Clinical trial NCT01085331: MEK Inhibitor MSC1936369B Plus FOLFIRI in Second Line K-Ras Mutated Metastatic Colorectal Cancer (mCRC)
Official title: A Double-blind, Randomized, Comparative, Multicenter, Exploratory, and Placebo-controlled Phase II Trial of FOLFIRI Plus MSC1936369B or Placebo With a Safety run-in Part as Second-line Treatment of Metastatic K Ras Mutated Colorectal Cancer Subjects
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Metastatic Colorectal Cancer
Keywords: Mek Inhibitor
Metastatic Colorectal Cancer
K-Ras Mutation
Phase II
Second line K-Ras mutated metastatic colorectal cancer
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
First posted: 2010-03-11
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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


Eligibility criteria: 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

Primary outcomes:
measure: Part 1 or Safety Run-in Part: Maximum Tolerated Dose (MTD)
timeFrame: Baseline up to Day 28 (Part 1)
measure: Part 2 or Phase 2 Randomised Part: Progression Free Survival (PFS)
timeFrame: From randomization up to first documented disease progression maximum up to 2 years
Secondary outcomes:
measure: 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
timeFrame: From the first dose of study drug administration up to 28 days after the last dose of study drug administration
measure: Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38
timeFrame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38
measure: Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38
timeFrame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38
measure: Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38
timeFrame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38
measure: Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38
timeFrame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38
measure: Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38
timeFrame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38
measure: Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38
timeFrame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38
measure: Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38
timeFrame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38
measure: Part 1 or Safety Run-in Part: Ratio of Cmax for Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15)
timeFrame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38
measure: Part 1 or Safety Run-in Part: Ratio of AUC0-inf of Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15)
timeFrame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan
measure: Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR)
timeFrame: Up to 2 years
measure: Part 1 or Safety Run-in Part: Circulating Biomarkers in Serum
timeFrame: Predose, Day 1, 2 and 16 of cycle 1 followed by Day 1 pre-dose of every second cycle up to 2 years
measure: Part 2 or Phase 2 Randomized Part: Circulating Biomarkers
timeFrame: Predose, Day 1, 2 and 16 of cycle 1 followed by Day 1 pre-dose of every second cycle up to 2 years
measure: Part 2 or Phase 2 Randomized Part: Best Overall Response
timeFrame: Up to 2 years
measure: Part 2 or Phase 2 Randomized Part: Number of Subjects With TEAEs, Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death
timeFrame: From the first dose of study drug administration up to 28 days after the last dose of study drug administration
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
Study officials:
affiliation: Merck Serono S.A., Geneva
name: Medical Responsible
role: STUDY_DIRECTOR
References: