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

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ClinicalTrials.gov Identifier: NCT02997228
Recruitment Status : Recruiting
First Posted : December 20, 2016
Last Update Posted : December 11, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This randomized 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 to other places in the body. Drugs used in chemotherapy, 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. Immunotherapy with monoclonal antibodies, such as bevacizumab and 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
Colorectal Adenocarcinoma Mismatch Repair Deficiency Stage IV Colorectal Cancer AJCC v7 Stage IVA Colorectal Cancer AJCC v7 Stage IVB Colorectal Cancer AJCC v7 Drug: Atezolizumab Biological: Bevacizumab Drug: Fluorouracil Drug: Leucovorin Calcium Drug: Oxaliplatin Other: Quality-of-Life Assessment Other: Questionnaire Administration Phase 3

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 347 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Colorectal Cancer Metastatic dMMR Immuno-Therapy (COMMIT) Study: A Randomized Phase III Study of mFOLFOX6/Bevacizumab Combination Chemotherapy With or Without Atezolizumab or Atezolizumab Monotherapy in the First-Line Treatment of Patients With Deficient DNA Mismatch Repair (dMMR) Metastatic Colorectal Cancer
Actual Study Start Date : November 7, 2017
Estimated Primary Completion Date : April 30, 2022
Estimated Study Completion Date : April 30, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Arm I (bevacizumab, mFOLFOX6)
Patients receive bevacizumab IV over 30-90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 of courses 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 courses in the absence of disease progression or unacceptable toxicity. Courses of bevacizumab, leucovorin calcium, and fluorouracil repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.
Biological: Bevacizumab
Given IV
Other Names:
  • Anti-VEGF
  • Anti-VEGF Humanized Monoclonal Antibody
  • Anti-VEGF rhuMAb
  • Avastin
  • Bevacizumab Biosimilar BEVZ92
  • Bevacizumab Biosimilar BI 695502
  • Bevacizumab Biosimilar CBT 124
  • Bevacizumab Biosimilar FKB238
  • Bevacizumab Biosimilar MIL60
  • Bevacizumab Biosimilar QL 1101
  • BEVACIZUMAB, LICENSE HOLDER UNSPECIFIED
  • 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
  • Recombinant Humanized Anti-VEGF Monoclonal Antibody
  • rhuMab-VEGF

Drug: Fluorouracil
Given IV
Other Names:
  • 5-Fluoro-2,4(1H, 3H)-pyrimidinedione
  • 5-Fluorouracil
  • 5-Fluracil
  • 5-FU
  • AccuSite
  • Carac
  • Fluoro Uracil
  • Fluouracil
  • Flurablastin
  • Fluracedyl
  • Fluracil
  • Fluril
  • Fluroblastin
  • Ribofluor
  • Ro 2-9757
  • Ro-2-9757

Drug: Leucovorin Calcium
Given IV
Other Names:
  • Adinepar
  • Calcifolin
  • Calcium (6S)-Folinate
  • Calcium Folinate
  • Calcium Leucovorin
  • Calfolex
  • Calinat
  • Cehafolin
  • Citofolin
  • Citrec
  • citrovorum factor
  • Cromatonbic Folinico
  • Dalisol
  • Disintox
  • Divical
  • Ecofol
  • Emovis
  • Factor, Citrovorum
  • Flynoken A
  • Folaren
  • Folaxin
  • FOLI-cell
  • Foliben
  • Folidan
  • Folidar
  • Folinac
  • Folinate Calcium
  • folinic acid
  • Folinic Acid Calcium Salt Pentahydrate
  • Folinoral
  • Folinvit
  • Foliplus
  • Folix
  • Imo
  • Lederfolat
  • Lederfolin
  • Leucosar
  • leucovorin
  • Rescufolin
  • Rescuvolin
  • Tonofolin
  • Wellcovorin

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

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 courses in the absence of disease progression or unacceptable toxicity.
Drug: Atezolizumab
Given IV
Other Names:
  • MPDL 3280A
  • MPDL 328OA
  • MPDL-3280A
  • MPDL3280A
  • MPDL328OA
  • RG7446
  • RO5541267
  • Tecentriq

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 courses 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 courses 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 courses in the absence of disease progression or unacceptable toxicity. Courses of bevacizumab, leucovorin calcium, and fluorouracil repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.
Drug: Atezolizumab
Given IV
Other Names:
  • MPDL 3280A
  • MPDL 328OA
  • MPDL-3280A
  • MPDL3280A
  • MPDL328OA
  • RG7446
  • RO5541267
  • Tecentriq

Biological: Bevacizumab
Given IV
Other Names:
  • Anti-VEGF
  • Anti-VEGF Humanized Monoclonal Antibody
  • Anti-VEGF rhuMAb
  • Avastin
  • Bevacizumab Biosimilar BEVZ92
  • Bevacizumab Biosimilar BI 695502
  • Bevacizumab Biosimilar CBT 124
  • Bevacizumab Biosimilar FKB238
  • Bevacizumab Biosimilar MIL60
  • Bevacizumab Biosimilar QL 1101
  • BEVACIZUMAB, LICENSE HOLDER UNSPECIFIED
  • 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
  • Recombinant Humanized Anti-VEGF Monoclonal Antibody
  • rhuMab-VEGF

Drug: Fluorouracil
Given IV
Other Names:
  • 5-Fluoro-2,4(1H, 3H)-pyrimidinedione
  • 5-Fluorouracil
  • 5-Fluracil
  • 5-FU
  • AccuSite
  • Carac
  • Fluoro Uracil
  • Fluouracil
  • Flurablastin
  • Fluracedyl
  • Fluracil
  • Fluril
  • Fluroblastin
  • Ribofluor
  • Ro 2-9757
  • Ro-2-9757

Drug: Leucovorin Calcium
Given IV
Other Names:
  • Adinepar
  • Calcifolin
  • Calcium (6S)-Folinate
  • Calcium Folinate
  • Calcium Leucovorin
  • Calfolex
  • Calinat
  • Cehafolin
  • Citofolin
  • Citrec
  • citrovorum factor
  • Cromatonbic Folinico
  • Dalisol
  • Disintox
  • Divical
  • Ecofol
  • Emovis
  • Factor, Citrovorum
  • Flynoken A
  • Folaren
  • Folaxin
  • FOLI-cell
  • Foliben
  • Folidan
  • Folidar
  • Folinac
  • Folinate Calcium
  • folinic acid
  • Folinic Acid Calcium Salt Pentahydrate
  • Folinoral
  • Folinvit
  • Foliplus
  • Folix
  • Imo
  • Lederfolat
  • Lederfolin
  • Leucosar
  • leucovorin
  • Rescufolin
  • Rescuvolin
  • Tonofolin
  • Wellcovorin

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

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies




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 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.


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. 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]) assessed by Response Evaluation Criteria in Solid Tumors (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.

  3. Incidence of adverse events as defined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [ Time Frame: Up to 30 days after last course ]
  4. 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.

  5. Disease control rate (CR + PR + stable disease [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.

  6. 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.

  7. PFS [ Time Frame: From randomization until first progression by retrospective central independent scan review or death from any cause, assessed up to 5 years ]

Other Outcome Measures:
  1. 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.

  2. Physical functioning, as measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life questionnaire (QLQ)-C30 physical functioning scale [ 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.

  3. Severity and frequency of quality of life (QOL) and patient-reported outcomes (PRO) assessed using the PROMIS fatigue, EORTC QLQ-C30, and PRO-CTCAE measures [ 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 the significance level of 0.05 (two-sided) and the clinical meaningfulness of the comparison will be considered.

  4. Health utility scores [ Time Frame: Up to 5 years ]
    Will be measured using the EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire.

  5. 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 ]
  6. Intratumoral lymphocyte PD-L1+ expression (>= 1 % is positive) by immunohistochemistry (IHC) as a predictive biomarker of efficacy [ Time Frame: Up to 5 years ]
  7. Efficacy dependent on the number of somatic mutations [ Time Frame: Up to 5 years ]
  8. Efficacy in tumors with MLH1 silencing [ Time Frame: Up to 5 years ]
  9. Change in quantification of cell free deoxyribonucleic acid (cfDNA) mutations [ Time Frame: Baseline up to 5 years ]
  10. Development of progression or relapse to treatment in cfDNA [ Time Frame: Up to 5 years ]
  11. Changes in T-cell repertoire diversity as a predictive biomarker of efficacy [ Time Frame: Baseline up to 5 years ]
  12. PFS of patients with high levels of diversity [ Time Frame: Up to 5 years ]
    Compared to patients with low levels of diversity.

  13. Change in T-cell diversity [ Time Frame: Baseline to first restaging between immunotherapy arms and the standard of care arm ]
  14. Mechanism of immune resistance to PD-1 blockade in mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) by comparative analysis of tumor samples collected [ Time Frame: Baseline up to 5 years ]


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.


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
  • 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
  • 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; Note: microsatellite instability high (MSI-H) diagnosed by microsatellite instability (MSI) testing (either Bethesda markers or Pentaplex panel) or by next-generation sequencing (NGS) is not eligible unless dMMR is confirmed by CLIA-certified immunohistochemical (IHC) assay with a panel of all four IHC markers including MLH1, MSH2, PMS2 and MSH6
  • An adequate amount of archived tumor tissue, either from primary colorectal cancer site or metastatic lesions, for central confirmation of dMMR status:

    • Either whole or part of the formalin-fixed paraffin-embedded (FFPE) block containing tumor tissue; or
    • At least 9 unstained slides containing tumor sections
  • Documentation by positron emission tomography(PET)/computed tomography (CT) scan, CT scan, or magnetic resonance imaging (MRI) that the patient has untreated 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 =< 1.5 x ULN (upper limit of normal) for the lab unless the patient has a bilirubin elevation > 1.5 x ULN to 3 x ULN due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin (obtained within 28 days prior randomization); and
  • Alkaline phosphatase must be =< 2.5 x ULN for the lab with the following exception: patients with documented liver metastases or bone involvement - alkaline phosphatase must be =< 5 x ULN (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)
  • Serum creatinine =< 1.5 x ULN for the lab or measured or calculated creatinine clearance >= 30 mL/min (obtained within 28 days prior randomization)
  • A urine sample tested for proteinuria by the dipstick method must indicate 0 -1+ protein; if dipstick reading is >= 2+, a 24-hour urine specimen must demonstrate < 1.0 g of protein per 24 hours
  • 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
  • Pregnancy test done within 14 days prior randomization must be negative (for women of childbearing potential only); pregnancy testing should be performed according to institutional standards; 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 must agree to use adequate contraception (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; men with female partners of child-bearing potential must agree to use adequate contraception prior to the study, for the duration of study participation, and for 6 months after the last dose of bevacizumab and 6 months after the last dose of mFOLFOX6

Exclusion Criteria:

  • Patients with central nervous system (CNS) metastases are excluded, with the following exceptions:

    • Patients with asymptomatic untreated CNS metastases may be enrolled, provided all eligibility criteria are met, as well as the following:

      • Evaluable or measurable disease outside the CNS
      • No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm)
      • No history of intracranial hemorrhage or spinal cord hemorrhage
      • No ongoing requirement for dexamethasone for CNS disease; patients on a stable dose of anticonvulsants are permitted.
      • No neurosurgical resection or brain biopsy within 28 days prior to randomization
    • Patients with asymptomatic treated CNS metastases may be enrolled, provided all eligibility criteria are met, as well as the following:

      • Radiographic demonstration of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study
      • No stereotactic radiation or whole-brain radiation within 28 days prior to randomization
      • Screening CNS radiographic study >= 28 days from completion of radiotherapy and >= 14 days from discontinuation of corticosteroids
  • 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 90 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
  • Any of the following cardiac conditions:

    • Documented New York Heart Association (NYHA) class III or IV congestive heart failure
    • Myocardial infarction within 6 months prior to randomization
    • Unstable angina within 6 months prior to randomization
    • Symptomatic arrhythmia
  • Serious or non-healing wound, skin ulcer, or bone fracture
  • History of transient ischemic attack (TIA), cerebrovascular accident (CVA), gastrointestinal (GI) perforation or arterial thrombotic event within 6 months prior to randomization or symptomatic peripheral ischemia
  • 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) in patients with no prior oxaliplatin therapy
  • Prior treatment with oxaliplatin chemotherapy within 6 months prior to randomization
  • 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
  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events (other than alopecia) due to agents administered more than 4 weeks earlier are excluded; however, the following therapies are allowed:

    • Hormone-replacement therapy or oral contraception
    • Herbal therapy > 7 days prior to randomization (herbal therapy intended as anticancer therapy must be discontinued at least 1 week prior to randomization)
    • Palliative radiotherapy for bone metastases > 14 days prior to randomization
  • Treatment with systemic immunostimulatory medications (including, but not limited to interferon [IFN]-alpha or interleukin [IL]-2 within 42 days prior to randomization
  • 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
  • Patients taking bisphosphonate therapy for symptomatic hypercalcemia; use of bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is allowed
  • Patients requiring treatment with a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor (e.g., denosumab) who cannot discontinue it before treatment with atezolizumab
  • Treatment with any other investigational agent within 4 weeks prior to randomization
  • 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
    • Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)
  • 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, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan; 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
  • Administration of a live, attenuated vaccine within 28 days prior to randomization or anticipation that such a live, attenuated vaccine will be required during the study and up to 5 months after the last dose of atezolizumab; Note: influenza vaccination should be given during influenza season only (approximately October to March); patients must not receive live, attenuated influenza vaccine within 28 days prior to randomization or at any time during the study
  • Psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with atezolizumab; (Note: pregnancy testing should be performed within 14 days prior to randomization according to institutional standards for women of childbearing potential)
  • Patients positive for human immunodeficiency virus (HIV) are NOT excluded from this study, but HIV-positive patients must have:

    • A stable regimen of highly active anti-retroviral therapy (HAART); and
    • No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections; and
    • A CD4 count above 250 cells/uL and an undetectable HIV viral load on standard PCR-based tests
  • Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation

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


  Show 262 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: James Lee NRG Oncology

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02997228     History of Changes
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: December 11, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Colorectal Neoplasms
Colonic Neoplasms
Adenocarcinoma
Brain Neoplasms
Neoplastic Syndromes, Hereditary
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Central Nervous System Neoplasms
Nervous System Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Bevacizumab
Oxaliplatin
Atezolizumab
Fluorouracil
Leucovorin
Folic Acid