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

NCT01085331 | Terminated Phase 1 Results

• 1 other identifier: EMR200066_004
• Study Type: interventional
• Target: 16
• Locations: 3 countries
• Sites: 3

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

Conditions

Metastatic Colorectal Cancer

Keywords

Mek Inhibitor; Metastatic Colorectal Cancer; K-Ras Mutation; Phase II; Second line K-Ras mutated metastatic colorectal cancer

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  From randomization up to first documented disease progression maximum up to 2 years

Secondary Outcomes (15)

• 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

  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

  Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38

• Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38

  Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38

• 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

  Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38

• 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

  Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38

Study Arms (3)

Part 1 or Safety Run-in Part: Pimasertib+FOLFIRI

EXPERIMENTAL

Drug: Pimasertib; Drug: FOLFIRI

Part 2 or Phase 2 Randomized part: Pimasertib+FOLFIRI

EXPERIMENTAL

Planned, not performed

Drug: Pimasertib; Drug: FOLFIRI

Part 2 or Phase 2 Randomized part: Placebo+FOLFIRI

EXPERIMENTAL

Planned, not performed

Drug: Placebo; Drug: FOLFIRI

Interventions

Pimasertib DRUG

Subjects will be administered with pimasertib orally once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle.

Also known as: MSC1936369B

Part 1 or Safety Run-in Part: Pimasertib+FOLFIRI; Part 2 or Phase 2 Randomized part: Pimasertib+FOLFIRI

Placebo DRUG

Subjects will be administered with placebo orally once daily on days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle.

Part 2 or Phase 2 Randomized part: Placebo+FOLFIRI

FOLFIRI DRUG

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.

Part 1 or Safety Run-in Part: Pimasertib+FOLFIRI; Part 2 or Phase 2 Randomized part: Pimasertib+FOLFIRI; Part 2 or Phase 2 Randomized part: Placebo+FOLFIRI

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• EMD Serono: lead

Study Sites (3)

Research Site

Leuven, Belgium

Location

Research Site

Napoli, Italy

Location

Research Site

Barcelona, Spain

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

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

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Limitations and Caveats

During the trial, the decision was made not to perform the Phase 2 part of the study due to the achieved MTD for pimasertib (45mg/day) in combination with FOLFIRI, so that no further dose escalation was possible as per the protocol.

Results Point of Contact

• Title: Merck KGaA Communication Center
• Organization: Merck Serono, a division of Merck KGaA

service@merckgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  Merck Serono S.A., Geneva

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 4, 2010
• First Posted: March 11, 2010
• Study Start: March 1, 2010
• Primary Completion: April 1, 2012
• Study Completion: April 1, 2012
• Last Updated: October 19, 2016
• Results First Posted: October 19, 2016

Record last verified: 2016-08

Locations

IT (1); BE (1); ES (1)