Apparent clearance at steady-state (CLss/f) of pimasertib		Cycle 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12, and 24 hours post dose; Days 3 and 8: 30 minutes pre-dose, 1 and 4 hours post dose; Day 15: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6 and 8 hours post dose and Day 16:Pre-dose; Cycles 2-4:Pre-dose and at EoT	No
Secondary	Apparent volume of distribution at terminal phase (Vz/f) of pimasertib		Cycle 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12, and 24 hours post dose; Days 3 and 8: 30 minutes pre-dose, 1 and 4 hours post dose; Day 15: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6 and 8 hours post dose and Day 16:Pre-dose; Cycles 2-4:Pre-dose and at EoT	No
Secondary	Apparent volume of distribution at steady-state (Vss/f) of pimasertib		Cycle 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12, and 24 hours post dose; Days 3 and 8: 30 minutes pre-dose, 1 and 4 hours post dose; Day 15: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6 and 8 hours post dose and Day 16:Pre-dose; Cycles 2-4:Pre-dose and at EoT	No
Secondary	Accumulation ratio for AUC (Racc(AUC)) of pimasertib		Cycle 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12, and 24 hours post dose; Days 3 and 8: 30 minutes pre-dose, 1 and 4 hours post dose; Day 15: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6 and 8 hours post dose and Day 16:Pre-dose; Cycles 2-4:Pre-dose and at EoT	No
Secondary	accumulation ratio for Cmax (Racc(Cmax)) of pimasertib		Cycle 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12, and 24 hours post dose; Days 3 and 8: 30 minutes pre-dose, 1 and 4 hours post dose; Day 15: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6 and 8 hours post dose and Day 16:Pre-dose; Cycles 2-4:Pre-dose and at EoT	No
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) will be reported.	Day 1 up to approximately Day 84 (end of cycle 4)	No
Secondary	Percentage of subjects with objective response	Percentage of subjects with objective response (CR plus PR) according to RECIST Version 1.1 will be reported.	Day 1 up to approximately Day 84 (end of cycle 4)	No
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 will be reported.	Day 1 up to approximately Day 84 (end of cycle 4)	No