A Multi-Centre Randomised Clinical Trial of Biomarker-Driven Maintenance Treatment for First-Line Metastatic Colorectal Cancer (MODUL)
Overview
- Phase
- Phase 2
- Intervention
- FOLFOX induction regimen
- Conditions
- Colorectal Cancer
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 1044
- Locations
- 154
- Primary Endpoint
- Progression-Free Survival (PFS)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This randomized, multi-center, active-controlled, open-label, parallel-group study will investigate the efficacy and safety of biomarker-driven maintenance treatment for first-line mCRC. Participants with mCRC are eligible for entry and cannot have received any prior chemotherapy in the metastatic setting. The entire study duration is anticipated to be approximately 7.5 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •ECOG PS of less than or equal to (\<=) 2
- •At least 16 weeks of life expectancy at time of entry into the study
- •Histologically confirmed colorectal cancer (CRC) with mCRC confirmed radiologically
- •Measureable, unresectable disease according to RECIST 1.1
- •No prior chemotherapy for CRC in the metastatic setting
- •Archival tumor formalin-fixed paraffin-embedded tissue block from the primary tumor obtained at the time of the initial diagnosis is available
- •Adequate hematological, liver and renal function
- •Agreement to use highly effective measures of contraception
- •Exclusion Criteria for All Participants:
- •Less than 6 months from completion of any prior neoadjuvant or adjuvant chemotherapy, radiotherapy
Exclusion Criteria
- Not provided
Arms & Interventions
Cohort 1: Induction Phase (IP)
Includes participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt). All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.
Intervention: FOLFOX induction regimen
Cohort 1: Induction Phase (IP)
Includes participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt). All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.
Intervention: Bevacizumab
Cohort 4 (IP)
Includes participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut). All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.
Intervention: FOLFOX induction regimen
Cohort 1: Induction Phase (IP)
Includes participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt). All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.
Intervention: 5-FU/LV
Cohort 2 (IP)
Includes participants with BRAFwt. All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.
Intervention: FOLFOX induction regimen
Cohort 2 (IP)
Includes participants with BRAFwt. All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.
Intervention: Bevacizumab
Cohort 2 (IP)
Includes participants with BRAFwt. All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.
Intervention: 5-FU/LV
Cohort 3 (IP)
Includes participants with human epidermal growth factor receptor 2 positive (HER2+). All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.
Intervention: FOLFOX induction regimen
Cohort 3 (IP)
Includes participants with human epidermal growth factor receptor 2 positive (HER2+). All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.
Intervention: Bevacizumab
Cohort 3 (IP)
Includes participants with human epidermal growth factor receptor 2 positive (HER2+). All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.
Intervention: 5-FU/LV
Cohort 4 (IP)
Includes participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut). All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.
Intervention: Bevacizumab
Cohort 4 (IP)
Includes participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut). All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.
Intervention: 5-FU/LV
Cohort 1 (Maintenance Phase[MP]):5-FU/LV,cetuximab,vemurafenib
Participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt) will receive 1600-2400 milligrams per square meter (mg/m\^2) 5-FU via 46-hour intravenous (IV) infusion in combination with 400 mg/m\^2 LV via 2-hour infusion on Day 1 of every 2-week cycle with 500 mg/m\^2 cetuximab via infusion on Day 1 of every 2-week cycle and 960 milligrams (mg) vemurafenib twice daily (BID) by mouth.
Intervention: Cetuximab
Cohort 1 (Maintenance Phase[MP]):5-FU/LV,cetuximab,vemurafenib
Participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt) will receive 1600-2400 milligrams per square meter (mg/m\^2) 5-FU via 46-hour intravenous (IV) infusion in combination with 400 mg/m\^2 LV via 2-hour infusion on Day 1 of every 2-week cycle with 500 mg/m\^2 cetuximab via infusion on Day 1 of every 2-week cycle and 960 milligrams (mg) vemurafenib twice daily (BID) by mouth.
Intervention: Vemurafenib
Cohort 1 (Maintenance Phase[MP]):5-FU/LV,cetuximab,vemurafenib
Participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt) will receive 1600-2400 milligrams per square meter (mg/m\^2) 5-FU via 46-hour intravenous (IV) infusion in combination with 400 mg/m\^2 LV via 2-hour infusion on Day 1 of every 2-week cycle with 500 mg/m\^2 cetuximab via infusion on Day 1 of every 2-week cycle and 960 milligrams (mg) vemurafenib twice daily (BID) by mouth.
Intervention: 5-FU/LV
Cohort 1 Control (MP): 5-FU/LV or capecitabin, bevacizumab
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Intervention: Fluoropyrimidine (5-FU/LV or capecitabine)
Cohort 1 Control (MP): 5-FU/LV or capecitabin, bevacizumab
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Intervention: Bevacizumab
Cohort 2 (MP):5-FU/LV or capecitabine,bevacizumab,atezolizumab
Participants with BRAFwt will receive fluoropyrimidine (1600-2400 mg/m\^2 5-FU via 46-hour IV infusion in combination with 400 mg/m\^2 LV via 2-hour infusion on Day 1 of every 2-week cycle or 1000 mg/m\^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break) with 5 milligrams per kilogram (mg/kg) bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle and 800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle.
Intervention: Fluoropyrimidine (5-FU/LV or capecitabine)
Cohort 2 (MP):5-FU/LV or capecitabine,bevacizumab,atezolizumab
Participants with BRAFwt will receive fluoropyrimidine (1600-2400 mg/m\^2 5-FU via 46-hour IV infusion in combination with 400 mg/m\^2 LV via 2-hour infusion on Day 1 of every 2-week cycle or 1000 mg/m\^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break) with 5 milligrams per kilogram (mg/kg) bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle and 800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle.
Intervention: Atezolizumab
Cohort 2 (MP):5-FU/LV or capecitabine,bevacizumab,atezolizumab
Participants with BRAFwt will receive fluoropyrimidine (1600-2400 mg/m\^2 5-FU via 46-hour IV infusion in combination with 400 mg/m\^2 LV via 2-hour infusion on Day 1 of every 2-week cycle or 1000 mg/m\^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break) with 5 milligrams per kilogram (mg/kg) bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle and 800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle.
Intervention: Bevacizumab
Cohort 2 Control (MP): 5-FU/LV or capecitabin, bevacizumab
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Intervention: Fluoropyrimidine (5-FU/LV or capecitabine)
Cohort 2 Control (MP): 5-FU/LV or capecitabin, bevacizumab
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Intervention: Bevacizumab
Cohort 3 (MP): capecitabine,trastuzumab,pertuzumab
Participants with human epidermal growth factor receptor 2 positive (HER2+) will receive 1000 mg/m\^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break with trastuzumab by IV infusion on Day 1 of every 3-week treatment cycle at an initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses, and pertuzumab by IV infusion on Day 1 of each 3-week treatment cycle at an initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses.
Intervention: Trastuzumab
Cohort 3 (MP): capecitabine,trastuzumab,pertuzumab
Participants with human epidermal growth factor receptor 2 positive (HER2+) will receive 1000 mg/m\^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break with trastuzumab by IV infusion on Day 1 of every 3-week treatment cycle at an initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses, and pertuzumab by IV infusion on Day 1 of each 3-week treatment cycle at an initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses.
Intervention: Pertuzumab
Cohort 3 (MP): capecitabine,trastuzumab,pertuzumab
Participants with human epidermal growth factor receptor 2 positive (HER2+) will receive 1000 mg/m\^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break with trastuzumab by IV infusion on Day 1 of every 3-week treatment cycle at an initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses, and pertuzumab by IV infusion on Day 1 of each 3-week treatment cycle at an initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses.
Intervention: Capecitabine
Cohort 3 Control (MP): 5-FU/LV or capecitabin, bevacizumab
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Intervention: Fluoropyrimidine (5-FU/LV or capecitabine)
Cohort 3 Control (MP): 5-FU/LV or capecitabin, bevacizumab
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Intervention: Bevacizumab
Cohort 4 (MP): Cobimetinib,atezolizumab
Participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut) will receive 60 mg cobimetinib orally for 3 weeks followed by a 1-week treatment break and atezolizumab at a fixed dose of 840 mg via 60-minute IV infusion on Day 1 of every 2-week cycle.
Intervention: Atezolizumab
Cohort 4 (MP): Cobimetinib,atezolizumab
Participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut) will receive 60 mg cobimetinib orally for 3 weeks followed by a 1-week treatment break and atezolizumab at a fixed dose of 840 mg via 60-minute IV infusion on Day 1 of every 2-week cycle.
Intervention: Cobimetinib
Cohort 4 Control (MP): 5-FU/LV or capecitabin, bevacizumab
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Intervention: Fluoropyrimidine (5-FU/LV or capecitabine)
Cohort 4 Control (MP): 5-FU/LV or capecitabin, bevacizumab
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Intervention: Bevacizumab
Early Progressing BRAFmut Cohort
BRAFmut participants experiencing early disease progression during induction treatment will have the option of proceeding immediately to receive second-line treatment with 5-FU/LV, cetuximab and vemurafenib if their primary tumor is MSS, or with a fluoropyrimidine (5-FU/LV or capecitabine), bevacizumab, and atezolizumab if their primary tumor is MSI-H. This cohort will be followed for adverse events during the study, but is not part of the Maintenance Phase study objectives.
Intervention: Cetuximab
Early Progressing BRAFmut Cohort
BRAFmut participants experiencing early disease progression during induction treatment will have the option of proceeding immediately to receive second-line treatment with 5-FU/LV, cetuximab and vemurafenib if their primary tumor is MSS, or with a fluoropyrimidine (5-FU/LV or capecitabine), bevacizumab, and atezolizumab if their primary tumor is MSI-H. This cohort will be followed for adverse events during the study, but is not part of the Maintenance Phase study objectives.
Intervention: Fluoropyrimidine (5-FU/LV or capecitabine)
Early Progressing BRAFmut Cohort
BRAFmut participants experiencing early disease progression during induction treatment will have the option of proceeding immediately to receive second-line treatment with 5-FU/LV, cetuximab and vemurafenib if their primary tumor is MSS, or with a fluoropyrimidine (5-FU/LV or capecitabine), bevacizumab, and atezolizumab if their primary tumor is MSI-H. This cohort will be followed for adverse events during the study, but is not part of the Maintenance Phase study objectives.
Intervention: Atezolizumab
Early Progressing BRAFmut Cohort
BRAFmut participants experiencing early disease progression during induction treatment will have the option of proceeding immediately to receive second-line treatment with 5-FU/LV, cetuximab and vemurafenib if their primary tumor is MSS, or with a fluoropyrimidine (5-FU/LV or capecitabine), bevacizumab, and atezolizumab if their primary tumor is MSI-H. This cohort will be followed for adverse events during the study, but is not part of the Maintenance Phase study objectives.
Intervention: Vemurafenib
Early Progressing BRAFmut Cohort
BRAFmut participants experiencing early disease progression during induction treatment will have the option of proceeding immediately to receive second-line treatment with 5-FU/LV, cetuximab and vemurafenib if their primary tumor is MSS, or with a fluoropyrimidine (5-FU/LV or capecitabine), bevacizumab, and atezolizumab if their primary tumor is MSI-H. This cohort will be followed for adverse events during the study, but is not part of the Maintenance Phase study objectives.
Intervention: Bevacizumab
Early Progressing BRAFmut Cohort
BRAFmut participants experiencing early disease progression during induction treatment will have the option of proceeding immediately to receive second-line treatment with 5-FU/LV, cetuximab and vemurafenib if their primary tumor is MSS, or with a fluoropyrimidine (5-FU/LV or capecitabine), bevacizumab, and atezolizumab if their primary tumor is MSI-H. This cohort will be followed for adverse events during the study, but is not part of the Maintenance Phase study objectives.
Intervention: 5-FU/LV
Outcomes
Primary Outcomes
Progression-Free Survival (PFS)
Time Frame: From randomization until disease progression or death from any cause, up to 5 years
PFS is defined as the time from randomization to the first occurrence of disease progression according to RECIST v1.1, or death from any cause, whichever occurs first. Progressive disease (PD) for target lesion: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/=5 mm. PD for non-target lesion: Unequivocal progression of existing non-target lesions.
Secondary Outcomes
- Time to Treatment Response(From randomization until disease progression or death from any cause, up to 5 years)
- Overall Survival (OS)(From randomization until death from any cause, up to 5 years)
- Overall Response(From randomization until disease progression, up to 5 years)
- Disease Control Rate (DCR)(From randomization until disease progression, up to 5 years)
- Duration of Response(From first objective response until disease progression or death from any cause, up to 5 years)
- Percentage of Participants With Adverse Events(From baseline until end of study (up to 5 years))
- Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score(From baseline until end of study (up to 5 years))