Nivolumab, Ipilimumab, and Radiation Therapy in Treating Patients with Colorectal or Pancreatic Cancer

Inclusion Criteria

• Participants must have histologically or cytologically confirmed adenocarcinoma of colorectal or pancreatic origin
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 for MSS participants or =< 2 for microsatellite instability (MSI) participants
• Life expectancy of greater than 3 months
• Absolute neutrophil count (ANC) >= 1000/mcL, performed within 21 days of protocol registration
• White blood count (WBC) >= 2000/mcL, performed within 21 days of protocol registration
• Platelets >= 75,000/mcL, performed within 21 days of protocol registration
• Hemoglobin >= 7.5 g/dL, performed within 21 days of protocol registration
• Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]); serum creatinine =< 1.5 x upper limit of normal (ULN) or creatinine clearance >= 40 mL/min (if using Cockcroft-Gault formula), performed within 21 days of protocol registration
• Serum total bilirubin =< 1.5 x ULN (subjects with Gilbert syndrome can have a total bilirubin < 3 mg/dL), performed within 21 days of protocol registration
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 X ULN OR =< 5 X ULN for subjects with liver metastases, performed within 21 days of protocol registration
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT is within therapeutic range of intended use of anticoagulants, performed within 21 days of protocol registration
• Activated partial thromboplastin time (aPTT) =< 2.5 X ULN unless subject is receiving anticoagulant therapy as long as PTT is within therapeutic range of intended use of anticoagulants, performed within 21 days of protocol registration
• Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception; WOCBP should use an adequate method to avoid pregnancy for 5 months (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug
• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG])
• Women must not be breastfeeding
• Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year; men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product; women who are not of childbearing potential, i.e., who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception
• Ability to understand and the willingness to sign a written informed consent document
• If applicable, stable dose of dexamethasone 2 mg or less for 7 days prior to initiation of treatment
• One previously unirradiated lesion amenable to radiotherapy 8 Gy x 3 and can meet dose constraints, and another unirradiated measurable lesion >= 1 cm in size outside the radiation field that can be used as measurable disease
• Colorectal patients must have documentation of microsatellite status; immunohistochemistry (IHC) is acceptable
• Moving forward after activation of AM17, previous combination chemotherapy is not required for MSI-H colorectal patients based on KeyNote 177. Additionally, after activation of AM17, MSI-H colorectal patients are required to have had previous PD-1 or PDL1 therapy
• Pancreas patients must have progressed on at least 1 prior line of chemotherapy

Exclusion Criteria

• Participants who have had chemotherapy, targeted small molecule therapy or study therapy within 14 days of protocol treatment, or those who have not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 2 weeks earlier; if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy; the following are considered exceptions to this criteria: subjects with < grade 2 lymphocyte count decrease, subjects with < grade 2 neuropathy, or subjects with < grade 2 fatigue
• Participants who are receiving any other investigational agents
• Patients are excluded if they have an active, known or suspected autoimmune disease other than those listed below; subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
• Patients are excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses less than 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; subjects are permitted to use topical, ocular, intraarticular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
• Colorectal patients are excluded if they have had prior systemic treatment with an anti-CTLA4 antibody. MSS colorectal patients are excluded if they have had prior systemic treatment with anti-PD1 or PDL1 antibody. Prior PD-1 or PDL1 therapy will be mandated for MSI-H colorectal patients; pancreatic patients are excluded if they have previously received anti-CTLA-4 therapy; prior PD-1 or PDL1 therapy will be permitted for pancreas patients
• Has a known history of active TB (Bacillus tuberculosis)
• Known hepatitis B virus (HBV) or hepatitis B virus (HCV) (patients are excluded if they are positive test for hepatitis B virus surface antigen [HBV sAg] or hepatitis C virus ribonucleic acid [HCV antibody] indicating acute or chronic infection)
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• 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 woman and 7 months for men, after the last dose of trial treatment
• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
• Has known history of, or any evidence of active, non-infectious pneumonitis
• Has an active infection requiring systemic therapy
• Has received a live vaccine within 30 days of planned start of study therapy; Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
• History of allergy to study drug components
• History of severe hypersensitivity reaction to any monoclonal antibody
• Uncontrolled brain metastases; patients treated with radiation >= 4 weeks prior with follow up imaging showing control are eligible