Temozolomide, Cisplatin, and Nivolumab for the Treatment of Patients with MMR-Proficient Locally Advanced, Unresectable or Metastatic Colorectal Cancer

Inclusion Criteria

• Subject or legally authorized representative is willing and able to provide written informed consent/assent for the trial
• Histologically- or cytologically- confirmed colorectal adenocarcinoma
• Locally advanced unresectable or metastatic CRC
• Undergone testing for microsatellite instability (MSI)/mismatch repair protein deficiency (dMMR) and determined to be microsatellite stable (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 standard chemotherapy, according to National Comprehensive Cancer Network (NCCN) guidelines for patients eligible for intensive therapy, or have received prior fluorouracil, leucovorin, oxaliplatin and irinotecan (FOLFOXIRI). Patients are considered refractory if progressed within 3 months of last dose, or within 6 months of completing adjuvant FOLFOX/capecitabine-oxaliplatin (CAPEOX). At a minimum, such therapies should include oxaliplatin, irinotecan and 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 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Absolute neutrophil count (ANC) > =1,500 /mcL (performed within 28 days of treatment initiation)
• Platelets >= 100,000/mcL (performed within 28 days of treatment initiation)
• White blood cells (WBC) >= 2000/uL (performed within 28 days of treatment initiation)
• Hemoglobin >= 9.0 g/dL (performed within 28 days of treatment initiation)
• Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (performed within 28 days of treatment initiation) * Creatinine clearance should be calculated per institutional standard
• Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (performed within 28 days of treatment initiation)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (performed within 28 days of treatment initiation)
• International normalized ratio (INR) or prothrombin time (PT) =<1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (performed within 28 days of treatment initiation)
• Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (performed within 28 days of treatment initiation)
• Female subject of childbearing potential should have a negative serum pregnancy within 28 days prior to starting treatment
• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 5 months after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 7 months after the last dose of study therapy. In addition, male subjects must be willing to refrain from sperm donation during this time

Exclusion Criteria

• Subject is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (> 10 mg/day prednisone, or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Inhaled or topical steroids are permitted in the absence of active autoimmune disease
• Prior chemotherapy, targeted small molecule therapy, or biological therapy, within 2 weeks 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 (exception [exc.] alopecia)
• If subject received major surgery, they must have recovered adequately prior to starting 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 the skin, or in situ cervical cancer that has undergone potentially curative therapy
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have 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 treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy, type 1 diabetes mellitus are permitted. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjogren’s syndrome will not be excluded from the study
• Has evidence of known interstitial lung disease or active, non-infectious pneumonitis
• Has an active infection requiring systemic therapy
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or it is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 5 months for females, 7 months for males after the last dose of trial treatment
• Prior anti-PD-1, anti-PDL-1, anti-PDL-2, anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody or any other antibody or drug specifically targeting T-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., hepatitis B surface antigen [HBsAg] reactive) or Hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Has received a live vaccine within 30 days prior to the first dose of trial treatment
• Subject is a prisoners, or compulsory detained