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

Inclusion Criteria:

• The patient must have signed and dated an Institutional Review Board (IRB)-approvedconsent 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 previouschemotherapy or any other systemic therapy for metastatic colorectal cancer exceptfor one cycle of FOLFOX or capecitabine and oxaliplatin (CAPOX), either with orwithout bevacizumab prior to enrollment. Upon enrollment, the preceding single cycleof FOLFOX or FOLFOX + bevacizumab, if the patient received one, will not counttowards patients' assessments per protocol. Cycle 1 day 1 (C1D1) of atezolizumab orC1D1 of mFOLFOX6/bevacizumab + atezolizumab will correspond to the first day thepatient received therapy on trial

• Tumor determined to be mismatch-repair deficient (dMMR) by Clinical LaboratoryImprovement Act (CLIA)-certified immunohistochemical (IHC) assay with a panel of allfour IHC markers, including MLH1, MSH2, PMS2, and MSH6; alternatively, MSI-Hdiagnosed by polymerase chain reaction (PCR)-based assessment of microsatellitealterations (either Bethesda markers or Pentaplex panel) or by next-generationsequencing (NGS) are eligible

• Documentation by PET/CT scan, CT scan, or MRI that the patient has measurablemetastatic disease per RECIST 1.1

• No immediate need for surgical intervention for the primary tumor or palliativediversion/bypass

• Absolute neutrophil count (ANC) must be >= 1500/mm^3 (obtained within 28 days priorrandomization)

• 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 daysprior randomization); and

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be =< 3 xULN for the lab with the following exception: for patients with documented livermetastases, AST and ALT must be =< 5 x ULN (obtained within 28 days priorrandomization)

• Calculated creatinine clearance >= 30 mL/min (obtained within 28 days priorrandomization)

• 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 24hours 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 urinemust be done and it must demonstrate < 1.0 g of protein per 24 hours or a UPCratio < 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 whoare therapeutically treated with an agent such as warfarin may participate if theyare on a stable dose and no underlying abnormality in coagulation parameters existsper medical history, regardless of PT/INR results

• Pregnancy test done within 28 days prior randomization must be negative (for womenof childbearing potential only); pregnancy testing should be performed according toinstitutional standards; administration of atezolizumab ormFOLFOX6/bevacizumab/atezolizumab may have an adverse effect on pregnancy and posesa risk to the human fetus, including embryo-lethality; should a woman becomepregnant or suspect she is pregnant while she or her partner is participating inthis study, she should inform her treating physician immediately

• Women of child-bearing potential and men must agree to use adequate contraceptionmethods 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, forthe duration of study participation, and for 5 months (150 days) after the last doseof atezolizumab, 6 months after the last dose of bevacizumab, and 6 months after thelast dose of mFOLFOX6; a woman is considered to be of childbearing potential if sheis not postmenopausal, has not reached a postmenopausal state (>= 12 continuousmonths of amenorrhea with no identified cause other than menopause), and has notundergone surgical sterilization (removal of ovaries and/or uterus); examples ofcontraceptive methods with a failure rate of < 1% per year include: bilateral tuballigation; male partner sterilization; intrauterine devices; the reliability ofsexual abstinence should be evaluated in relation to the duration of the clinicalstudy and the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawalare not acceptable methods of contraception; men must refrain from donating spermduring this same period

Exclusion Criteria:

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

• Uncontrolled high blood pressure defined as systolic blood pressure (BP) > 150 mmHgor diastolic BP > 100 mmHg with or without anti-hypertensive medication; patientswith initial BP elevations are eligible if initiation or adjustment of BP medicationlowers pressure to meet entry criteria

• Documented New York Heart Association (NYHA) class III or IV congestive heartfailure

• 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 orrecent arterial thrombosis or symptomatic peripheral ischemia, transient ischemicattack [TIA], cerebrovascular accident [CVA] or arterial thrombotic event),abdominal fistula, intra-abdominal abscess, or active GI bleeding (with cause notaddressed) within 6 months prior to randomization, or other medical condition in theopinion of the treating oncologist that makes the risk of cardiovascular or bleedingcomplications with bevacizumab use unacceptably high

• Other malignancies are excluded unless the patient has completed therapy for themalignancy >= 12 months prior to randomization and is considered disease-free;patients with the following cancers are eligible if diagnosed and treated within thepast 12 months: in situ carcinomas or basal cell and squamous cell carcinoma of theskin

• Known DPD (dihydro pyrimidine dehydrogenase) deficiency

• Symptomatic peripheral sensory neuropathy >= grade 2 (Common Terminology Criteriafor 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 orpathway-targeting agents; patients who have received prior treatment withanti-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 thelast dose to randomization

• No history of severe immune-related adverse effects (CTCAE grade 3 and 4) fromanti-CTLA-4

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

• Patients who have received acute, low dose, systemic immunosuppressantmedications (e.g., a one-time dose of dexamethasone for nausea; or chronicdaily treatment with corticosteroids with a dose of =< 10 mg/daymethylprednisolone equivalent) may be enrolled

• The use of inhaled corticosteroids and mineralocorticoids (e.g.,fludrocortisone) for patients with orthostatic hypotension or adrenocorticalinsufficiency is allowed

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

• Patients with past or resolved hepatitis B infection (defined as having anegative hepatitis B surface antigen [HbsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible ifpolymerase 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 ifpolymerase chain reaction (PCR) is negative for HCV RNA per local guidelines

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

• Patients with a history of autoimmune hypothyroidism on a stable dose ofthyroid replacement hormone may be eligible

• Patients with controlled type 1 diabetes mellitus on a stable insulin regimenmay be eligible

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

• Patients with psoriasis must have a baseline ophthalmologic exam to ruleout ocular manifestations

• Rash must cover less than 10% of body surface area (BSA)

• Disease is well controlled at baseline and only requiring low potencytopical 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 ororal steroids)

• History of idiopathic pulmonary fibrosis, organizing pneumonia (i.e., bronchiolitisobliterans, cryptogenic organizing pneumonia, etc.), or active or recently active (within 90 days of randomization) pneumonitis (including drug induced) that requiredsystemic immunosuppressive therapy (i.e. corticosteroids, etc.). History ofradiation pneumonitis in the radiation field (fibrosis) is permitted

• History of severe allergic, anaphylactic, or other hypersensitivity reactions tochimeric 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 limitedto, 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 tractinfection or chronic obstructive pulmonary disease) are eligible

• Major surgical procedure, open biopsy, or significant traumatic injury within 28days prior to randomization or anticipation of need for a major surgical procedureduring the course of the study

• The administration of a live, attenuated vaccine within 28 days prior torandomization

• Pregnant women are excluded from this study because atezolizumab is an agent withthe potential for teratogenic or abortifacient effects; because there is an unknownbut potential risk for adverse events in nursing infants secondary to treatment ofthe mother with atezolizumab, breastfeeding should be discontinued if the mother istreated with atezolizumab; these potential risks may also apply to other agents usedin this study; (Note: pregnancy testing should be performed within 28 days prior torandomization according to institutional standards for women of childbearingpotential)

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• Patients with prior allogeneic bone marrow transplantation or prior solid organtransplantation