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

Description
Phase 3 mFOLFOX6/Bevacizumab, and/or Atezolizumab in treating patients with dMMR MCRC

Objective

The purpose of this study is to learn if adding an experimental drug, atezolizumab (MPDL3280A), to a usual treatment or giving the experimental drug alone is better than the usual treatment alone. The usual treatment in this study is the chemotherapy drugs,
5-flouorouracil (5-FU), leucovorin, and oxaliplatin. This combination is called FOLFOX. In addition to FOLFOX, bevacizumab will be given. Bevacizumab is in a group of drugs called biologic therapy. FOLFOX and bevacizumab are approved by the FDA to treat metastatic CRC.
To be better than FOLFOX and bevacizumab, atezolizumab given with FOLFOX and bevacizumab or atezolizumab given alone should keep your cancer from growing for more than 7 months

Another purpose of this study is to test the good and bad effects of atezolizumab when added to the usual treatment and when given alone. Atezolizumab may keep your cancer from growing but it can also cause side effects. Atezolizumab is FDA-approved for treating metastatic cancers of the bladder and lung. Atezolizumab is considered experimental in this study because it is not approved to treat metastatic CRC

Treatment This study has three study groups:

Group 1 will get FOLFOX and bevacizumab.

Group 2 will get atezolizumab alone.

Group 3 will receive FOLFOX and bevacizumab plus atezolizumab

Key Eligibility
Must be 18 years of age or greater

ECOG Performance status of 0-2

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 CLIA-certified immunohistochemical (IHC) assay with a panel of all four IHC markers, including MLH1,
MSH2, PMS2, and MSH6. Note: MSI-H diagnosed by 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 FFPE block containing tumor tissue; or at least 9 unstained slides containing tumor sections

Documentation by PET/CT scan, CT scan, or MRI that the patient has untreated measurable metastatic disease per RECIST 1.1

Adequate hematologic, hepatic and renal function

Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence)

Men with female partners of child-bearing potential must agree to use adequate contraception

EXCLUSION

Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies, fluoropyrimidines, folic acid derivatives or oxaliplatin

Uncontrolled high blood pressure

Any of the following cardiac conditions: Documented 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

Known DPD (dihydro pyrimidine dehydrogenase) deficiency

Symptomatic peripheral sensory neuropathy ≥ grade 2 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 effect from antiCTLA-4

Pt's taking bisphosphonate therapy for symptomatic hypercalcemia

Patients requiring treatment with a RANKL inhibitor (e.g., denosumab) who cannot discontinue it before treatment with atezolizumab

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

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, Sjögren s syndrome, Bell s palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or
glomerulonephritis

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

Patients positive for human immunodeficiency virus are NOT excluded from this study, but HIV-positive pt's must have: stable regimen of highly active anti-retroviral therapy, and
No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections; CD4 count above 250 cells/µL and an undetectable HIV viral load on standard PCR tests

Applicable Disease Sites
Colon and Rectum

Participating Institutions
Bellin Memorial Hospital/Cancer Team at Bellin Health; DN Greenwald Center; Mercy Health Systems, Janesville ; Oconomowoc Memorial Hospital, Waukesha Memorial; UW Cancer Center at ProHealth; UW Health 1 S. Park Medical Center; UW Health Eastpark Medical Center; UW Health University Hospital; Waukesha Memorial Hosp