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Combination Chemotherapy, Bevacizumab, and/or Atezolizumab in Treating Patients With Deficient DNA Mismatch Repair Metastatic Colorectal Cancer, the COMMIT Study

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02997228
Recruitment Status : Recruiting
First Posted : December 20, 2016
Last Update Posted : June 11, 2024
Sponsor:
Collaborator:
NRG Oncology
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE December 19, 2016
First Posted Date  ICMJE December 20, 2016
Last Update Posted Date June 11, 2024
Actual Study Start Date  ICMJE January 19, 2018
Estimated Primary Completion Date November 30, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 8, 2020)		 Progression free survival (PFS) [ Time Frame: From the time from randomization until first confirmed progression or death from any cause, assessed up to 5 years ]
The analysis set is intent-to-treat (ITT). The experimental arms will be compared to the control arm by the log-rank test stratified by BRAF status (V600E mutation or not), metastatic disease: (liver-only, extra-hepatic), and prior adjuvant therapy for colon cancer (yes, no). Hazard ratios and associated confidence intervals from a stratified Cox regression model will also be reported along with estimates of the distributions of time to PFS event by the method of Kaplan and Meier. Sensitivity analyses accounting for 2 or more consecutively missed scheduled tumor imaging scans before progression/death will also be conducted.
Original Primary Outcome Measures  ICMJE
 (submitted: December 19, 2016)		 PFS [ Time Frame: From the time from randomization until first confirmed progression or death from any cause, assessed up to 5 years ]
The experimental arms will be compared to the control arm by the log-rank test stratified by BRAF status, metastatic disease: (liver-only, extra-hepatic), and prior adjuvant therapy for colon cancer (yes, no). Hazard ratios and associated confidence intervals from a stratified Cox regression model will also be reported along with estimates of the distributions of time to PFS event by the method of Kaplan and Meier.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 8, 2020)
  • Overall survival (OS) [ Time Frame: The time from randomization to death from any cause, assessed up to 5 years ]
    Will be analyzed using the stratified log rank test and the ITT population. Kaplan-Meier plots will illustrate the distribution of these endpoints by treatment. Stratified Cox regression models will be used to estimate hazard ratios and associated confidence intervals.
  • Objective response rate (ORR) (complete response [CR] or partial response [PR]) [ Time Frame: Up to 5 years ]
    Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Will be analyzed by a logistic regression models that control for the stratification factors (BRAF status, liver involvement, and adjuvant chemotherapy [chemo]) using the ITT population. Observed proportions along with confidence intervals will be presented by treatment.
  • Incidence of adverse events [ Time Frame: Up to 30 days after last cycle ]
    Defined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The safety profile will be described by tabulating the maximum observed grade of adverse event for each individual adverse event, for each system organ class, and overall using the Safety population.
  • Rate of PFS [ Time Frame: At 12 months ]
  • Disease control rate (CR + PR + stable disease [SD]) [ Time Frame: At 12 months ]
    Assessed by RECIST 1.1. Will be analyzed by a logistic regression models that control for the stratification factors (BRAF status, liver involvement, and adjuvant chemo) using the ITT population. Observed proportions along with confidence intervals will be presented by treatment.
  • Duration of overall response (CR or PR) [ Time Frame: From the time of first response to first confirmed progression by the study investigator or death from any cause, assessed up to 5 years ]
    Assessed by RECIST 1.1. Will be analyzed using the stratified log rank test and the ITT population. Kaplan-Meier plots will illustrate the distribution of these endpoints by treatment. Stratified Cox regression models will be used to estimate hazard ratios and associated confidence intervals.
  • Duration of SD [ Time Frame: From the time of first on-study assessment of SD to first progression by the study investigator or death from any cause, assessed up to 5 years ]
    Assessed per RECIST 1.1. Will be analyzed using the stratified log rank test and the ITT population. Kaplan-Meier plots will illustrate the distribution of these endpoints by treatment. Stratified Cox regression models will be used to estimate hazard ratios and associated confidence intervals.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 19, 2016)
  • Disease control rate (CR + PR + SD) assessed by RECIST 1.1 [ Time Frame: At 12 months ]
    Will be analyzed by a logistic regression models that control for the stratification factors (BRAF status, liver involvement, and adjuvant chemo). Observed proportions along with confidence intervals will be presented by treatment.
  • Duration of overall response (CR or PR) as assessed by RECIST 1.1 [ Time Frame: From the time of first response to first confirmed progression by the study investigator or death from any cause, assessed up to 5 years ]
    Will be analyzed using the stratified log rank test. Kaplan-Meier plots will illustrate the distribution of these endpoints by treatment. Stratified Cox regression models will be used to estimate hazard ratios and associated confidence intervals.
  • Incidence of adverse events as defined by CTCAE version 4 [ Time Frame: Up to 30 days after last course ]
  • ORR (CR or PR) assessed by RECIST 1.1 [ Time Frame: Up to 5 years ]
    Will be analyzed by a logistic regression models that control for the stratification factors (BRAF status, liver involvement, and adjuvant chemo). Observed proportions along with confidence intervals will be presented by treatment.
  • OS [ Time Frame: The time from randomization to death from any cause, assessed up to 5 years ]
    Will be analyzed using the stratified log rank test. Kaplan-Meier plots will illustrate the distribution of these endpoints by treatment. Stratified Cox regression models will be used to estimate hazard ratios and associated confidence intervals.
  • Physical functioning, as measured by the PROMIS physical function short form 6a questionnaire [ Time Frame: At 16 weeks ]
    Will be compared between the control arm (Chemo-Bev) and the atezolizumab monotherapy arm by means of ordinal logistic regression with adjustment for the corresponding baseline measurement and stratification variables. The comparison will be performed at the significance level of 0.05 (two-sided) and the clinical meaningfulness of the comparison will be considered.
  • Severity and frequency of quality of life (QOL) and patient-reported outcomes (PRO) [ Time Frame: Up to 5 years ]
    The corresponding item (PRO-CTCAE severity, PRO-CTCAE frequency, or QOL scale) will be compared between the control arm (Chemo-Bev) and each experimental arm in turn (atezolizumab monotherapy and Chemo-Bev plus atezolizumab combination therapy) using a mixed regression model for repeated measures with the response being ordinal for the PRO-CTCAE items and linear for QOL scales. The model will also include the corresponding baseline measurement, time, and stratification variables. Presence of treatment-by-time interaction will be investigated for each model. Each comparison will be performed at
  • Severity of fatigue, as measured by the Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue questionnaire [ Time Frame: At 16 weeks ]
    Will be compared between the control arm (Chemo-Bev) and the atezolizumab monotherapy arm by means of ordinal logistic regression with adjustment for the corresponding baseline measurement and stratification variables. The comparison will be performed at the significance level of 0.05 (two-sided) and the clinical meaningfulness of the comparison will be considered.
  • Surgical conversion rate defined as the proportion of patients that have surgery with curative intent [ Time Frame: Up to 5 years ]
    Will be analyzed by a logistic regression models that control for the stratification factors (BRAF status, liver involvement, and adjuvant chemo). Observed proportions along with confidence intervals will be presented by treatment.
Current Other Pre-specified Outcome Measures
 (submitted: March 30, 2023)
  • Severity of fatigue [ Time Frame: At 16 weeks ]
    Will use the ITT population. Measured by the Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue questionnaire. Will be compared between the control arm (Chemo-bevacizumab [Bev]) and the experimental arm by means of ordinal logistic regression with adjustment for the corresponding baseline measurement and stratification variables. The comparison will be performed at the significance level of 0.05 (two-sided) and the clinical meaningfulness of the comparison will be considered.
  • Physical functioning [ Time Frame: At 16 weeks ]
    Will use the ITT population. Measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life questionnaire (QLQ)-C30 physical functioning scale. Will be compared between the control arm (Chemo-Bev) and the experimental arm by means of ordinal logistic regression with adjustment for the corresponding baseline measurement and stratification variables. The comparison will be performed at the significance level of 0.05 (two-sided) and the clinical meaningfulness of the comparison will be considered.
  • Health utility scores [ Time Frame: Up to 5 years ]
    Will use the ITT population. Will be measured using the EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire.
  • Proportion of patients reporting each response option at each assessment timepoint by treatment arm for item GP5 from the Functional Assessment of Cancer Therapy - General (FACT-G) [ Time Frame: Up to 5 years ]
    Will use the ITT population.
  • Intratumoral lymphocyte PD-L1+ expression (>= 1 % is positive) by immunohistochemistry (IHC) as a predictive biomarker of efficacy [ Time Frame: Up to 5 years ]
    Will use the ITT population.
  • Efficacy dependent on the number of somatic mutations [ Time Frame: Up to 5 years ]
    Will use the ITT population.
  • Efficacy in tumors with MLH1 silencing [ Time Frame: Up to 5 years ]
    Will use the ITT population.
  • Change in quantification of cell free deoxyribonucleic acid (cfDNA) mutations [ Time Frame: Baseline up to 5 years ]
    Will use the ITT population.
  • Development of progression or relapse to treatment in cfDNA [ Time Frame: Up to 5 years ]
    Will use the ITT population.
  • Changes in T-cell repertoire diversity as a predictive biomarker of efficacy [ Time Frame: Baseline up to 5 years ]
    Will use the ITT population.
  • PFS of patients with high levels of diversity [ Time Frame: Up to 5 years ]
    Compared to patients with low levels of diversity. Will use the ITT population.
  • Change in T-cell diversity [ Time Frame: Baseline to first restaging between immunotherapy arms and the standard of care arm ]
    Will use the ITT population.
  • Mechanism of immune resistance to PD-1 blockade in mismatch repair deficient (dMMR)/microsatellite instability-high metastatic colorectal cancer (mCRC) by comparative analysis of tumor samples collected [ Time Frame: Baseline up to 5 years ]
    Will use the ITT population.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Combination Chemotherapy, Bevacizumab, and/or Atezolizumab in Treating Patients With Deficient DNA Mismatch Repair Metastatic Colorectal Cancer, the COMMIT Study
Official Title  ICMJE Colorectal Cancer Metastatic dMMR/MSI-H Immuno-Therapy (COMMIT) Study: A Randomized Phase III Study of mFOLFOX6/Bevacizumab/Atezolizumab Combination Versus Single Agent Atezolizumab in the First-Line Treatment of Patients With Deficient DNA Mismatch Repair (dMMR)/Microsatellite Instability-High (MSI-H) Metastatic Colorectal Cancer
Brief Summary This phase III trial studies how well combination chemotherapy, bevacizumab, and/or atezolizumab work in treating patients with deficient deoxyribonucleic acid (DNA) mismatch repair colorectal cancer that has spread from where it first started (primary site) to other places in the body (metastatic). Chemotherapy drugs, such as fluorouracil, oxaliplatin, and leucovorin calcium, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Bevacizumab may stop or slow colorectal cancer by blocking the growth of new blood vessels necessary for tumor growth. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving combination chemotherapy, bevacizumab, and atezolizumab may work better in treating patients with colorectal cancer.
Detailed Description

PRIMARY OBJECTIVE:

I. To determine the efficacy, based on progression-free survival (PFS), of fluorouracil, oxaliplatin, and leucovorin calcium (modified [m]FOLFOX6)/bevacizumab plus atezolizumab (combination) as compared to single agent atezolizumab.

SECONDARY OBJECTIVES:

I. To compare the overall survival. II. To compare the objective response rates (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

III. To determine the safety profiles of single agent atezolizumab and the combination of mFOLFOX6/bevacizumab/atezolizumab in patients with mismatch-repair deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC).

IV. To determine the duration of response. V. To determine the duration of stable disease. VI. To determine the rate of progression-free survival (PFS) at 12 months. VII. To evaluate the disease control rate (complete response [CR] + partial response [PR] + stable disease [SD]) at 12 months.

TRANSLATIONAL OBJECTIVE:

I. To bank tissue and blood samples for other future correlative studies from patients enrolled on the study.

OUTLINE: Patients are randomized to 1 of 3 arms.

ARM I: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 of cycles 1-10, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1 and 2. Treatment with oxaliplatin repeats every 2 weeks for up to 10 cycles in the absence of disease progression or unacceptable toxicity. Treatment of bevacizumab, leucovorin calcium, and fluorouracil repeat every 2 weeks for up to 48 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) with or without positron emission tomography (PET) or magnetic resonance imaging (MRI) throughout the trial. Patients may also undergo collection of optional blood samples throughout the trial. (CLOSED TO ACCRUAL)

ARM II: Patients receive atezolizumab IV over 30-60 minutes on day 1. Treatment repeats every 2 weeks for up to 48 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT with or without PET or MRI throughout the trial. Patients may also undergo collection of optional blood samples throughout the trial.

ARM III: Patients receive atezolizumab IV over 30-60 minutes on day 1. Treatment repeats every 2 weeks for up to 48 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive bevacizumab IV over 30-90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 cycles 1-10, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on day 1. Treatment with oxaliplatin repeats every 2 weeks for up to 10 cycles in the absence of disease progression or unacceptable toxicity. Treatment of bevacizumab, leucovorin calcium, and fluorouracil repeat every 2 weeks for up to 48 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT with or without PET or MRI throughout the trial. Patients may also undergo collection of optional blood samples throughout the trial.

After completion of study treatment, patients are followed up every 8 weeks for 18 months, and then every 12 weeks for up to 5 years.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Metastatic Colorectal Adenocarcinoma
  • Stage IV Colorectal Cancer AJCC v7
Intervention  ICMJE
  • Drug: Atezolizumab
    Given IV
    Other Names:
    • MPDL 3280A
    • MPDL 328OA
    • MPDL-3280A
    • MPDL3280A
    • MPDL328OA
    • RG7446
    • RO5541267
    • Tecentriq
  • Biological: Bevacizumab
    Given IV
    Other Names:
    • ABP 215
    • Anti-VEGF
    • Anti-VEGF Humanized Monoclonal Antibody
    • Anti-VEGF Monoclonal Antibody SIBP04
    • Anti-VEGF rhuMAb
    • Avastin
    • BAT 1706
    • BAT-1706
    • BAT1706
    • BAT1706 Biosimilar
    • Bevacizumab awwb
    • Bevacizumab Biosimilar ABP 215
    • Bevacizumab Biosimilar BAT1706
    • Bevacizumab Biosimilar BEVZ92
    • Bevacizumab Biosimilar BI 695502
    • Bevacizumab Biosimilar CBT 124
    • Bevacizumab Biosimilar CT-P16
    • Bevacizumab Biosimilar FKB238
    • Bevacizumab Biosimilar GB-222
    • Bevacizumab Biosimilar HD204
    • Bevacizumab Biosimilar HLX04
    • Bevacizumab Biosimilar IBI305
    • Bevacizumab Biosimilar LY01008
    • Bevacizumab Biosimilar MIL60
    • Bevacizumab Biosimilar Mvasi
    • Bevacizumab Biosimilar MYL-1402O
    • Bevacizumab Biosimilar QL 1101
    • Bevacizumab Biosimilar QL1101
    • Bevacizumab Biosimilar RPH-001
    • Bevacizumab Biosimilar SCT501
    • Bevacizumab Biosimilar Zirabev
    • Bevacizumab-adcd
    • Bevacizumab-awwb
    • Bevacizumab-bvzr
    • BP102
    • BP102 Biosimilar
    • CT-P16
    • HD204
    • Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
    • Mvasi
    • MYL-1402O
    • QL1101
    • Recombinant Humanized Anti-VEGF Monoclonal Antibody
    • rhuMab-VEGF
    • SCT501
    • SIBP 04
    • SIBP-04
    • SIBP04
    • Vegzelma
    • Zirabev
  • Procedure: Biospecimen Collection
    Undergo collection of blood samples
    Other Names:
    • Biological Sample Collection
    • Biospecimen Collected
    • Specimen Collection
  • Procedure: Computed Tomography
    Undergo CT or CT/PET
    Other Names:
    • CAT
    • CAT Scan
    • Computed Axial Tomography
    • Computerized Axial Tomography
    • Computerized axial tomography (procedure)
    • Computerized Tomography
    • Computerized Tomography (CT) scan
    • CT
    • CT Scan
    • tomography
  • Drug: Fluorouracil
    Given IV
    Other Names:
    • 5 Fluorouracil
    • 5 Fluorouracilum
    • 5 FU
    • 5-Fluoro-2,4(1H, 3H)-pyrimidinedione
    • 5-Fluorouracil
    • 5-Fluracil
    • 5-Fu
    • 5FU
    • AccuSite
    • Carac
    • Fluoro Uracil
    • Fluouracil
    • Flurablastin
    • Fluracedyl
    • Fluracil
    • Fluril
    • Fluroblastin
    • Ribofluor
    • Ro 2-9757
    • Ro-2-9757
  • Drug: Leucovorin
    Given IV
    Other Name: Folinic acid
  • Procedure: Magnetic Resonance Imaging
    Undergo MRI
    Other Names:
    • Magnetic Resonance
    • Magnetic Resonance Imaging (MRI)
    • Magnetic resonance imaging (procedure)
    • Magnetic Resonance Imaging Scan
    • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
    • MR
    • MR Imaging
    • MRI
    • MRI Scan
    • MRIs
    • NMR Imaging
    • NMRI
    • Nuclear Magnetic Resonance Imaging
    • sMRI
    • Structural MRI
  • Drug: Oxaliplatin
    Given IV
    Other Names:
    • 1-OHP
    • Ai Heng
    • Aiheng
    • Dacotin
    • Dacplat
    • Diaminocyclohexane Oxalatoplatinum
    • Eloxatin
    • Eloxatine
    • JM-83
    • Oxalatoplatin
    • Oxalatoplatinum
    • RP 54780
    • RP-54780
    • SR-96669
  • Procedure: Positron Emission Tomography
    Undergo CT/PET
    Other Names:
    • Medical Imaging, Positron Emission Tomography
    • PET
    • PET Scan
    • Positron emission tomography (procedure)
    • Positron Emission Tomography Scan
    • Positron-Emission Tomography
    • proton magnetic resonance spectroscopic imaging
    • PT
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Name: Quality of Life Assessment
  • Other: Questionnaire Administration
    Ancillary studies
Study Arms  ICMJE
  • Active Comparator: Arm I (bevacizumab, mFOLFOX6)
    Patients receive bevacizumab intravenously (IV) over 30-90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 of cycles 1-10, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1 and 2. Treatment with oxaliplatin repeats every 2 weeks for up to 10 cycles in the absence of disease progression or unacceptable toxicity. Treatment of bevacizumab, leucovorin calcium, and fluorouracil repeat every 2 weeks for up to 48 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT with or without PET or MRI throughout the trial. Patients may also undergo collection of optional blood samples throughout the trial. (CLOSED TO ACCRUAL)
    Interventions:
    • Biological: Bevacizumab
    • Procedure: Biospecimen Collection
    • Procedure: Computed Tomography
    • Drug: Fluorouracil
    • Drug: Leucovorin
    • Procedure: Magnetic Resonance Imaging
    • Drug: Oxaliplatin
    • Procedure: Positron Emission Tomography
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
  • Experimental: Arm II (atezolizumab)
    Patients receive atezolizumab IV over 30-60 minutes on day 1. Treatment repeats every 2 weeks for up to 48 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT with or without PET or MRI throughout the trial. Patients may also undergo collection of optional blood samples throughout the trial.
    Interventions:
    • Drug: Atezolizumab
    • Procedure: Biospecimen Collection
    • Procedure: Computed Tomography
    • Procedure: Magnetic Resonance Imaging
    • Procedure: Positron Emission Tomography
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
  • Experimental: Arm III (atezolizumab, bevacizumab, mFOLFOX6)
    Patients receive atezolizumab IV over 30-60 minutes on day 1. Treatment repeats every 2 weeks for up to 48 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive bevacizumab IV over 30-90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 cycles 1-10, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on day 1. Treatment with oxaliplatin repeats every 2 weeks for up to 10 cycles in the absence of disease progression or unacceptable toxicity. Treatment of bevacizumab, leucovorin calcium, and fluorouracil repeat every 2 weeks for up to 48 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT with or without PET or MRI throughout the trial. Patients may also undergo collection of optional blood samples throughout the trial.
    Interventions:
    • Drug: Atezolizumab
    • Biological: Bevacizumab
    • Procedure: Biospecimen Collection
    • Procedure: Computed Tomography
    • Drug: Fluorouracil
    • Drug: Leucovorin
    • Procedure: Magnetic Resonance Imaging
    • Drug: Oxaliplatin
    • Procedure: Positron Emission Tomography
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 30, 2023)		 120
Original Estimated Enrollment  ICMJE
 (submitted: December 19, 2016)		 439
Estimated Study Completion Date  ICMJE November 30, 2024
Estimated Primary Completion Date November 30, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • The patient must have signed and dated an Institutional Review Board (IRB)-approved consent form that conforms to federal and institutional guidelines
  • Age >= 18 years
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
  • Diagnosis of metastatic adenocarcinoma of colon or rectum without previous chemotherapy or any other systemic therapy for metastatic colorectal cancer except for one cycle of FOLFOX or capecitabine and oxaliplatin (CAPOX), either with or without bevacizumab prior to enrollment. Upon enrollment, the preceding single cycle of FOLFOX or FOLFOX + bevacizumab, if the patient received one, will not count towards patients' assessments per protocol. Cycle 1 day 1 (C1D1) of atezolizumab or C1D1 of mFOLFOX6/bevacizumab + atezolizumab will correspond to the first day the patient received therapy on trial
  • Tumor determined to be mismatch-repair deficient (dMMR) by Clinical Laboratory Improvement Act (CLIA)-certified immunohistochemical (IHC) assay with a panel of all four IHC markers, including MLH1, MSH2, PMS2, and MSH6; alternatively, MSI-H diagnosed by polymerase chain reaction (PCR)-based assessment of microsatellite alterations (either Bethesda markers or Pentaplex panel) or by next-generation sequencing (NGS) are eligible
  • Documentation by PET/CT scan, CT scan, or MRI that the patient has measurable metastatic disease per RECIST 1.1
  • No immediate need for surgical intervention for the primary tumor or palliative diversion/bypass
  • Absolute neutrophil count (ANC) must be >= 1500/mm^3 (obtained within 28 days prior randomization)
  • Platelet count must be >= 100,000/mm^3 (obtained within 28 days prior randomization)
  • Hemoglobin must be >= 8 g/dL (obtained within 28 days prior randomization)
  • Total bilirubin must be =< 4 x ULN (upper limit of normal) (obtained within 28 days prior randomization); and
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be =< 3 x ULN for the lab with the following exception: for patients with documented liver metastases, AST and ALT must be =< 5 x ULN (obtained within 28 days prior randomization)
  • Calculated creatinine clearance >= 30 mL/min (obtained within 28 days prior randomization)

  • A urine sample tested for proteinuria by either the dipstick method, urinalysis (UA), or a urine protein creatinine (UPC) ratio:

    • The dipstick method must indicate 0-1+ protein; if dipstick reading is >= 2+, a 24-hour urine must be done and it must demonstrate < 1.0 g of protein per 24 hours or a UPC ratio < 1.0
    • A urine protein creatinine (UPC) ratio must be < 1.0; if the UPC ratio is >= 1.0 a 24-hour urine must be done and it must demonstrate < 1.0 g of protein per 24 hours
    • Urinalysis must indicate < 30 mg/dl. If urinalysis >= 30 mg/dl, a 24-hour urine must be done and it must demonstrate < 1.0 g of protein per 24 hours or a UPC ratio < 1.0
  • International normalized ratio of prothrombin time (INR) and prothrombin time (PT) must be =< 1.5 x ULN for the lab within 28 days before randomization; patients who are therapeutically treated with an agent such as warfarin may participate if they are on a stable dose and no underlying abnormality in coagulation parameters exists per medical history, regardless of PT/INR results
  • Pregnancy test done within 28 days prior randomization must be negative (for women of childbearing potential only); pregnancy testing should be performed according to institutional standards; administration of atezolizumab or mFOLFOX6/bevacizumab/atezolizumab may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Women of child-bearing potential and men must agree to use adequate contraception methods that result in a failure rate of < 1% per year during the treatment period (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 5 months (150 days) after the last dose of atezolizumab, 6 months after the last dose of bevacizumab, and 6 months after the last dose of mFOLFOX6; a woman is considered to be of childbearing potential if she is not postmenopausal, has not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus); examples of contraceptive methods with a failure rate of < 1% per year include: bilateral tubal ligation; male partner sterilization; intrauterine devices; the reliability of sexual abstinence should be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception; men must refrain from donating sperm during this same period

Exclusion Criteria:

  • Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies, fluoropyrimidines, folic acid derivatives or oxaliplatin
  • Uncontrolled high blood pressure defined as systolic blood pressure (BP) > 150 mmHg or diastolic BP > 100 mmHg with or without anti-hypertensive medication; patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria
  • Documented New York Heart Association (NYHA) class III or IV congestive heart failure
  • Serious or non-healing wound, skin ulcer, or bone fracture
  • History of inherited bleeding diathesis, gastrointestinal (GI) perforation, significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis or symptomatic peripheral ischemia, transient ischemic attack [TIA], cerebrovascular accident [CVA] or arterial thrombotic event), abdominal fistula, intra-abdominal abscess, or active GI bleeding (with cause not addressed) within 6 months prior to randomization, or other medical condition in the opinion of the treating oncologist that makes the risk of cardiovascular or bleeding complications with bevacizumab use unacceptably high
  • Other malignancies are excluded unless the patient has completed therapy for the malignancy >= 12 months prior to randomization and is considered disease-free; patients with the following cancers are eligible if diagnosed and treated within the past 12 months: in situ carcinomas or basal cell and squamous cell carcinoma of the skin
  • Known DPD (dihydro pyrimidine dehydrogenase) deficiency
  • Symptomatic peripheral sensory neuropathy >= grade 2 (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5.0)
  • Prior treatment with oxaliplatin chemotherapy within 6 months prior to randomization
  • History of grade 2 hemoptysis (defined as 2.5 mL of bright red blood per episode) within 1 month prior to screening

  • Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents; patients who have received prior treatment with anti-CTLA-4 may be enrolled provided the following requirements are met:

    • Minimum of 12 weeks from the first dose of anti-CTLA-4 and > 6 weeks from the last dose to randomization
    • No history of severe immune-related adverse effects (CTCAE grade 3 and 4) from anti-CTLA-4

  • Treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 14 days prior to randomization; however,

    • Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea; or chronic daily treatment with corticosteroids with a dose of =< 10 mg/day methylprednisolone equivalent) may be enrolled
    • The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed

  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease; however,

    • Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HbsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible if polymerase chain reaction (PCR) for hepatits B virus (HBV) ribonucleic acid (RNA) is negative per local guidelines
    • Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA per local guidelines

  • History or risk of autoimmune disease, including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis; however,

    • Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible
    • Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible

    • Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:

      • Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations
      • Rash must cover less than 10% of body surface area (BSA)
      • Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)
      • No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
  • History of idiopathic pulmonary fibrosis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or active or recently active (within 90 days of randomization) pneumonitis (including drug induced) that required systemic immunosuppressive therapy (i.e. corticosteroids, etc.). History of radiation pneumonitis in the radiation field (fibrosis) is permitted
  • History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  • Patients with known active tuberculosis (TB) are excluded
  • Severe infections within 28 days prior to randomization, including but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
  • Signs or symptoms of infection within 14 days prior to randomization
  • Received oral or intravenous (IV) antibiotics within 14 days prior to randomization; patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization or anticipation of need for a major surgical procedure during the course of the study
  • The administration of a live, attenuated vaccine within 28 days prior to randomization
  • Pregnant women are excluded from this study because atezolizumab is an agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with atezolizumab, breastfeeding should be discontinued if the mother is treated with atezolizumab; these potential risks may also apply to other agents used in this study; (Note: pregnancy testing should be performed within 28 days prior to randomization according to institutional standards for women of childbearing potential)
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  • Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02997228
Other Study ID Numbers  ICMJE NCI-2016-01961
NCI-2016-01961 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-GI004/S1610
NRG-GI004 ( Other Identifier: NRG Oncology )
NRG-GI004 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party National Cancer Institute (NCI)
Original Responsible Party Same as current
Current Study Sponsor  ICMJE National Cancer Institute (NCI)
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE NRG Oncology
Investigators  ICMJE
Principal Investigator: Caio Max S Rocha Lima NRG Oncology
PRS Account National Cancer Institute (NCI)
Verification Date March 2024

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP