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

Primary Purpose

Metastatic Colorectal Cancer

Status

Terminated

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Pimasertib

Placebo

FOLFIRI

About this trial

This is an interventional treatment trial for Metastatic Colorectal Cancer focused on measuring Mek Inhibitor, Metastatic Colorectal Cancer, K-Ras Mutation, Phase II, Second line K-Ras mutated metastatic colorectal cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Research Site
Research Site
Research Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

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

Arm Description

Planned, not performed

Outcomes

Primary Outcome Measures

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.

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.

Secondary Outcome Measures

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.

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

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

Area under the plasma concentration-time curve from time zero to the last sampling time (AUC0-t) at which the concentration is at or above the lower limit of quantification.

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

The AUC(0-inf) of pimasertib and irinotecan was estimated by determining the total area under the concentration time curve extrapolated to infinity.

Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38

The t1/2 was defined as the time required for the plasma concentration of pimasertib and irinotecan to decrease 50% in the final stage of elimination.

Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38

Clearance of a drug was a measure of the rate at which drug was metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed.

Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed.

Part 1 or Safety Run-in Part: Ratio of Cmax for Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15)

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)

The AUC(0-inf) was estimated by determining the total area under the concentration time curve extrapolated to infinity.

Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR)

BOR was defined based on Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST V1.0) as following: Complete response (CR) was defined as the disappearance of all target and non-target lesions and no appearance of new lesions. Partial response (PR) was defined as at least a 30 percent (%) decrease in the sum of the longest diameters (SLD) of the targeted lesions. CR and PR had to be documented on 2 occasions separated by at least 4 weeks (28 days). Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify as progressive disease (PD) being demonstrated during the first 4 weeks. PD was defined as at least a 20% increase in the SLD of target lesions compared to the smallest SLD since the study treatment started.

Part 1 or Safety Run-in Part: Circulating Biomarkers in Serum

Part 2 or Phase 2 Randomized Part: Circulating Biomarkers

Part 2 or Phase 2 Randomized Part: Best Overall Response

BOR was defined based on Response Evaluation Criteria In Solid Tumors Version 1.0 (RECIST V1.0) as following: Complete response (CR) was defined as the disappearance of all target and non-target lesions and no appearance of new lesions. Partial response (PR) was defined as at least a 30 percent (%) decrease in the sum of the longest diameters (SLD) of the targeted lesions. CR and PR had to be documented on 2 occasions separated by at least 4 weeks (28 days). Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify as progressive disease (PD) being demonstrated during the first 4 weeks. PD was defined as at least a 20% increase in the SLD of target lesions compared to the smallest SLD since the study treatment started.

Part 2 or Phase 2 Randomized Part: Number of Subjects With 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. TEAES between first dose of study drug administration and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

Full Information

NCT ID

NCT01085331

First Posted

March 4, 2010

Last Updated

August 24, 2016

Sponsor

EMD Serono

1. Study Identification

Unique Protocol Identification Number

NCT01085331

Brief Title

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

2. Study Status

Record Verification Date

August 2016

Overall Recruitment Status

Terminated

Why Stopped

Conduct the randomized Phase 2 part not recommended due to the achieved MTD for pimasertib (45mg/day) in combination with FOLFIRI

Study Start Date

March 2010 (undefined)

Primary Completion Date

April 2012 (Actual)

Study Completion Date

April 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

EMD Serono

4. Oversight

Data Monitoring Committee

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Metastatic Colorectal Cancer

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

16 (Actual)

8. Arms, Groups, and Interventions

Arm Title

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

Arm Type

Experimental

Arm Title

Part 2 or Phase 2 Randomized part: Pimasertib+FOLFIRI

Arm Type

Experimental

Arm Description

Planned, not performed

Arm Title

Part 2 or Phase 2 Randomized part: Placebo+FOLFIRI

Arm Type

Experimental

Arm Description

Planned, not performed

Intervention Type

Drug

Intervention Name(s)

Pimasertib

Other Intervention Name(s)

MSC1936369B

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

FOLFIRI

Intervention Description

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.

Primary Outcome Measure Information:

Title

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

Description

Time Frame

Baseline up to Day 28 (Part 1)

Title

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

Description

Time Frame

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

Secondary Outcome Measure Information:

Title

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

Description

Time Frame

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

Title

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

Time Frame