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

24. srpna 2016 aktualizováno: EMD Serono

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

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

Přehled studie

Postavení

Ukončeno

Podmínky

Intervence / Léčba

Typ studie

Intervenční

Zápis (Aktuální)

16

Fáze

  • Fáze 2
  • Fáze 1

Kontakty a umístění

Tato část poskytuje kontaktní údaje pro ty, kteří studii provádějí, a informace o tom, kde se tato studie provádí.

Studijní místa

  • Belgie
      • Leuven, Belgie
        • Research Site
  • Itálie
      • Napoli, Itálie
        • Research Site
  • Španělsko
      • Barcelona, Španělsko
        • Research Site

Kritéria účasti

Výzkumníci hledají lidi, kteří odpovídají určitému popisu, kterému se říká kritéria způsobilosti. Některé příklady těchto kritérií jsou celkový zdravotní stav osoby nebo předchozí léčba.

Kritéria způsobilosti

Věk způsobilý ke studiu

18 let a starší (Dospělý, Starší dospělý)

Přijímá zdravé dobrovolníky

Ne

Pohlaví způsobilá ke studiu

Všechno

Popis

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

Studijní plán

Tato část poskytuje podrobnosti o studijním plánu, včetně toho, jak je studie navržena a co studie měří.

Jak je studie koncipována?

Detaily designu

  • Primární účel: Léčba
  • Přidělení: Randomizované
  • Intervenční model: Paralelní přiřazení
  • Maskování: Dvojnásobek

Zbraně a zásahy

Skupina účastníků / Arm
Intervence / Léčba
Experimentální: Part 1 or Safety Run-in Part: Pimasertib+FOLFIRI
Lék: 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.
Ostatní jména:
  • MSC1936369B
Lék: 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.
Experimentální: Part 2 or Phase 2 Randomized part: Pimasertib+FOLFIRI
Planned, not performed
Lék: 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.
Ostatní jména:
  • MSC1936369B
Lék: 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.
Experimentální: Part 2 or Phase 2 Randomized part: Placebo+FOLFIRI
Planned, not performed
Lék: 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.
Lék: 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.

Co je měření studie?

Primární výstupní opatření

Měření výsledku
Popis opatření
Časové okno
Part 1 or Safety Run-in Part: Maximum Tolerated Dose (MTD)
Časové okno: Baseline up to Day 28 (Part 1)
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)
Časové okno: From randomization up to first documented disease progression maximum up to 2 years
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

Sekundární výstupní opatření

Měření výsledku
Popis opatření
Časové okno
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
Časové okno: From the first dose of study drug administration up to 28 days after the last dose of study drug administration
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
Časové okno: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for 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
Časové okno: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for 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
Časové okno: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for 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
Časové okno: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for 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
Časové okno: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for 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
Časové okno: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for 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
Časové okno: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for 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)
Časové okno: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for 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: Ratio of AUC0-inf of Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15)
Časové okno: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan
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)
Časové okno: Up to 2 years
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
Časové okno: Predose, Day 1, 2 and 16 of cycle 1 followed by Day 1 pre-dose of every second cycle up to 2 years
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
Časové okno: Predose, Day 1, 2 and 16 of cycle 1 followed by Day 1 pre-dose of every second cycle up to 2 years
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
Časové okno: Up to 2 years
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
Časové okno: From the first dose of study drug administration up to 28 days after the last dose of study drug administration
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

Spolupracovníci a vyšetřovatelé

Zde najdete lidi a organizace zapojené do této studie.

Sponzor

EMD Serono

Vyšetřovatelé

  • Ředitel studie: Medical Responsible, Merck Serono S.A., Geneva

Termíny studijních záznamů

Tato data sledují průběh záznamů studie a předkládání souhrnných výsledků na ClinicalTrials.gov. Záznamy ze studií a hlášené výsledky jsou před zveřejněním na veřejné webové stránce přezkoumány Národní lékařskou knihovnou (NLM), aby se ujistily, že splňují specifické standardy kontroly kvality.

Hlavní termíny studia

Začátek studia

1. března 2010

Primární dokončení (Aktuální)

1. dubna 2012

Dokončení studie (Aktuální)

1. dubna 2012

Termíny zápisu do studia

První předloženo

4. března 2010

První předloženo, které splnilo kritéria kontroly kvality

10. března 2010

První zveřejněno (Odhad)

11. března 2010

Aktualizace studijních záznamů

Poslední zveřejněná aktualizace (Odhad)

19. října 2016

Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality

24. srpna 2016

Naposledy ověřeno

1. srpna 2016

Více informací

Termíny související s touto studií

Klíčová slova

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Další identifikační čísla studie

  • EMR200066_004

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