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

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ClinicalTrials.gov Identifier: NCT02291289
Recruitment Status : Suspended (Following iDMC review of cohort 4 data a temporary recruitment halt to the whole study and a temporary halt to randomisation into cohort 4 has been undertaken)
First Posted : November 14, 2014
Last Update Posted : May 4, 2018
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Drug: Cetuximab Drug: FOLFOX induction regimen Drug: Fluoropyrimidine (5-FU/LV or capecitabine) Drug: Atezolizumab Drug: Vemurafenib Drug: Bevacizumab Drug: Trastuzumab Drug: Pertuzumab Drug: Cobimetinib Drug: 5-FU/LV Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multi-Centre Randomised Clinical Trial of Biomarker-Driven Maintenance Treatment for First-Line Metastatic Colorectal Cancer (MODUL)
Actual Study Start Date : April 17, 2015
Estimated Primary Completion Date : May 31, 2019
Estimated Study Completion Date : December 29, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Induction Treatment Phase
All patients 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
Drug: FOLFOX induction regimen
Administered per the Investigator's discretion in accordance with locally approved prescribing information.

Drug: Bevacizumab
5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information
Other Name: RO4876646

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.

Experimental: 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.
Drug: Cetuximab
500 mg/m^2 via IV infusion on Day 1 of every 2-week cycle

Drug: Vemurafenib
960 mg vermurafenib BID by mouth
Other Name: RO5185426

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.

Experimental: 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.
Drug: Fluoropyrimidine (5-FU/LV or capecitabine)
Per Investigator's discretion: 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.

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
Other Name: MPDL3280A, RO5541267

Drug: Bevacizumab
5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information
Other Name: RO4876646

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.

Experimental: 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.
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
Other Name: RO0452317

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
Other Name: RO4368451

Experimental: Cohort 4 (MP): Experimental arm 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.
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
Other Name: MPDL3280A, RO5541267

Drug: Cobimetinib
60 mg orally once daily for 3 weeks followed by a 1-week treatment break
Other Name: RO5514041

Active Comparator: 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.
Drug: Fluoropyrimidine (5-FU/LV or capecitabine)
Per Investigator's discretion: 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.

Drug: Bevacizumab
5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information
Other Name: RO4876646

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.

Experimental: BRAFmut Early Progression (EP): 5-FU/LV,cetuximab,vemurafenib
Participants with MSS, will receive will receive 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 with 500 mg/m^2 cetuximab via infusion on Day 1 of every 2-week cycle and 960 mg vemurafenib BID by mouth.
Drug: Vemurafenib
960 mg vermurafenib BID by mouth
Other Name: RO5185426

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.

Experimental: BRAFmut EP: 5-FU/LV or capecitabine,bevacizumab,atezolizumab
Participants with MSI-H 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 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.
Drug: Fluoropyrimidine (5-FU/LV or capecitabine)
Per Investigator's discretion: 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.

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
Other Name: MPDL3280A, RO5541267

Drug: Bevacizumab
5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information
Other Name: RO4876646

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.




Primary Outcome Measures :
  1. Progression-Free Survival Evaluated According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: From randomization until disease progression or death from any cause, up to 7.5 years ]

Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: From randomization until death from any cause, up to 7.5 years ]
  2. Overall Response, Calculated as the Proportion of Participants with a Best Overall Response of Complete Response (CR) or Partial Response (PR) Determined According to RECIST 1.1 [ Time Frame: From randomization until disease progression, up to 7.5 years ]
  3. Disease Control, Calculated as the Proportion of Participants with a Best Overall Response of CR, PR or Stable Disease Determined According to RECIST 1.1 [ Time Frame: From randomization until disease progression, up to 7.5 years ]
  4. Time to Treatment Response, Calculated as the Time from Randomization to the First Occurrence of a Documented Objective Response (CR or PR) Determined According to RECIST 1.1 [ Time Frame: From randomization until disease progression or death from any cause, up to 7.5 years ]
  5. Duration of Response, Defined as the Time from the First Assessment of CR or PR until Disease Progression or Death from Any Cause, Whichever Occurs First [ Time Frame: From first objective response until disease progression or death from any cause, up to 7.5 years ]
  6. Change from Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score [ Time Frame: From baseline until end of study (up to 7.5 years) ]
  7. Percentage of Participants with Adverse Events [ Time Frame: From baseline until end of study (up to 7.5 years) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02291289


  Show 167 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02291289     History of Changes
Other Study ID Numbers: MO29112
2014-001017-61 ( EudraCT Number )
First Posted: November 14, 2014    Key Record Dates
Last Update Posted: May 4, 2018
Last Verified: May 2018

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Bevacizumab
Atezolizumab
Pertuzumab
Vemurafenib
Capecitabine
Trastuzumab
Cetuximab
Fluorouracil
Antibodies, Monoclonal
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents