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Trial record 2 of 2 for:    GI004
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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 : May 24, 2023
Sponsor:
Collaborator:
NRG Oncology
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Description
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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.

Condition or disease Intervention/treatment Phase
Metastatic Colorectal Adenocarcinoma Stage IV Colorectal Cancer AJCC v7 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 Phase 3

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Study Design
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Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : November 7, 2017
Estimated Primary Completion Date : November 30, 2024
Estimated Study Completion Date : November 30, 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
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)
 Biological: Bevacizumab
Given IV
Other Names:
  • ABP 215
  • Anti-VEGF
  • Anti-VEGF Humanized Monoclonal Antibody
  • Anti-VEGF Monoclonal Antibody SIBP04
  • Anti-VEGF rhuMAb
  • Avastin
  • Bevacizumab awwb
  • Bevacizumab Biosimilar ABP 215
  • 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-awwb
  • Bevacizumab-bvzr
  • BP102
  • BP102 Biosimilar
  • 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
  • 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
  • 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 (procedure)
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI
  • MRI Scan
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging

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
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.
 Drug: Atezolizumab
Given IV
Other Names:
  • MPDL 3280A
  • MPDL 328OA
  • MPDL-3280A
  • MPDL3280A
  • MPDL328OA
  • RG7446
  • RO5541267
  • Tecentriq

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
  • CT
  • CT Scan
  • tomography

Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
  • Magnetic Resonance
  • Magnetic resonance imaging (procedure)
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI
  • MRI Scan
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging

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
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.
 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
  • Bevacizumab awwb
  • Bevacizumab Biosimilar ABP 215
  • 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-awwb
  • Bevacizumab-bvzr
  • BP102
  • BP102 Biosimilar
  • 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
  • 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
  • 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 (procedure)
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI
  • MRI Scan
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging

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


Outcome Measures
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Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. Rate of PFS [ Time Frame: At 12 months ]
  5. 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.

  6. 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.

  7. 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.


Other Outcome Measures:
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. Efficacy dependent on the number of somatic mutations [ Time Frame: Up to 5 years ]
    Will use the ITT population.

  7. Efficacy in tumors with MLH1 silencing [ Time Frame: Up to 5 years ]
    Will use the ITT population.

  8. Change in quantification of cell free deoxyribonucleic acid (cfDNA) mutations [ Time Frame: Baseline up to 5 years ]
    Will use the ITT population.

  9. Development of progression or relapse to treatment in cfDNA [ Time Frame: Up to 5 years ]
    Will use the ITT population.

  10. Changes in T-cell repertoire diversity as a predictive biomarker of efficacy [ Time Frame: Baseline up to 5 years ]
    Will use the ITT population.

  11. 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.

  12. 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.

  13. 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.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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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): NCT02997228


Locations
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Sponsors and Collaborators
National Cancer Institute (NCI)
NRG Oncology
Investigators
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Principal Investigator: Caio Max S Rocha Lima NRG Oncology
More Information
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02997228    
Other Study ID Numbers: 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 )
First Posted: December 20, 2016    Key Record Dates
Last Update Posted: May 24, 2023
Last Verified: April 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Leucovorin
Bevacizumab
Antineoplastic Agents, Immunological
Atezolizumab
 Fluorouracil
Oxaliplatin
Endothelial Growth Factors
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunoglobulin G
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Immunologic Factors
Antimetabolites