MEK Inhibitor MSC1936369B Plus FOLFIRI in Second Line K-Ras Mutated Metastatic Colorectal Cancer (mCRC)

Phase 2TerminatedNCT01085331

EMD Serono16 enrolled

Overview

The research trial is testing the experimental treatment pimasertib (MSC1936369B) in combination with FOLFIRI, as second-line treatment in metastatic K Ras mutated colorectal cancer subjects. The study will be run in two parts: Part 1, or Safety Run-in Part: Will determine the maximum tolerated dose and the recommended Phase 2 dose (RP2D) of pimasertib combined with FOLFIRI as second-line treatment in subjects with metastatic K Ras mutated colorectal cancer. Part 2 or Phase 2 Randomised Part: Will assess the anti-tumor activity of pimasertib combined with FOLFIRI compared to FOLFIRI with placebo as second-line treatment in metastatic K Ras mutated colorectal cancer subjects. Phase I which Is an open label dose escalation "3+3" cohort, non-randomized, safety Phase II which is a double blind randomized safety/efficacy

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Metastatic Colorectal Cancer

Interventions

FOLFIRIDRUG

Subjects will be administered with FOLFIRI (laevoleucovorin 200 milligram per square meter \[mg/m\^2\] intravenous \[i.v\] infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 milliliter \[mL\] dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: For Safety Run-in and Part 2 or Phase 2 Randomised Part * Histologically confirmed K-Ras mutated colon/rectum cancer * Subject's disease must have progressed during or after a first-line treatment for metastatic disease with oxaliplatin and fluoropyrimidines based chemotherapy with or without bevacizumab * Evidence of metastatic measurable disease at trial entry as per Response Evaluation Criteria in Solid Tumors. Complete tumor assessment performed within 14 days prior to first trial drug administration * Male/female subjects aged greater than or equal to (\>=) 18 years * Subject has read and understood the informed consent form * Women of childbearing potential must have a negative blood pregnancy test at the screening visit. Subjects and their partners must be willing to avoid pregnancy during the trial Exclusion Criteria: For Safety Run-in and Part 2 or Phase 2 Randomised Part * Bone marrow impairment * Renal impairment * Liver function and liver cell integrity abnormality * History of central nervous system (CNS) metastases * History of difficulty of swallowing, malabsorption or other chronic gastrointestinal disease * Eastern Cooperative Oncology Group Performance Status (ECOG PS) greater than (\>)1 * Known human immunodeficiency virus (HIV) positivity, active hepatitis C, or active hepatitis B * Has received extensive prior radiotherapy on more than 30 percent (%) of bone marrow reserves, or prior bone marrow/stem cell transplantation * Has received chemotherapy, any investigational drug, or having participated in another clinical trial within the past 4 weeks prior to trial first drug administration * Has a history of any other significant medical disease * Past or current history (within the last 2 years prior to inclusion) of malignancies except for the indication under this study * Has significant cardiac conduction abnormalities and/or pacemaker * Is a pregnant or nursing female * Has retinal degenerative disease, history of uveitis, or history of retinal vein occlusion * Other significant disease that in the Investigator's opinion would exclude the subject from the trial * Known hypersensitivity to the trial treatment(s) or diluents (when applicable), including placebo or other comparator drug(s) * Legal incapacity or limited legal capacity

Locations (3)

Research Site

Leuven, Belgium

Research Site

Naples, Italy

Research Site

Barcelona, Spain

Outcomes

Primary Outcomes

Part 1 or Safety Run-in Part: Maximum Tolerated Dose (MTD)

MTD was defined as the dose level, at which the treatment-related dose limiting toxicity (DLT) occurred in \>1 of 3 subjects or in \>1 of 6 subjects. DLT was defined using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Any Grade \>=3 non-hematological toxicity except for Grade 4 asymptomatic increases in liver function tests (LFTs) reversible within 7 days in subjects with liver involvement, Grade 3 asymptomatic increases in LFTs reversible within 7 days in subjects without liver involvement, Grade 3 vomiting controlled with adequate and optimal therapy and prophylaxis, and Grade 3 diarrhea controlled with adequate and optimal anti-diarrhea therapy; any Grade 4 neutropenia lasing \>5 days/ febrile neutropenia lasting \>1 day; any Grade 4 thrombocytopenia/Grade 3 with bleeding; any treatment delay \>2 weeks due to trial treatment-related adverse effects at any dose level and judged to be possibly or probably related to the trial treatment.

Time frame: Baseline up to Day 28 (Part 1)

Part 2 or Phase 2 Randomised Part: Progression Free Survival (PFS)

PFS was defined as time (in months) from the date of randomization to the first documentation of disease progression as reported and documented by the Investigator (i.e. radiological progression per RECIST v1.0) or death for any cause.

Time frame: From randomization up to first documented disease progression maximum up to 2 years

Secondary Outcomes

Part 1 or Safety Run-in Part: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death

An AE is defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An 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. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

Time frame: From the first dose of study drug administration up to 28 days after the last dose of study drug administration

Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38