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

This study has been terminated.
(The sponsor decided not to conduct the expansion part of trial (part 2))
Sponsor:
Collaborator:
Merck Serono Co., Ltd., Japan
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT01668017
First received: August 15, 2012
Last updated: October 19, 2015
Last verified: October 2015
  Purpose

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.


Condition Intervention Phase
Advanced Solid Tumors
Hepatocellular Carcinoma
Drug: Pimasertib
Phase 1

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

Resource links provided by NLM:


Further study details as provided by Merck KGaA:

Primary Outcome Measures:
  • Number of subjects Who Experienced at least one Dose Limiting Toxicity (DLT) During Treatment Cycle 1 (days 1-21) by arm and treatment level [ Time Frame: Days 1-21 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Number of subjects who experienced treatment-emergent adverse events (TEAEs) [ Time Frame: Day 1 up to approximately Day 84 (end of cycle 4) ] [ Designated as safety issue: Yes ]
  • Maximum observed concentration (Cmax) of Pimasertib [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Time to reach maximum concentration (Tmax) [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Area under the concentration time curve from 0-24 hours (AUC0-24) of pimasertib [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Area under the concentration over time (AUCt) [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Apparent terminal half-life (t1/2) of pimasertib [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Apparent clearance (CL/f) of pimasertib [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Apparent clearance at steady-state (CLss/f) of pimasertib [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Apparent volume of distribution at terminal phase (Vz/f) of pimasertib [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Apparent volume of distribution at steady-state (Vss/f) of pimasertib [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Accumulation ratio for AUC (Racc(AUC)) of pimasertib [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • accumulation ratio for Cmax (Racc(Cmax)) of pimasertib [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Percentage of subjects with best overall response [ Time Frame: Day 1 up to approximately Day 84 (end of cycle 4) ] [ Designated as safety issue: No ]
    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.

  • Percentage of subjects with objective response [ Time Frame: Day 1 up to approximately Day 84 (end of cycle 4) ] [ Designated as safety issue: No ]
    Percentage of subjects with objective response (CR plus PR) according to RECIST Version 1.1 will be reported.

  • Percentage of subjects with disease control [ Time Frame: Day 1 up to approximately Day 84 (end of cycle 4) ] [ Designated as safety issue: No ]
    Percentage of subjects with disease control (CR plus PR plus greater than 12 weeks SD) according to RECIST Version 1.1 will be reported.


Enrollment: 26
Study Start Date: September 2012
Study Completion Date: April 2015
Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Pimasertib
Pimasertib taken as assigned in doses between the 45 mg twice a day (BID) up to the recommended phase 2 dose (RP2D) expected to be between 60-75mg BID.
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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 ≥ 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01668017

Locations
Japan
Please contact
Merck Serono Co., Ltd for recruiting locations in, Japan
Sponsors and Collaborators
Merck KGaA
Merck Serono Co., Ltd., Japan
Investigators
Study Director: Medical Responsible Merck Serono Co., Ltd., Tokyo, an affiliate of Merck KGaA, Darmstadt, Germany
  More Information

Responsible Party: Merck KGaA
ClinicalTrials.gov Identifier: NCT01668017     History of Changes
Other Study ID Numbers: EMR 200066-010 
Study First Received: August 15, 2012
Last Updated: October 19, 2015
Health Authority: Japan: Pharmaceuticals and Medical Devices Agency

Keywords provided by Merck KGaA:
Advanced solid tumors
Hepatocellular carcinoma
cancer, liver

Additional relevant MeSH terms:
Carcinoma, Hepatocellular
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Niacinamide
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 21, 2016