Temozolomide, Cisplatin, and Nivolumab in People With Colorectal Cancer

Inclusion Criteria:

• Subject or legally authorized representative is willing and able to provide writteninformed consent/assent for the trial.

• Histologically- or cytologically- confirmed colorectal adenocarcinoma.

• Locally advanced unresectable or metastatic CRC.

• Undergone testing for MSI/dMMR and determined to be MSS or MMR proficient.

• Undergone testing for BRAF and POLE and determined to be wild type.

• Subjects must be refractory to, or intolerant of, at least 2 lines of standardchemotherapy, according to NCCN guidelines for patients eligible for intensivetherapy, or have received prior FOLFOXIRI. Patients are considered refractory ifprogressed within 3 months of last dose, or within 6 months of completing adjuvantFOLFOX/CAPEOX. At a minimum, such therapies should include oxaliplatin, irinotecanand a fluoropyrimidine.

• At least one index lesion which is measurable based on RECIST 1.1.

• Be ≥ 18 years of age on day of signing informed consent.

• Consent for use of archival tissue and blood draws for research purposes.

• Have an ECOG performance status of 0 or 1.

• Demonstrate adequate organ function as defined in Table 6.1, all screening labsshould be performed within 28 days of treatment initiation.

• Adequate organ function, defined as:

• Absolute Neutrophil Count ≥ 1,500/mcL.

• Platelet count ≥ 100,000/mcL.

• Serum creatinine ≤ 1.5 x ULN or CrCl ≥60 mL/min for subjects with creatininelevels >1.5 ULN.

• WBC ≥ 2000/μL

• Hemoglobin ≥ 9.0 g/dL

• AST and ALT ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with liver metastases.

• Bilirubin ≤ 1.5 × ULN or Direct bilirubin ≤ ULN for subjects with bilirubinlevels >1.5

• INR/PT and PTT ≤1.5 X ULN unless on anticoagulant therapy and PT/PTT withintherapeutic range.

aCreatinine clearance should be calculated per institutional standard.

• Adequate method of contraception.

Exclusion Criteria:

• Subject is currently participating in or has participated in a study of aninvestigational agent or using an investigational device within 4 weeks of the firstdose of treatment.

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (>10mg/day prednisone, or equivalent) or any other form of immunosuppressive therapywithin 7 days prior to the first dose of trial treatment. Inhaled or topicalsteroids are permitted in the absence of active autoimmune disease

• Prior chemotherapy, targeted small molecule therapy, or biological therapy, within 2weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline)from adverse events due to a previously administered agent (exc. alopecia).

• If subject received major surgery, they must have recovered adequately prior tostarting therapy.

• Has a known additional malignancy that is progressing or requires active treatment.

• Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of theskin, or in situ cervical cancer that has undergone potentially curative therapy.

• Has known active central nervous system (CNS) metastases and/or carcinomatousmeningitis. Subjects with previously treated brain metastases may participateprovided they are stable (without evidence of progression by imaging for at leastfour weeks prior to the first dose of trial treatment and any neurologic symptomshave returned to baseline), have no evidence of new or enlarging brain metastases,and are not using steroids for at least 7 days prior to trial treatment.

• Has an active, known or suspected autoimmune disease requiring systemic treatmentwithin the past 3 months or a documented history of clinically severe autoimmunedisease, or a syndrome that requires systemic steroids or immunosuppressive agents.Subjects with vitiligo or resolved childhood asthma/atopy, type 1 diabetes mellitusare permitted. Subjects that require intermittent use of bronchodilators or localsteroid injections would not be excluded from the study. Subjects withhypothyroidism stable on hormone replacement or Sjogren's syndrome will not beexcluded from the study.

• Has an active infection requiring systemic therapy

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the trial, interfere with thesubject's participation for the full duration of the trial, or it is not in the bestinterest of the subject to participate, in the opinion of the treating investigator.

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

• Is pregnant or breastfeeding, or expecting to conceive or father children within theprojected duration of the trial, starting with the pre-screening or screening visitthrough 5 months for females, 7 months for males after the last dose of trialtreatment.

• Prior anti-PD-1, anti-PDL-1, anti-PDL-2, anti-Cytotoxic T-lymphocyte-associatedantigen-4 (CTLA-4) antibody or any other antibody or drug specifically targetingT-cell co-stimulation or checkpoint pathways.

• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

• Has received a live vaccine within 30 days prior to the first dose of trialtreatment.

• Subject is a prisoners, or compulsory detained