A Study of Biomarker-Driven Therapy in Metastatic Colorectal Cancer (mCRC)

NCT ID: NCT02291289

Last Updated: 2024-05-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 1044 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-04-17
• Study Completion Date: 2021-03-24

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.

Conditions

Colorectal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: OTHER

FOLFOX induction regimen

Intervention Type: DRUG

Administered per the Investigator's discretion in accordance with locally approved prescribing information.

Bevacizumab

Intervention Type: DRUG

5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

5-FU/LV

Intervention Type: DRUG

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 until disease progression per the Investigator's assessment using modified Response Evaluation Criteria in Solid Tumors or death from any cause, whichever occurs first. The fluoropyrimidine should be administered in accordance with local prescribing information.

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.

Group Type: OTHER

FOLFOX induction regimen

Intervention Type: DRUG

Administered per the Investigator's discretion in accordance with locally approved prescribing information.

Bevacizumab

Intervention Type: DRUG

5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

5-FU/LV

Intervention Type: DRUG

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 until disease progression per the Investigator's assessment using modified Response Evaluation Criteria in Solid Tumors or death from any cause, whichever occurs first. The fluoropyrimidine should be administered in accordance with local prescribing information.

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.

Group Type: OTHER

FOLFOX induction regimen

Intervention Type: DRUG

Administered per the Investigator's discretion in accordance with locally approved prescribing information.

Bevacizumab

Intervention Type: DRUG

5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

5-FU/LV

Intervention Type: DRUG

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 until disease progression per the Investigator's assessment using modified Response Evaluation Criteria in Solid Tumors or death from any cause, whichever occurs first. The fluoropyrimidine should be administered in accordance with local prescribing information.

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.

Group Type: OTHER

FOLFOX induction regimen

Intervention Type: DRUG

Administered per the Investigator's discretion in accordance with locally approved prescribing information.

Bevacizumab

Intervention Type: DRUG

5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

5-FU/LV

Intervention Type: DRUG

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 until disease progression per the Investigator's assessment using modified Response Evaluation Criteria in Solid Tumors or death from any cause, whichever occurs first. The fluoropyrimidine should be administered in accordance with local prescribing information.

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.

Group Type: EXPERIMENTAL

Cetuximab

Intervention Type: DRUG

500 mg/m\^2 via IV infusion on Day 1 of every 2-week cycle

Vemurafenib

Intervention Type: DRUG

960 mg vermurafenib BID by mouth

5-FU/LV

Intervention Type: DRUG

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 until disease progression per the Investigator's assessment using modified Response Evaluation Criteria in Solid Tumors or death from any cause, whichever occurs first. The fluoropyrimidine should be administered in accordance with local prescribing information.

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.

Group Type: ACTIVE_COMPARATOR

Fluoropyrimidine (5-FU/LV or capecitabine)

Intervention Type: DRUG

Per Investigator's discretion: 5-FU 1600-2400 mg/m\^2 administered via 46-hour IV infusion on Day 1 of every 2-week cycle and LV 400 mg/m\^2 administered via a 2-hour infusion on Day 1 every 2 weeks or 1000 mg/m\^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The chosen fluoropyrimidine should be administered in accordance with local prescribing information.

Bevacizumab

Intervention Type: DRUG

5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

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.

Group Type: EXPERIMENTAL

Fluoropyrimidine (5-FU/LV or capecitabine)

Intervention Type: DRUG

Per Investigator's discretion: 5-FU 1600-2400 mg/m\^2 administered via 46-hour IV infusion on Day 1 of every 2-week cycle and LV 400 mg/m\^2 administered via a 2-hour infusion on Day 1 every 2 weeks or 1000 mg/m\^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The chosen fluoropyrimidine should be administered in accordance with local prescribing information.

Atezolizumab

Intervention Type: DRUG

800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle, or a fixed dose of 840 mg

Bevacizumab

Intervention Type: DRUG

5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

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.

Group Type: ACTIVE_COMPARATOR

Fluoropyrimidine (5-FU/LV or capecitabine)

Intervention Type: DRUG

Per Investigator's discretion: 5-FU 1600-2400 mg/m\^2 administered via 46-hour IV infusion on Day 1 of every 2-week cycle and LV 400 mg/m\^2 administered via a 2-hour infusion on Day 1 every 2 weeks or 1000 mg/m\^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The chosen fluoropyrimidine should be administered in accordance with local prescribing information.

Bevacizumab

Intervention Type: DRUG

5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

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.

Group Type: EXPERIMENTAL

Trastuzumab

Intervention Type: DRUG

Initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses by IV infusion on Day 1 of every 3-week treatment cycle

Pertuzumab

Intervention Type: DRUG

Initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses by IV infusion on Day 1 of each 3-week treatment cycle

Capecitabine

Intervention Type: DRUG

1000 mg/m\^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The fluoropyrimidine should be administered in accordance with local prescribing information.

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.

Group Type: ACTIVE_COMPARATOR

Fluoropyrimidine (5-FU/LV or capecitabine)

Intervention Type: DRUG

Per Investigator's discretion: 5-FU 1600-2400 mg/m\^2 administered via 46-hour IV infusion on Day 1 of every 2-week cycle and LV 400 mg/m\^2 administered via a 2-hour infusion on Day 1 every 2 weeks or 1000 mg/m\^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The chosen fluoropyrimidine should be administered in accordance with local prescribing information.

Bevacizumab

Intervention Type: DRUG

5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

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.

Group Type: EXPERIMENTAL

Atezolizumab

Intervention Type: DRUG

800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle, or a fixed dose of 840 mg

Cobimetinib

Intervention Type: DRUG

60 mg orally once daily for 3 weeks followed by a 1-week treatment break

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.

Group Type: ACTIVE_COMPARATOR

Fluoropyrimidine (5-FU/LV or capecitabine)

Intervention Type: DRUG

Per Investigator's discretion: 5-FU 1600-2400 mg/m\^2 administered via 46-hour IV infusion on Day 1 of every 2-week cycle and LV 400 mg/m\^2 administered via a 2-hour infusion on Day 1 every 2 weeks or 1000 mg/m\^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The chosen fluoropyrimidine should be administered in accordance with local prescribing information.

Bevacizumab

Intervention Type: DRUG

5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

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.

Group Type: OTHER

Cetuximab

Intervention Type: DRUG

500 mg/m\^2 via IV infusion on Day 1 of every 2-week cycle

Fluoropyrimidine (5-FU/LV or capecitabine)

Intervention Type: DRUG

Per Investigator's discretion: 5-FU 1600-2400 mg/m\^2 administered via 46-hour IV infusion on Day 1 of every 2-week cycle and LV 400 mg/m\^2 administered via a 2-hour infusion on Day 1 every 2 weeks or 1000 mg/m\^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The chosen fluoropyrimidine should be administered in accordance with local prescribing information.

Atezolizumab

Intervention Type: DRUG

800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle, or a fixed dose of 840 mg

Vemurafenib

Intervention Type: DRUG

960 mg vermurafenib BID by mouth

Bevacizumab

Intervention Type: DRUG

5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

5-FU/LV

Intervention Type: DRUG

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 until disease progression per the Investigator's assessment using modified Response Evaluation Criteria in Solid Tumors or death from any cause, whichever occurs first. The fluoropyrimidine should be administered in accordance with local prescribing information.

Interventions

Cetuximab

500 mg/m\^2 via IV infusion on Day 1 of every 2-week cycle

Intervention Type: DRUG

FOLFOX induction regimen

Administered per the Investigator's discretion in accordance with locally approved prescribing information.

Intervention Type: DRUG

Fluoropyrimidine (5-FU/LV or capecitabine)

Per Investigator's discretion: 5-FU 1600-2400 mg/m\^2 administered via 46-hour IV infusion on Day 1 of every 2-week cycle and LV 400 mg/m\^2 administered via a 2-hour infusion on Day 1 every 2 weeks or 1000 mg/m\^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The chosen fluoropyrimidine should be administered in accordance with local prescribing information.

Intervention Type: DRUG

Atezolizumab

800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle, or a fixed dose of 840 mg

Intervention Type: DRUG

Vemurafenib

960 mg vermurafenib BID by mouth

Intervention Type: DRUG

Bevacizumab

5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

Intervention Type: DRUG

Trastuzumab

Initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses by IV infusion on Day 1 of every 3-week treatment cycle

Intervention Type: DRUG

Pertuzumab

Initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses by IV infusion on Day 1 of each 3-week treatment cycle

Intervention Type: DRUG

Cobimetinib

60 mg orally once daily for 3 weeks followed by a 1-week treatment break

Intervention Type: DRUG

5-FU/LV

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 until disease progression per the Investigator's assessment using modified Response Evaluation Criteria in Solid Tumors or death from any cause, whichever occurs first. The fluoropyrimidine should be administered in accordance with local prescribing information.

Intervention Type: DRUG

Capecitabine

1000 mg/m\^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The fluoropyrimidine should be administered in accordance with local prescribing information.

Intervention Type: DRUG

Other Intervention Names

MPDL3280A, RO5541267; RO5185426; RO4876646; RO0452317; RO4368451; RO5514041

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

• Less than 6 months from completion of any prior neoadjuvant or adjuvant chemotherapy, radiotherapy
• Prior or current treatment with bevacizumab or any other anti-angiogenic drug (vascular endothelial growth factor or vascular endothelial growth factor receptor therapies or tyrosine kinase inhibitors)
• Current or recent (within 10 days of study enrollment) use of aspirin (more than [>] 325 milligrams per day [mg/day]), clopidogrel (> 75 mg/day), or current or recent (within 10 days prior to the start of study induction treatment) use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes (prophylactic uses allowed)
• Active infection requiring intravenous antibiotics at the start of study induction treatment
• Previous or concurrent malignancy, except for adequately treated basal or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the participant has been disease-free for 5 years prior to study entry
• Inadequately controlled hypertension; prior history of hypertensive crisis or hypertensive encephalopathy
• Clinically significant (active) cardiovascular disease, for example cerebrovascular accidents <= 6 months prior to start of study induction treatment, myocardial infarction <= 6 months prior to study enrollment, unstable angina, New York Heart Association (NYHA) Functional Classification Grade II or greater congestive heart failure, or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with protocol treatment
• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of start of study induction treatment
• Active symptomatic or untreated central nervous system (CNS) metastases; CNS disease other than supratentorial or cerebellar metastases (in other words, patients with metastases to midbrain, pons, medulla or spinal cord are excluded); history of or known carcinomatous meningitis
• Known hypersensitivity to any component of any of the study induction or maintenance treatment medications
• Pregnancy or lactation

• Inability to swallow pills
• Refractory nausea and vomiting, malabsorption, external biliary shunt or significant bowel resection that would preclude adequate absorption
• History or presence of clinically significant ventricular or atrial dysrhythmias
• Corrected QT (QTc) interval >= 450 millisecond assessed within 3 weeks prior to randomization, long QT syndrome or, uncorrectable electrolyte abnormalities (including magnesium) or requirement for medicinal products known to prolong the QT interval
• ECOG PS > 2

• History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
• Prior allogeneic bone marrow transplantation or prior solid organ transplantation
• History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis at most recent chest imaging (computed tomography [CT] scan or magnetic resonance imaging [MRI])
• Positive test for human immunodeficiency virus (HIV)
• Active hepatitis B virus (HBV) or hepatitis C virus (HCV) at Screening
• Active tuberculosis
• Severe infection within 4 weeks prior to start of maintenance treatment including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia; has signs or symptoms of significant infection or has received oral or IV antibiotics within 2 weeks prior to start of maintenance treatment
• Administration of a live, attenuated vaccine within 4 weeks prior to start of maintenance treatment or anticipation that such a live attenuated vaccine will be required during the remainder of the study
• Prior treatment with cluster of differentiation (CD) 137 agonists, anti-cytotoxic T-lymphocyte-associated antigen (CTLA) 4, anti-programmed death-1 (PD-1), or anti-programmed death-ligand 1 (PD-L1) therapeutic antibody or pathway-targeting agents
• Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is longer, prior to start of maintenance treatment
• Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to start of maintenance treatment, or anticipated requirement for systemic immunosuppressive medications during the remainder of the study
• If receiving receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor (for example, denosumab) and unwilling to adopt alternative treatment such as bisphosphonates while receiving atezolizumab

• Inability to swallow pills
• Left ventricular ejection fraction (LVEF) less than (<) 50 percent (%) as assessed after completion of induction treatment by either 2-dimensional echocardiogram or multiple-gated acquisition
• Clinically significant cardiovascular disease, including unstable angina, history of or active congestive heart failure of ≥ NYHA Grade 2, history of or ongoing serious cardiac arrhythmia requiring treatment (except for controlled atrial fibrillation and/or paroxysmal supraventricular tachycardia).
• Current uncontrolled hypertension with or without medication
• Current dyspnea at rest due to complications of advanced malignancy or other disease requiring continuous oxygen therapy
• Insulin-dependent diabetes
• Current known infection with HIV, HBV, or HCV (active infection or carriers)
• Requirement for concurrent use of the antiviral agent sorivudine (antiviral) or chemically related analogues, such as brivudine
• Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, or ulcerative colitis
• Known hypersensitivity to murine proteins

• Inability to swallow medications
• History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
• History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on most recent chest imaging (CT scan or MRI)
• Malabsorption condition that would alter the absorption of orally administered medications
• Amylase or lipase ≥ 1.5 times the upper limit of normal within 14 days prior to maintenance treatment initiation
• Serum albumin less than (<) 2.5 grams per deciliter (g/dL)
• LVEF < institutional lower limit of normal or < 50%, whichever is lower
• Poorly controlled hypertension
• Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage more than once every 28 days. Indwelling drainage catheters are allowed
• Unstable angina, new onset angina within last 3 months, myocardial infarction within last 6 months and current congestive heart failure ≥ NYHA Grade 2
• History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 6 months prior to initiation of maintenance treatment
• History or evidence of intracranial hemorrhage or spinal cord hemorrhage
• Evidence of clinically significant vasogenic edema
• Any hemorrhage or bleeding event ≥ National Cancer Institute Common Terminology Criteria for Adverse Events Grade 3 within 28 days prior to initiation of maintenance treatment
• History or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for central serous retinopathy, retinal vein occlusion, or neovascular macular degeneration
• Positive HIV test
• Active HBV or HCV
• Active tuberculosis
• Severe infection within 4 weeks prior to start of maintenance treatment including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia; has signs or symptoms of significant infection or has received oral or IV antibiotics within 2 weeks prior to start of maintenance treatment.
• Prior allogeneic bone marrow transplantation or prior solid organ transplantation
• Administration of a live, attenuated vaccine within 4 weeks prior to start of study maintenance treatment or anticipation that such a live attenuated vaccine will be required during the study
• Prior treatment with CD137 agonists, anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents
• Prior treatment with a mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) or ERK inhibitor
• Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is longer, prior to start of study maintenance treatment
• Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to start of study maintenance treatment, or requirement for systemic immunosuppressive medications during the trial.
• If receiving a RANKL inhibitor (for example, denosumab), unwilling to adopt alternative treatment such as (but not limited to) bisphosphonates, while receiving atezolizumab.
• Consumption of foods, supplements or drugs that are potent cytochrome P450 3A4 (CYP3A4) enzyme inducers or inhibitors ≤ 7 days before initiation of study maintenance treatment or expected concomitant use during maintenance treatment. These include St. John's wort or hyperforin (potent CYP3A4 enzyme inducer) and grapefruit juice (potent CYP3A4 enzyme inhibitor)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

Hospital de Gastroenterologia Dr. Bonorino Udaondo ; Servicio de Oncología

Buenos Aires, , Argentina

Centro Oncologico Riojano Integral (CORI)

La Rioja, , Argentina

Clínica Viedma

Viedma Rio Negro, , Argentina

Institut Jules Bordet X

Brussels, , Belgium

Hospital Erasme

Brussels, , Belgium

UZ Leuven Gasthuisberg

Leuven, , Belgium

CHC MontLégia

Liège, , Belgium

AZ Delta (Campus Rumbeke)

Roeselare, , Belgium

University Clinical Center of the Republic of Srpska

Banja Luka, , Bosnia and Herzegovina

Hospital da Cidade de Passo Fundo; Centro de Pesquisa em Oncologia

Passo Fundo, Rio Grande do Sul, Brazil

Hospital das Clinicas - UFRGS

Porto Alegre, Rio Grande do Sul, Brazil

Hospital Nossa Senhora da Conceicao

Porto Alegre, Rio Grande do Sul, Brazil

Hospital de Cancer de Barretos

Barretos, São Paulo, Brazil

Hospital Amaral Carvalho

Jaú, São Paulo, Brazil

Faculdade de Medicina de Sao Jose do Rio Preto - FAMERP*X*

São José do Rio Preto, São Paulo, Brazil

Instituto de Ensino e Pesquisa Sao Lucas - IEP

São Paulo, São Paulo, Brazil

Herlev Hospital; Afdeling for Kræftbehandling

Herlev, , Denmark

Regionshospitalet Gødstrup; Kræftafdelingen

Herning, , Denmark

Rigshospitalet; Onkologisk Klinik

København Ø, , Denmark

Odense Universitetshospital, Onkologisk Afdeling R

Odense C, , Denmark

Sygehus Syd Roskilde; Onkologisk/haematologisk ambulatorium

Roskilde, , Denmark

National Cancer Institute

Cairo, , Egypt

Ain Shams University Hospital; Oncology

Cairo, , Egypt

Clinique Sainte Catherine

Avignon, , France

HOPITAL JEAN MINJOZ; Oncologie

Besançon, , France

Hopital Augustin Morvan; Federation De Cancerologie

Brest, , France

Chu Estaing; Chir Generale Digestive A Et B

Clermont-Ferrand, , France

Hôpital Franco-Britannique- Fondation Cognacq-Jay; Cancerologie

Levallois-Perret, , France

Hopital Claude Huriez; Medecine Interne Oncologie

Lille, , France

Ch De Montbeliard;Chir Generale Digestive

Montbéliard, , France

Hopital Caremeau; Gastro Enterologie

Nîmes, , France

Hopital Saint Antoine; Oncologie Medicale

Paris, , France

Hopital Haut Leveque

Pessac, , France

Chu La Miletrie; Gastro Enterologie Endoscopies

Poitiers, , France

ICANS

Strasbourg, , France

Hopital Rangueil; Gastro Enterologie Et Nutrition

Toulouse, , France

Institut Gustave Roussy; Departement Oncologie Medicale

Villejuif, , France

Hämatologie Onkologie im Zentrum MVZ GmbH

Augsburg, , Germany

Onkologische Schwerpunktpraxis Kurfürstendamm

Berlin, , Germany

DRK Kliniken Berlin Köpenick Darmzentrum

Berlin, , Germany

BAG Freiberg-Richter, Jacobasch, Illmer, Wolf; Gemeinschaftspraxis Hämatologie-Onkologie

Dresden, , Germany

Krankenhaus Nordwest; Klinik f. Onkologie und Hämatologie

Frankfurt, , Germany

PIOH PD Dr. R. Schnell ? Dr. H. Schulz ? Dr. M. Hellmann

Frechen, , Germany

Klinik Fulda, Medizinisches Versorgungszentrum Osthessen GmbH

Fulda, , Germany

Universitätsklinikum Hamburg-Eppendorf, Onkologisches Zentrum, Studienzentrale der II. Med. Klinik

Hamburg, , Germany

Medizinische Hochschule Hannover; Zentrum Innere Medizin; Abt. Hämatologie u. Onkologie

Hanover, , Germany

SLK-Kliniken Heilbronn GmbH; Klinik für Innere Medizin III; Schwerpunkt Häma./Onko./Palliativm.

Heilbronn, , Germany

Klinik der Ruhr-Uni Bochum; Marien-Hospital Herne

Herne, , Germany

Gemeinschaftspraxis für Hämatologie und Onkologie, PD Dr. Bauer, Dr. Thiel

Lebach, , Germany

Onkologische Gemeinschaftspraxis

Magdeburg, , Germany

Klinikum Magdeburg gGmbH Klinik für Allgemein- und Viszeralchirurgie

Magdeburg, , Germany

Universitätsklinikum Magdeburg Klinik für Gastroenterologie und Hepatologie

Mageburg, , Germany

Kliniken Maria Hilf GmbH, Krankenhaus St. Franziskus

Mönchengladbach, , Germany

Städt. Klinikum München GmbH Klinikum Neuperlach Klinik f.Hämatologie u.Onkologie

München, , Germany

Gemeinschaftspraxis für Hämatologie und Onkologie

Münster, , Germany

Brüderkrankenhaus St. Josef

Paderborn, , Germany

Studienzentrum Onkologie Ravensburg GbR; Onkologie Ravensburg

Ravensburg, , Germany

Prosper-Hospital, Medizinische Klinik I

Recklinghausen, , Germany

Krankenhaus Barmherziger Brüder; Klinik für Internistische Onkologie / Hämatologie

Regensburg, , Germany

Klinikum am Steinenberg / Ermstalklinik

Reutlingen, , Germany

Praxis für Hämatologie & Onkologie

Saarbrücken, , Germany

MVZ für Hämatologie, Onkologie, Strahlentherapie und Palliativmedizin -; Klinik Dr. Hancken

Stade, , Germany

Klinikum Mutterhaus der Borromaeerinnen gGmbH; Haematologie/Onkologie

Trier, , Germany

Klinikum Wetzlar-Braunfels, Klinik für Hämatologie/Onkologie und Palliativmedizin

Wetzlar, , Germany

Agioi Anargyroi; 3Rd Dept. of Medical Oncology

Athens, , Greece

Univ General Hosp Heraklion; Medical Oncology

Heraklion, , Greece

Uni Hospital of Ioannina; Oncology Dept.

Ioannina, , Greece

University Hospital of Patras Medical Oncology

Pátrai, , Greece

Thermi Clinic; Oncology Clinic

Thermi Thessalonikis, , Greece

Bioclinic Thessaloniki

Thessaloniki, , Greece

Euromedical General Clinic of Thessaloniki; Oncology Department

Thessaloniki, , Greece

IRCCS Ospedale Casa Sollievo Della Sofferenza; Oncologia

San Giovanni Rotondo, Apulia, Italy

IRCCS Istituto Nazionale Tumori Fondazione Pascale; Oncologia Medica A

Napoli, Campania, Italy

IRST Istituto Scientifico Romagnolo Per Lo Studio E Cura Dei Tumori, Sede Meldola; Oncologia Medica

Meldola, Emilia-Romagna, Italy

A.O. Universitaria Di Parma; Oncologia Medica

Parma, Emilia-Romagna, Italy

Istituto Regina Elena; Oncologia Medica A

Rome, Lazio, Italy

Policlinico Universitario "Agostino Gemelli"; U.O.C. Oncologia Medica

Rome, Lazio, Italy

Humanitas Gavazzeni;U.O. Oncologia Medica

Bergamo, Lombardy, Italy

Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 1

Milan, Lombardy, Italy

Irccs Istituto Europeo Di Oncologia (IEO); Oncologia Medica

Milan, Lombardy, Italy

Asst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia

Milan, Lombardy, Italy

Azienda Ospedaliero-Universitaria Careggi;S.C. Oncologia Medica 1

Florence, Tuscany, Italy

IRCCS Istituto Oncologico Veneto (IOV); Oncologia Medica Prima

Padua, Veneto, Italy

A.O.U.I. VERONA-OSPEDALE POLICLINICO G.B. ROSSI BORGO ROMA;ONCOLOGIA MEDICA-d.U.

Verona, Veneto, Italy

Fundacion Rodolfo Padilla Padilla A.C.

León, Guanajuato, Mexico

Oaxaca Site Management Organization

Oaxaca City, Oaxaca, Mexico

Cancerologia de Queretaro; Oncologia

Queretaro, Queretaro, Querétaro, Mexico

Instituto Nacional de Cancerologia; Oncology

Mexico City, , Mexico

Antoni van Leeuwenhoek Ziekenhuis

Amsterdam, , Netherlands

Ijsselland Ziekenhuis; Inwendige Geneeskunde

Capelle aan den IJssel, , Netherlands

Deventer Ziekenhuis; Interne Geneeskunde

Deventer, , Netherlands

Albert Schweitzer Ziekenhuis - loc Dordrecht

Dordrecht, , Netherlands

Catharina ZKHS; Inwendige Geneeskunde Afd.

Eindhoven, , Netherlands

St. Antonius locatie Leidsche Rijn

Utrecht, , Netherlands

Isala Klinieken

Zwolle, , Netherlands

Szpital Uniwersytecki w Krakowie, Oddzia? Kliniczny Kliniki Onkologii

Krakow, , Poland

Narodowy Instytut Onkologii im. M. Sklodowskiej-Curie; Klinika Onkologii i Radioterapii,

Warsaw, , Poland

HUC; Servico de Oncologia Medica

Coimbra, , Portugal

Hospital de Santa Maria; Servico de Oncologia Medica

Lisbon, , Portugal

Bashkirian Republican Clinical Oncology Dispensary

Ufa, Bashkortostan Republic, Russia

Russian Oncology Research Center n.a. N.N. Blokhin Dpt of Clinical Pharmacology and Chemotherapy

Moscow, Moscow Oblast, Russia

Institute for Oncology and Radiology of Serbia; Clinic for Medical Oncology

Belgrade, , Serbia

Narodny Onkologicky Ustav; Oddelenie klinickej onkologie E

Bratislava, , Slovakia

POKO Poprad; Department of Oncology

Poprad, , Slovakia

Institute of Oncology Ljubljana

Ljubljana, , Slovenia

Seoul National University Hospital

Seoul, , South Korea

Severance Hospital, Yonsei University Health System

Seoul, , South Korea

Asan Medical Center

Seoul, , South Korea

Samsung Medical Center

Seoul, , South Korea

Hospital General Universitario de Elche; Servicio de Oncologia

Elche, Alicante, Spain

Hospital Universitario Son Espases

Palma de Mallorca, Balearic Islands, Spain

Hospital Universitari Germans Trias i Pujol; Servicio de Oncologia

Badalona, Barcelona, Spain

Hospital Univ Vall d'Hebron; Servicio de Oncologia

Sant Andreu de la Barca, Barcelona, Spain

Hospital Universitario Marques de Valdecilla; Servicio de Oncologia

Santander, Cantabria, Spain

Hospital Universitario Reina Sofia; Servicio de Oncologia

Córdoba, Cordoba, Spain

Hospital de Donostia; Servicio de Oncologia Medica

Donostia / San Sebastian, Guipuzcoa, Spain

Complejo Hospitalario Universitario de Santiago (CHUS) ; Servicio de Oncologia

Santiago de Compostela, LA Coruña, Spain

Hospital Universitario Puerta de Hierro; Servicio de Oncologia

Majadahonda, Madrid, Spain

Hospital de Navarra; Servicio de Oncologia

Navarra, Navarre, Spain

Hospital Univ. Central de Asturias; Servicio de Oncologia

Oviedo, Principality of Asturias, Spain

Complejo Hospitalario Nuestra Señora de la Candelaria; Servicio de Oncologia

Santa Cruz de Tenerife, Tenerife, Spain

Hospital General Univ. de Alicante; Servicio de Oncologia

Alicante, , Spain

Complejo Hospitalario de Jaen-Hospital Universitario Medico Quirurgico; Servicio de Oncologia

Jaén, , Spain

Hospital Universitari Arnau de Vilanova de Lleida; Servicio de Oncologia

Lleida, , Spain

Hospital General Universitario Gregorio Marañon; Servicio de Oncologia

Madrid, , Spain

Hospital Ramon y Cajal; Servicio de Oncologia

Madrid, , Spain

Hospital Universitario 12 de Octubre; Servicio de Oncologia

Madrid, , Spain

Hospital Universitario La Paz; Servicio de Oncologia

Madrid, , Spain

Hospital Regional Universitario Carlos Haya; Servicio de Oncologia

Málaga, , Spain

Complejo Hospitalario de Orense; Servicio de Oncologia

Ourense, , Spain

Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia

Valencia, , Spain

Hospital General Universitario de Valencia; Servicio de oncologia

Valencia, , Spain

Hospital Universitario la Fe; Servicio de Oncologia

Valencia, , Spain

Hospital Clinico Universitario Lozano Blesa; Servicio de Oncologia

Zaragoza, , Spain

Hospital Universitario Miguel Servet; Servicio Oncologia

Zaragoza, , Spain

Skånes University Hospital, Skånes Department of Onclology

Lund, , Sweden

Karolinska Hospital; Oncology - Radiumhemmet

Stockholm, , Sweden

Acibadem University School of Medicine, Adana Hospital; General Surgery

Adana, , Turkey (Türkiye)

Trakya University Medical Faculty Research And Practice Hospital Medical Oncology Department

Edirne, , Turkey (Türkiye)

Istanbul Uni Capa Medical Faculty; Inst. of Oncology

Istanbul, , Turkey (Türkiye)

Marmara Uni Faculty of Medicine; Medical Oncology

Istanbul, , Turkey (Türkiye)

Ege Uni Medical Faculty Hospital; Oncology Dept

Izmir, , Turkey (Türkiye)

Hacettepe Uni Medical Faculty Hospital; Oncology Dept

Sihhiye/Ankara, , Turkey (Türkiye)

Aberdeen Royal Infirmary; Medical Oncology Dept

Aberdeen, , United Kingdom

Birmingham Heartlands Hospital

Birmingham, , United Kingdom

Broomfield Hospital; Oncology

Chelsmford, , United Kingdom

Castle Hill Hospital; The Queens Centre for Oncology and Haematology

Cottingham, , United Kingdom

Guys and St Thomas NHS Foundation Trust, Guys Hospital

London, , United Kingdom

Royal Marsden Hospital; Dept of Med-Onc

London, , United Kingdom

Christie Hospital Nhs Trust; Medical Oncology

Manchester, , United Kingdom

Mount Vernon Hospital

Middlesex, , United Kingdom

Queen's Hospital

Romford, , United Kingdom

Southampton General Hospital; Medical Oncology

Southampton, , United Kingdom

Royal Marsden Hospital; Dept. of Medicine

Sutton, , United Kingdom

Countries

Argentina; Belgium; Bosnia and Herzegovina; Brazil; Denmark; Egypt; France; Germany; Greece; Italy; Mexico; Netherlands; Poland; Portugal; Russia; Serbia; Slovakia; Slovenia; South Korea; Spain; Sweden; Turkey (Türkiye); United Kingdom

References

Ducreux M, Tabernero J, Grothey A, Arnold D, O'Dwyer PJ, Gilberg F, Abbas A, Thakur MD, Prizant H, Irahara N, Tahiri A, Schmoll HJ, Van Cutsem E, de Gramont A. Clinical and exploratory biomarker findings from the MODUL trial (Cohorts 1, 3 and 4) of biomarker-driven maintenance therapy for metastatic colorectal cancer. Eur J Cancer. 2023 May;184:137-150. doi: 10.1016/j.ejca.2023.01.023. Epub 2023 Feb 4.

Reference Type: DERIVED

PMID: 36921494 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2014-001017-61

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MO29112

Identifier Type: -

Identifier Source: org_study_id