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

Phase 2

Completed

Conditions: Colorectal Cancer

Interventions: Drug: FOLFOX induction regimen
Drug: Fluoropyrimidine (5-FU/LV or capecitabine)
Drug: Cetuximab
Drug: Trastuzumab
Drug: Bevacizumab
Drug: Pertuzumab
Drug: Vemurafenib
Drug: Atezolizumab
Drug: Cobimetinib
Drug: 5-FU/LV
Drug: Capecitabine

Registration Number: NCT02291289

Lead Sponsor: Hoffmann-La Roche

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1044

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
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

Exclusion Criteria for Participants in Cohort 1 (MP):

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

Exclusion Criteria for Participants in Cohort 2 (MP):

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

Exclusion Criteria for Participants in Cohort 3 (MP):

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

Exclusion Criteria for Participants in Cohort 4 (MP):

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)

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 2 (IP)	FOLFOX induction regimen	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.
Cohort 4 (IP)	Bevacizumab	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.
Cohort 1 Control (MP): 5-FU/LV or capecitabin, bevacizumab	Fluoropyrimidine (5-FU/LV or capecitabine)	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.
Cohort 1: Induction Phase (IP)	FOLFOX induction regimen	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.
Cohort 1: Induction Phase (IP)	5-FU/LV	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.
Cohort 3 (IP)	FOLFOX induction regimen	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.
Cohort 4 (IP)	FOLFOX induction regimen	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.
Cohort 3 (IP)	5-FU/LV	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.
Cohort 4 (IP)	5-FU/LV	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.
Cohort 1 (Maintenance Phase[MP]):5-FU/LV,cetuximab,vemurafenib	5-FU/LV	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.
Cohort 2 (IP)	5-FU/LV	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.
Cohort 2 (MP):5-FU/LV or capecitabine,bevacizumab,atezolizumab	Fluoropyrimidine (5-FU/LV or capecitabine)	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.
Cohort 2 Control (MP): 5-FU/LV or capecitabin, bevacizumab	Fluoropyrimidine (5-FU/LV or capecitabine)	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.
Cohort 3 Control (MP): 5-FU/LV or capecitabin, bevacizumab	Fluoropyrimidine (5-FU/LV or capecitabine)	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.
Cohort 4 Control (MP): 5-FU/LV or capecitabin, bevacizumab	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.
Cohort 2 (MP):5-FU/LV or capecitabine,bevacizumab,atezolizumab	Bevacizumab	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.
Cohort 3 (MP): capecitabine,trastuzumab,pertuzumab	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.
Cohort 4 Control (MP): 5-FU/LV or capecitabin, bevacizumab	Fluoropyrimidine (5-FU/LV or capecitabine)	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.
Early Progressing BRAFmut Cohort	Fluoropyrimidine (5-FU/LV or capecitabine)	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.
Early Progressing BRAFmut Cohort	5-FU/LV	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.
Early Progressing BRAFmut Cohort	Bevacizumab	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.
Cohort 1: Induction Phase (IP)	Bevacizumab	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.
Cohort 2 (IP)	Bevacizumab	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.
Cohort 3 (IP)	Bevacizumab	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.
Cohort 1 (Maintenance Phase[MP]):5-FU/LV,cetuximab,vemurafenib	Cetuximab	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.
Cohort 1 (Maintenance Phase[MP]):5-FU/LV,cetuximab,vemurafenib	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.
Cohort 1 Control (MP): 5-FU/LV or capecitabin, bevacizumab	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.
Cohort 2 (MP):5-FU/LV or capecitabine,bevacizumab,atezolizumab	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.
Cohort 3 (MP): capecitabine,trastuzumab,pertuzumab	Trastuzumab	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.
Cohort 2 Control (MP): 5-FU/LV or capecitabin, bevacizumab	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.
Cohort 3 Control (MP): 5-FU/LV or capecitabin, bevacizumab	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.
Cohort 4 (MP): Cobimetinib,atezolizumab	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.
Cohort 3 (MP): capecitabine,trastuzumab,pertuzumab	Capecitabine	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.
Cohort 4 (MP): Cobimetinib,atezolizumab	Cobimetinib	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.
Early Progressing BRAFmut Cohort	Cetuximab	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.
Early Progressing BRAFmut Cohort	Atezolizumab	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.
Early Progressing BRAFmut Cohort	Vemurafenib	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.

Primary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS)	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 Outcome Measures

Name	Time	Method
Time to Treatment Response	From randomization until disease progression or death from any cause, up to 5 years	Calculated as the time from randomization to the first Occurrence of a documented Objective Response (CR or PR) determined according to RECIST 1.1. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Overall Survival (OS)	From randomization until death from any cause, up to 5 years	OS is defined as the time from randomization into the MTP to time of death from any cause.
Overall Response	From randomization until disease progression, up to 5 years	Calculated as the number of participants with a best overall response of CR or PR according to RECIST 1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR= CR + PR.
Disease Control Rate (DCR)	From randomization until disease progression, up to 5 years	DCR is defined as the percentage of participants with CR, PR, or stable disease (SD) at 16 weeks. Per RECIST v1.1, CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum on study. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline, or the appearance of one or more new lesions.
Duration of Response	From first objective response until disease progression or death from any cause, up to 5 years	Defined as the time from the first assessment of CR or PR until disease progression or death from any cause, whichever occurs first. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
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)

Trial Locations

Locations (154): Hospital de Gastroenterologia Dr. Bonorino Udaondo ; Servicio de Oncología
🇦🇷
Buenos Aires, Argentina
Institut Jules Bordet X
🇧🇪
Brussels, Belgium
Hospital Erasme
🇧🇪
Bruxelles, Belgium
AZ Delta (Campus Rumbeke)
🇧🇪
Roeselare, Belgium
University Clinical Center of the Republic of Srpska
🇧🇦
Banja Luka, Bosnia and Herzegovina
Hospital Nossa Senhora da Conceicao
🇧🇷
Porto Alegre, RS, Brazil
Hospital Amaral Carvalho
🇧🇷
Jau, SP, Brazil
Hopital Augustin Morvan; Federation De Cancerologie
🇫🇷
Brest, France
Chu Estaing; Chir Generale Digestive A Et B
🇫🇷
Clermont Ferrand, France
PIOH PD Dr. R. Schnell ? Dr. H. Schulz ? Dr. M. Hellmann
🇩🇪
Frechen, Germany
Medizinische Hochschule Hannover; Zentrum Innere Medizin; Abt. Hämatologie u. Onkologie
🇩🇪
Hannover, Germany
SLK-Kliniken Heilbronn GmbH; Klinik für Innere Medizin III; Schwerpunkt Häma./Onko./Palliativm.
🇩🇪
Heilbronn, Germany
Onkologische Gemeinschaftspraxis
🇩🇪
Magdeburg, Germany
Kliniken Maria Hilf GmbH, Krankenhaus St. Franziskus
🇩🇪
Mönchengladbach, Germany
Städt. Klinikum München GmbH Klinikum Neuperlach Klinik f.Hämatologie u.Onkologie
🇩🇪
München, Germany
Prosper-Hospital, Medizinische Klinik I
🇩🇪
Recklinghausen, Germany
Agioi Anargyroi; 3Rd Dept. of Medical Oncology
🇬🇷
Athens, Greece
Bioclinic Thessaloniki
🇬🇷
Thessaloniki, Greece
Asst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia
🇮🇹
Milano, Lombardia, Italy
Severance Hospital, Yonsei University Health System
🇰🇷
Seoul, Korea, Republic of
Szpital Uniwersytecki w Krakowie, Oddzia? Kliniczny Kliniki Onkologii
🇵🇱
Kraków, Poland
Bashkirian Republican Clinical Oncology Dispensary
🇷🇺
UFA, Baskortostan, Russian Federation
Russian Oncology Research Center n.a. N.N. Blokhin Dpt of Clinical Pharmacology and Chemotherapy
🇷🇺
Moscow, Moskovskaja Oblast, Russian Federation
Narodny Onkologicky Ustav; Oddelenie klinickej onkologie E
🇸🇰
Bratislava, Slovakia
Hospital Universitario Reina Sofia; Servicio de Oncologia
🇪🇸
Córdoba, Cordoba, Spain
Complejo Hospitalario Universitario de Santiago (CHUS) ; Servicio de Oncologia
🇪🇸
Santiago de Compostela, LA Coruña, Spain
Hospital General Universitario Gregorio Marañon; Servicio de Oncologia
🇪🇸
Madrid, Spain
Hospital Ramon y Cajal; Servicio de Oncologia
🇪🇸
Madrid, Spain
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
Hospital da Cidade de Passo Fundo; Centro de Pesquisa em Oncologia
🇧🇷
Passo Fundo, RS, Brazil
Albert Schweitzer Ziekenhuis - loc Dordrecht
🇳🇱
Dordrecht, Netherlands
Samsung Medical Center
🇰🇷
Seoul, Korea, Republic of
Hopital Rangueil; Gastro Enterologie Et Nutrition
🇫🇷
Toulouse, France
Centro Oncologico Riojano Integral (CORI)
🇦🇷
La Rioja, Argentina
Hopital Haut Leveque
🇫🇷
Pessac, France
Clínica Viedma
🇦🇷
Viedma Rio Negro, Argentina
Hospital de Cancer de Barretos
🇧🇷
Barretos, SP, Brazil
Clinique Sainte Catherine
🇫🇷
Avignon, France
Krankenhaus Nordwest; Klinik f. Onkologie und Hämatologie
🇩🇪
Frankfurt, Germany
DRK Kliniken Berlin Köpenick Darmzentrum
🇩🇪
Berlin, Germany
Hospital das Clinicas - UFRGS
🇧🇷
Porto Alegre, RS, Brazil
Chu La Miletrie; Gastro Enterologie Endoscopies
🇫🇷
Poitiers, France
Institut Gustave Roussy; Departement Oncologie Medicale
🇫🇷
Villejuif, France
Klinik Fulda, Medizinisches Versorgungszentrum Osthessen GmbH
🇩🇪
Fulda, Germany
Praxis für Hämatologie & Onkologie
🇩🇪
Saarbruecken, Germany
Uni Hospital of Ioannina; Oncology Dept.
🇬🇷
Ioannina, Greece
Istituto Regina Elena; Oncologia Medica A
🇮🇹
Roma, Lazio, Italy
Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 1
🇮🇹
Milano, Lombardia, Italy
Onkologische Schwerpunktpraxis Kurfürstendamm
🇩🇪
Berlin, Germany
Hôpital Franco-Britannique- Fondation Cognacq-Jay; Cancerologie
🇫🇷
Levallois-Perret, France
Ain Shams University Hospital; Oncology
🇪🇬
Cairo, Egypt
Hopital Claude Huriez; Medecine Interne Oncologie
🇫🇷
Lille, France
Hopital Caremeau; Gastro Enterologie
🇫🇷
Nimes, France
Gemeinschaftspraxis für Hämatologie und Onkologie, PD Dr. Bauer, Dr. Thiel
🇩🇪
Lebach, Germany
Klinikum am Steinenberg / Ermstalklinik
🇩🇪
Reutlingen, Germany
Klinikum Mutterhaus der Borromaeerinnen gGmbH; Haematologie/Onkologie
🇩🇪
Trier, Germany
Klinikum Wetzlar-Braunfels, Klinik für Hämatologie/Onkologie und Palliativmedizin
🇩🇪
Wetzlar, Germany
Univ General Hosp Heraklion; Medical Oncology
🇬🇷
Heraklion, Greece
Irccs Istituto Europeo Di Oncologia (IEO); Oncologia Medica
🇮🇹
Milano, Lombardia, Italy
IRST Istituto Scientifico Romagnolo Per Lo Studio E Cura Dei Tumori, Sede Meldola; Oncologia Medica
🇮🇹
Meldola, Emilia-Romagna, Italy
IRCCS Istituto Oncologico Veneto (IOV); Oncologia Medica Prima
🇮🇹
Padova, Veneto, Italy
Studienzentrum Onkologie Ravensburg GbR; Onkologie Ravensburg
🇩🇪
Ravensburg, Germany
MVZ für Hämatologie, Onkologie, Strahlentherapie und Palliativmedizin -; Klinik Dr. Hancken
🇩🇪
Stade, Germany
Krankenhaus Barmherziger Brüder; Klinik für Internistische Onkologie / Hämatologie
🇩🇪
Regensburg, Germany
IRCCS Ospedale Casa Sollievo Della Sofferenza; Oncologia
🇮🇹
San Giovanni Rotondo, Puglia, Italy
Oaxaca Site Management Organization
🇲🇽
Oaxaca de Juárez, Oaxaca, Mexico
Antoni van Leeuwenhoek Ziekenhuis
🇳🇱
Amsterdam, Netherlands
Hospital Universitari Germans Trias i Pujol; Servicio de Oncologia
🇪🇸
Badalona, Barcelona, Spain
Institute of Oncology Ljubljana
🇸🇮
Ljubljana, Slovenia
Hospital Univ Vall d'Hebron; Servicio de Oncologia
🇪🇸
Sant Andreu de La Barca, Barcelona, Spain
Hospital Clinico Universitario Lozano Blesa; Servicio de Oncologia
🇪🇸
Zaragoza, Spain
Hospital Universitario Miguel Servet; Servicio Oncologia
🇪🇸
Zaragoza, Spain
CHC MontLégia
🇧🇪
Liege, Belgium
UZ Leuven Gasthuisberg
🇧🇪
Leuven, Belgium
Faculdade de Medicina de Sao Jose do Rio Preto - FAMERP*X*
🇧🇷
Sao Jose do Rio Preto, SP, Brazil
Instituto de Ensino e Pesquisa Sao Lucas - IEP
🇧🇷
Sao Paulo, SP, Brazil
Herlev Hospital; Afdeling for Kræftbehandling
🇩🇰
Herlev, Denmark
National Cancer Institute
🇪🇬
Cairo, Egypt
HOPITAL JEAN MINJOZ; Oncologie
🇫🇷
Besancon, France
Ch De Montbeliard;Chir Generale Digestive
🇫🇷
Montbeliard, France
Hopital Saint Antoine; Oncologie Medicale
🇫🇷
Paris, France
ICANS
🇫🇷
Strasbourg, France
Hämatologie Onkologie im Zentrum MVZ GmbH
🇩🇪
Augsburg, Germany
BAG Freiberg-Richter, Jacobasch, Illmer, Wolf; Gemeinschaftspraxis Hämatologie-Onkologie
🇩🇪
Dresden, Germany
Universitätsklinikum Hamburg-Eppendorf, Onkologisches Zentrum, Studienzentrale der II. Med. Klinik
🇩🇪
Hamburg, Germany
Klinik der Ruhr-Uni Bochum; Marien-Hospital Herne
🇩🇪
Herne, Germany
Gemeinschaftspraxis für Hämatologie und Onkologie
🇩🇪
Münster, Germany
Klinikum Magdeburg gGmbH Klinik für Allgemein- und Viszeralchirurgie
🇩🇪
Magdeburg, Germany
Universitätsklinikum Magdeburg Klinik für Gastroenterologie und Hepatologie
🇩🇪
Mageburg, Germany
Brüderkrankenhaus St. Josef
🇩🇪
Paderborn, Germany
Thermi Clinic; Oncology Clinic
🇬🇷
Thermi Thessalonikis, Greece
University Hospital of Patras Medical Oncology
🇬🇷
Patras, Greece
A.O. Universitaria Di Parma; Oncologia Medica
🇮🇹
Parma, Emilia-Romagna, Italy
Euromedical General Clinic of Thessaloniki; Oncology Department
🇬🇷
Thessaloniki, Greece
IRCCS Istituto Nazionale Tumori Fondazione Pascale; Oncologia Medica A
🇮🇹
Napoli, Campania, Italy
Humanitas Gavazzeni;U.O. Oncologia Medica
🇮🇹
Bergamo, Lombardia, Italy
Policlinico Universitario "Agostino Gemelli"; U.O.C. Oncologia Medica
🇮🇹
Roma, Lazio, Italy
Azienda Ospedaliero-Universitaria Careggi;S.C. Oncologia Medica 1
🇮🇹
Firenze, Toscana, Italy
A.O.U.I. VERONA-OSPEDALE POLICLINICO G.B. ROSSI BORGO ROMA;ONCOLOGIA MEDICA-d.U.
🇮🇹
Verona, Veneto, Italy
Seoul National University Hospital
🇰🇷
Seoul, Korea, Republic of
Fundacion Rodolfo Padilla Padilla A.C.
🇲🇽
León, Guanajuato, Mexico
Asan Medical Center
🇰🇷
Seoul, Korea, Republic of
Cancerologia de Queretaro; Oncologia
🇲🇽
Queretaro, Queretaro, Queretaro, Mexico
Ijsselland Ziekenhuis; Inwendige Geneeskunde
🇳🇱
Capelle A/d IJssel, Netherlands
Instituto Nacional de Cancerologia; Oncology
🇲🇽
Mexico City, Mexico
Deventer Ziekenhuis; Interne Geneeskunde
🇳🇱
Deventer, Netherlands
Catharina ZKHS; Inwendige Geneeskunde Afd.
🇳🇱
Eindhoven, Netherlands
St. Antonius locatie Leidsche Rijn
🇳🇱
Utrecht, Netherlands
HUC; Servico de Oncologia Medica
🇵🇹
Coimbra, Portugal
Isala Klinieken
🇳🇱
Zwolle, Netherlands
Institute for Oncology and Radiology of Serbia; Clinic for Medical Oncology
🇷🇸
Belgrade, Serbia
Narodowy Instytut Onkologii im. M. Sklodowskiej-Curie; Klinika Onkologii i Radioterapii,
🇵🇱
Warszawa, Poland
Hospital de Santa Maria; Servico de Oncologia Medica
🇵🇹
Lisboa, Portugal
POKO Poprad; Department of Oncology
🇸🇰
Poprad, Slovakia
Hospital General Universitario de Elche; Servicio de Oncologia
🇪🇸
Elche, Alicante, Spain
Hospital de Donostia; Servicio de Oncologia Medica
🇪🇸
San Sebastian, Guipuzcoa, Spain
Hospital Univ. Central de Asturias; Servicio de Oncologia
🇪🇸
Oviedo, Asturias, Spain
Hospital Universitario Puerta de Hierro; Servicio de Oncologia
🇪🇸
Majadahonda, Madrid, Spain
Hospital Universitario Marques de Valdecilla; Servicio de Oncologia
🇪🇸
Santander, Cantabria, Spain
Hospital Universitario Son Espases
🇪🇸
Palma De Mallorca, Islas Baleares, Spain
Hospital Universitario La Paz; Servicio de Oncologia
🇪🇸
Madrid, Spain
Complejo Hospitalario Nuestra Señora de la Candelaria; Servicio de Oncologia
🇪🇸
Santa Cruz de Tenerife, Tenerife, Spain
Complejo Hospitalario de Jaen-Hospital Universitario Medico Quirurgico; Servicio de Oncologia
🇪🇸
Jaen, Spain
Hospital Universitari Arnau de Vilanova de Lleida; Servicio de Oncologia
🇪🇸
Lerida, Spain
Hospital Universitario 12 de Octubre; Servicio de Oncologia
🇪🇸
Madrid, Spain
Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia
🇪🇸
Valencia, Spain
Hospital Regional Universitario Carlos Haya; Servicio de Oncologia
🇪🇸
Malaga, Spain
Hospital de Navarra; Servicio de Oncologia
🇪🇸
Navarra, Spain
Complejo Hospitalario de Orense; Servicio de Oncologia
🇪🇸
Orense, Spain
Skånes University Hospital, Skånes Department of Onclology
🇸🇪
Lund, Sweden
Hospital Universitario la Fe; Servicio de Oncologia
🇪🇸
Valencia, Spain
Istanbul Uni Capa Medical Faculty; Inst. of Oncology
🇹🇷
Istanbul, Turkey
Acibadem University School of Medicine, Adana Hospital; General Surgery
🇹🇷
Adana, Turkey
Karolinska Hospital; Oncology - Radiumhemmet
🇸🇪
Stockholm, Sweden
Hospital General Universitario de Valencia; Servicio de oncologia
🇪🇸
Valencia, Spain
Trakya University Medical Faculty Research And Practice Hospital Medical Oncology Department
🇹🇷
Edirne, Turkey
Ege Uni Medical Faculty Hospital; Oncology Dept
🇹🇷
Izmir, Turkey
Hacettepe Uni Medical Faculty Hospital; Oncology Dept
🇹🇷
Sihhiye/Ankara, Turkey
Guys and St Thomas NHS Foundation Trust, Guys Hospital
🇬🇧
London, United Kingdom
Aberdeen Royal Infirmary; Medical Oncology Dept
🇬🇧
Aberdeen, United Kingdom
Birmingham Heartlands Hospital
🇬🇧
Birmingham, United Kingdom
Marmara Uni Faculty of Medicine; Medical Oncology
🇹🇷
Istanbul, Turkey
Royal Marsden Hospital; Dept. of Medicine
🇬🇧
Sutton, United Kingdom
Broomfield Hospital; Oncology
🇬🇧
Chelsmford, United Kingdom
Castle Hill Hospital; The Queens Centre for Oncology and Haematology
🇬🇧
Cottingham, United Kingdom
Royal Marsden Hospital; Dept of Med-Onc
🇬🇧
London, United Kingdom
Christie Hospital Nhs Trust; Medical Oncology
🇬🇧
Manchester, United Kingdom
Southampton General Hospital; Medical Oncology
🇬🇧
Southampton, United Kingdom
Mount Vernon Hospital
🇬🇧
Middlesex, United Kingdom
Queen's Hospital
🇬🇧
Romford, United Kingdom
Hospital General Univ. de Alicante; Servicio de Oncologia
🇪🇸
Alicante, Spain