Neoplasms

Digestive System Diseases

All Conditions

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Micronutrients

Vitamins

Irinotecan

Leucovorin

Fluorouracil

Levoleucovorin

Folinic Acid

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.

Pimasertib

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.

Placebo

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.

FOLFIRI

Medical Responsible

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

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

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

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.

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.

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.

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.

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

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.

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.

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.

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

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.

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.

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.

EMD Serono

Pimasertib was administered orally at a dose of 45 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 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 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 45 mg +FOLFIRI

Pimasertib was administered orally at a dose of 60 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 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 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 60 mg +FOLFIRI

Total

Age, Continuous

Sex: Female, Male

The safety analysis set included all subjects who received at least one (non-zero) administration of the trial medication (any of the 3 FOLFIRI drugs and pimasertib).

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.

Merck KGaA Communication Center

Pimasertib was administered orally once daily 45 mg/day and 60 mg/day on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 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 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.

Pimasertib+FOLFIRI (Overall)

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

Pimasertib was to be administered orally once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 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 as a 90-minute infusion in 500 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 2 or Phase 2 Randomized Part: Pimasertib+FOLFIRI

Placebo was to be administered orally once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 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 as a 90-minute infusion in 500 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 2 or Phase 2 Randomized Part: Placebo +FOLFIRI

Part 2 or Phase 2 Randomized Part of the trial was not conducted. Hence, PFS was not evaluated for this study.

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

TEAE

Serious TEAE

TEAEs leading to discontinuation

TEAEs leading to death

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

Pimasertib: Day 1 (n=9, 6)

Pimasertib: Day 8 (n=9, 6)

Irinotecan: Day 1 (n=10, 6)

Irinotecan: Day 15 (n=8, 6)

SN-38: Day 1 (n=10, 6)

SN-38: Day 15 (n=8, 6)

The pharmacokinetic (PK) evaluation set included subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). "n" signifies number of subjects evaluable in each category, respectively.

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

Pimasertib: Day 1 (n=9, 5)

Pimasertib: Day 8 (n=8, 5)

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

Pimasertib: Day 1 (n=7, 5)

Irinotecan: Day 1 (n=9, 6)

SN-38: Day 1 (n=9, 6)

The PK analysis population set included all subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). Here, N (total number of subjects analyzed) signifies number of evaluable subjects for this outcome measure. "n" signifies number of subjects evaluable per each category, respectively.

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

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

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

Pimasertib (n=8, 5)

Irinotecan (n=8, 6)

SN-38 (n=8, 6)

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

Pimasertib (n=7, 4)

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)

Not evaluable

The efficacy analysis set included all subjects who received at least 1 trial drug dose (any of the three FOLFIRI drugs and pimasertib) and had a baseline tumor assessment and at least 1 post-baseline efficacy assessment.

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

Number of subjects enrolled in the safety run-in part of the trial was less and it would not provide sufficient statistical power to perform any analysis. Hence, the biomarker samples were not analyzed as part of the trial.

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

Placebo was to be administered orally once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 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 as a 90-minute infusion in 500 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 2 or Phase 2 Randomized Part: Placebo+FOLFIRI

Part 2 or Phase 2 Randomized Part of the trial was not conducted. Hence, circulating biomarkers were not evaluated.

Part 2 or Phase 2 Randomized Part: Circulating Biomarkers

Part 2 or Phase 2 Randomized Part of the trial was not conducted. Hence, Best overall response was not evaluated.

Part 2 or Phase 2 Randomized Part: Best Overall Response

Part 2 or Phase 2 Randomized Part of the trial was not conducted. Hence, safety outcome measure could not be performed.

Part 2 or Phase 2 Randomized Part: Number of Subjects With TEAEs, Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death

Pimasertib was administered orally at a dose of 45 milligrams per day (mg/day) once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along 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.

Pimasertib was administered orally at a dose of 60 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along 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; 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.

Spots Global Cancer Trial Database for MEK Inhibitor MSC1936369B Plus FOLFIRI in Second Line K-Ras Mutated Metastatic Colorectal Cancer (mCRC)

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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