Panitumumab, Nivolumab, and Ipilimumab in Treating Patients with KRAS, NRAS, or BRAF Wild-Type MSS Refractory Metastatic Colorectal Cancer That Cannot Be Removed by Surgery

Inclusion Criteria

• Histologically or cytologically confirmed colorectal adenocarcinoma, with unresectable metastatic or locally advanced disease documented on diagnostic imaging studies
• Previously received 1-2 prior lines of therapy; subjects who relapse within 6 months of adjuvant chemotherapy comprised of oxaliplatin and a fluoropyrimidine will have their adjuvant therapy count as one prior line of therapy
• Confirmed wild-type in KRAS and NRAS codons 12, 13, 59, 61, 117, and 146; and BRAF codon 600, by standard of care testing of tumor specimen; tissue used for testing may have been collected from primary or metastatic site
• Microsatellite stable as detected by polymerase chain reaction (PCR)-based assay OR Clinical Laboratory Improvement Act (CLIA)-certified sequencing methodology such as Foundation One; OR mismatch repair proficient as detected by immunohistochemistry showing intact nuclear staining of MLH1, MSH2, MSH6, and PMS2
• Radiographically measurable disease present per RECIST 1.1
• Age >= 18 years at the time of consent
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Absolute neutrophil count >= 1,500/mm^3, performed within 3 weeks prior to starting study therapy * Note: hematology and other lab parameters that are =< grade 2 BUT still meet criteria for study entry are allowed; furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Platelets >= 100,000/mm^3, performed within 3 weeks prior to starting study therapy * Note: hematology and other lab parameters that are =< grade 2 BUT still meet criteria for study entry are allowed; furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Hemoglobin >= 9 g/dL, performed within 3 weeks prior to starting study therapy * Note: hematology and other lab parameters that are =< grade 2 BUT still meet criteria for study entry are allowed; furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Total bilirubin =< 1.5 x upper limit of normal (ULN), performed within 3 weeks prior to starting study therapy
• Alanine aminotransferase and aspartate aminotransferase =< 3 x ULN, performed within 3 weeks prior to starting study therapy
• Albumin >= 2.5 g/dL, performed within 3 weeks prior to starting study therapy
• Serum creatinine performed within 3 weeks prior to starting study therapy must be =< 1.5 x ULN, or have calculated creatinine clearance (using Cockcroft-Gault formula) of >= 50 mL/minute
• Females of childbearing potential must have a negative serum pregnancy test within 24 hours prior to receiving the first dose of study medication; females of childbearing potential must agree to use 2 methods of effective contraception or abstain from heterosexual sex throughout the treatment period and for 5 months after the last dose of study treatment; females of childbearing potential are women who have not been surgically sterilized (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or have not been free of menses for > 1 year
• Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 6 months after the last dose of study treatment
• Written informed consent and Response Evaluation Criteria in Solid Tumors (HIPAA) authorization for release of personal health information * NOTE: HIPAA authorization may be included in the informed consent or obtained separately
• An adequate amount of archival tumor tissue must be available at baseline to be eligible for enrollment in the study; if archival tissue is not available or is inadequate, then the subject must consent to undergo a mandatory biopsy at baseline in order to participate in the study

Exclusion Criteria

• Past treatment with an antibody targeting EGFR including cetuximab or panitumumab
• Past treatment with an antibody targeting immune checkpoints including CTLA-4, PD-1, PD-L1, PD-L2, or CD137
• Known untreated brain metastasis or brain metastasis treated within 3 months prior to enrollment in this trial
• Has evidence of interstitial lung disease or active, non-infectious pneumonitis
• Has a known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years
• Treatment within 21 days of the first dose of study drug with any other chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment for the treatment of malignancy, or failure to recover from adverse effects of prior therapies administered over 4 weeks prior to study day 1; all toxicities from prior therapies must be =< grade 1 (or =< grade 2 for alopecia or peripheral neuropathy); prior systemic treatment in the adjuvant setting is allowed
• Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject’s safety, obtaining informed consent, or compliance to the study procedures
• Pregnant, or planning to become pregnant within 6 months after the end of treatment; (NOTE: breast feeding and storage of breast milk is not allowed while mother is being treated, and for up to 5 months after stopping nivolumab, 2 months after stopping panitumumab and/or ipilimumab)
• History of organ allograft or other history of immunodeficiency, or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before the first dose of investigational treatment
• Inability or unwillingness to comply with study and/or follow-up requirements
• Any major surgery, extensive radiotherapy, chemotherapy with clinically significant delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to randomization and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to randomization
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug
• Known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection; subjects with laboratory evidence of cleared HBV and HCV infection will be permitted
• Active autoimmune disease requiring systemic treatment in the past 3 months (for example with disease modifying agents, corticosteroids, or immunosuppressive drugs); replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators, local steroid injections, or inhaled or topical steroids 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
• Active infection requiring intravenous systemic therapy