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

Study Overview
=================
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

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

Conditions
-----------------
Metastatic Colorectal Cancer

Intervention / Treatment
-----------------
* Drug: Pimasertib
* Drug: Placebo
* Drug: FOLFIRI


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 or Safety Run-in Part: Pimasertib+FOLFIRI<br> | Drug: Pimasertib<br>* 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.<br>* Other names: MSC1936369B;Drug: FOLFIRI<br>* 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.<br>|
| Experimental: Part 2 or Phase 2 Randomized part: Pimasertib+FOLFIRI<br>Planned, not performed | Drug: Pimasertib<br>* 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.<br>* Other names: MSC1936369B;Drug: FOLFIRI<br>* 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.<br>|
| Experimental: Part 2 or Phase 2 Randomized part: Placebo+FOLFIRI<br>Planned, not performed | Drug: Placebo<br>* 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.<br>Drug: FOLFIRI<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 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. | 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 | The AUC(0-inf) of pimasertib and irinotecan was estimated by determining the total area under the concentration time curve extrapolated to infinity. | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 | 
| 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. | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 | 
| 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. | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 | 
| 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. | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 | 
| Part 1 or Safety Run-in Part: Ratio of Cmax for Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) |  | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 | 
| 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. | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan | 
| 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. | Up to 2 years | 
| Part 1 or Safety Run-in Part: Circulating Biomarkers in Serum |  | Predose, Day 1, 2 and 16 of cycle 1 followed by Day 1 pre-dose of every second cycle up to 2 years | 
| Part 2 or Phase 2 Randomized Part: Circulating Biomarkers |  | Predose, Day 1, 2 and 16 of cycle 1 followed by Day 1 pre-dose of every second cycle up to 2 years | 
| 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. | Up to 2 years | 
| 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. | From the first dose of study drug administration up to 28 days after the last dose of study drug administration | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
K-Ras Mutation, Mek Inhibitor, Metastatic Colorectal Cancer, Phase II, Second line K-Ras mutated metastatic colorectal cancer