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

NCT01668017 | Terminated Phase 1 Results DMC

• 1 other identifier: EMR 200066-010
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

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.

Conditions

Advanced Solid Tumors; Hepatocellular Carcinoma

Keywords

Advanced solid tumors; Hepatocellular carcinoma; cancer, liver

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (34)

• 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

• 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

• 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

• 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

Study Arms (5)

Part 1: Pimasertib 30mg in Solid Tumor

EXPERIMENTAL

Drug: Pimasertib

Part 1: Pimasertib 45 mg in Solid Tumor

EXPERIMENTAL

Drug: Pimasertib

Part 1: Pimasertib 60 mg in Solid Tumor

EXPERIMENTAL

Drug: Pimasertib

Part 1: Pimasertib 30 mg in Hepatocellular Carcinoma (HCC)

EXPERIMENTAL

Drug: Pimasertib

Part 1: Pimasertib 45 mg in HCC

EXPERIMENTAL

Drug: Pimasertib

Interventions

Pimasertib DRUG

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.

Part 1: Pimasertib 30mg in Solid Tumor

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Merck KGaA, Darmstadt, Germany: lead
• Merck Serono Co., Ltd., Japan: collaborator

Study Sites (1)

Please contact

Merck Serono Co., Ltd For Recruiting Locations in, Japan

Location

MeSH Terms

Conditions

Carcinoma, Hepatocellular; Liver Neoplasms

Interventions

N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Limitations and Caveats

Due to the Sponsor's decision not to pursue the study drug as monotherapy, the Expansion Phase (Part 2) of the study was not conducted.

Results Point of Contact

• Title: Merck KGaA Communication Center
• Organization: Merck Healthcare, a business of Merck KGaA, Darmstadt, Germany

service@merckgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  Merck Serono Co., Ltd., Tokyo, an affiliate of Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 15, 2012
• First Posted: August 17, 2012
• Study Start: September 30, 2012
• Primary Completion: May 31, 2015
• Study Completion: May 31, 2015
• Last Updated: August 23, 2017
• Results First Posted: March 29, 2017

Record last verified: 2017-07

Locations

JP (1)