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

This study has been terminated.
(Conduct the randomized Phase 2 part not recommended due to the achieved MTD for pimasertib (45mg/day) in combination with FOLFIRI)
Sponsor:
Information provided by (Responsible Party):
EMD Serono
ClinicalTrials.gov Identifier:
NCT01085331
First received: March 4, 2010
Last updated: August 24, 2016
Last verified: August 2016
  Purpose

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


Condition Intervention Phase
Metastatic Colorectal Cancer
Drug: Pimasertib
Drug: Placebo
Drug: FOLFIRI
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by EMD Serono:

Primary Outcome Measures:
  • Part 1 or Safety Run-in Part: Maximum Tolerated Dose (MTD) [ Time Frame: Baseline up to Day 28 (Part 1) ] [ Designated as safety issue: Yes ]
    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) [ Time Frame: From randomization up to first documented disease progression maximum up to 2 years ] [ Designated as safety issue: No ]
    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 [ Time Frame: From the first dose of study drug administration up to 28 days after the last dose of study drug administration ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 ] [ Designated as safety issue: No ]
  • Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 [ Time Frame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 ] [ Designated as safety issue: No ]
  • 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 [ Time Frame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 ] [ Designated as safety issue: No ]
  • 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) [ Time Frame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan ] [ Designated as safety issue: No ]
    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) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    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 [ Time Frame: Predose, Day 1, 2 and 16 of cycle 1 followed by Day 1 pre-dose of every second cycle up to 2 years ] [ Designated as safety issue: No ]
  • Part 2 or Phase 2 Randomized Part: Circulating Biomarkers [ Time Frame: Predose, Day 1, 2 and 16 of cycle 1 followed by Day 1 pre-dose of every second cycle up to 2 years ] [ Designated as safety issue: No ]
  • Part 2 or Phase 2 Randomized Part: Best Overall Response [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    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 [ Time Frame: From the first dose of study drug administration up to 28 days after the last dose of study drug administration ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 16
Study Start Date: March 2010
Study Completion Date: April 2012
Primary Completion Date: April 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part 1 or Safety Run-in Part: Pimasertib+FOLFIRI Drug: Pimasertib
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.
Other Name: MSC1936369B
Drug: FOLFIRI
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.
Experimental: Part 2 or Phase 2 Randomized part: Pimasertib+FOLFIRI
Planned, not performed
Drug: Pimasertib
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.
Other Name: MSC1936369B
Drug: FOLFIRI
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.
Experimental: Part 2 or Phase 2 Randomized part: Placebo+FOLFIRI
Planned, not performed
Drug: Placebo
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.
Drug: FOLFIRI
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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01085331

Locations
Belgium
Research Site
Leuven, Belgium
Italy
Research Site
Napoli, Italy
Spain
Research Site
Barcelona, Spain
Sponsors and Collaborators
EMD Serono
Investigators
Study Director: Medical Responsible Merck Serono S.A., Geneva
  More Information

Responsible Party: EMD Serono
ClinicalTrials.gov Identifier: NCT01085331     History of Changes
Other Study ID Numbers: EMR200066_004 
Study First Received: March 4, 2010
Results First Received: August 24, 2016
Last Updated: August 24, 2016
Health Authority: United States: Food and Drug Administration
Belgium: Federal Agency for Medicinal Products and Health Products
Belgium: The Federal Public Service (FPS) Health, Food Chain Safety and Environment
Italy: Ethics Committee
Italy: Ministry of Health
Spain: Comité Ético de Investigación Clínica
Spain: Agencia Española de Medicamentos y Productos Sanitarios

Keywords provided by EMD Serono:
Mek Inhibitor
Metastatic Colorectal Cancer
K-Ras Mutation
Phase II
Second line K-Ras mutated metastatic colorectal cancer

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Niacinamide
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on December 09, 2016