Neoadjuvant Dupilumab and Toripalimab in MSS CRC Subjects With Resectable Liver Metastases

INCLUSION CRITERIA: Histological diagnosis of non-MSI-H/pMMR CRC • Subjects who have biology-proven non-MSI-H/pMMR CRC and with radiographic findings suggestive of liver metastases may be eligible. Resectable liver metastases including: * synchronous liver metastases (present at the time of diagnosis of MSS CRC) and treatment-naïve * metachronous liver metastasis (developed after resection of the primary tumor) without prior adjuvant chemotherapy * metachronous liver metastasis (developed after resection of the primary tumor) with adjuvant chemotherapy completed greater than 3 months from the time of consent. Surgical candidate for resection Age ≥ 18 years. Rationale: Because no dosing or adverse event data are currently available on the use of dupilumab in combination with toripalimab in subjects \<18 years of age, children are excluded from this study. ECOG Performance Status 0-1 (Karnofsky ≥60%,) • Subjects with performance status \>1 carrying long-term disability (such as cerebral palsy) where the disability is not acute nor progressive, and unlikely to significantly affect their response to therapy may be enrolled at the investigator's discretion Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception upon study entry, for the duration of study participation, and for 3 months following completion of therapy. * A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: * Has not undergone a hysterectomy or bilateral oophorectomy; or * Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). Ability to understand and the willingness to sign a written informed consent. Legally authorized representatives may sign and give informed consent on behalf of study participants. Adequate organ and marrow function as defined: * Hematologic o Absolute neutrophil count (ANC) ≥1,000 /mcL * Platelets ≥75,000 /mcL * Hemoglobin ≥8 g/dL * Renal\* o Serum creatinine ≤1.5 X upper limit of normal (ULN) OR Measured or calculated (Creatinine clearance should be calculated per institutional standard) creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥45 mL/min for subjects with creatinine levels \> 1.5 X institutional ULN * Hepatic\* o Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN; ≤ 3 X ULN for subjects with liver metastases o AST ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases * ALT ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases * Albumin \>2.5 mg/dL * Coagulation\* * 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 * Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PTT is within therapeutic range of intended use of anticoagulants \* If laboratory criteria are not met due to what the investigator determines to be a biologic cause (e.g. Gilbert's syndrome causing elevated bilirubin or excessive muscle mass affecting creatinine) or drug-related cause (e.g. elevating in transaminases due to HAART therapy, elevated INR due to anticoagulation) then the lab values will not be used to exclude subject from this trial. This determination will be made by PI. EXCLUSION CRITERIA: History of autoimmune disorder with the following exceptions: * Vitiligo, alopecia, psoriasis or any chronic skin condition that does not require systemic therapy * Hypothyroidism (e.g. following autoimmune thyroiditis) stable on thyroid replacement * Celiac disease controlled by diet alone Treatment, for any reason, with an immunomodulatory drug, within 8 weeks from time of consent. Prior treatment with dupilumab within the last 8 weeks. Prior treatment with chemotherapy for MSS CRC or locoregional therapy to the target lesion (that will be biopsied and subsequently resected) within 3 months prior to entering the study. • Previous therapy for a different cancer (a different primary) is acceptable. Use of investigational agents for treatment of cancer. Subjects with extrahepatic metastases that are not amendable to resectable or locoregional therapy, for whom the intent of surgery would not be curative. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring antibiotics (exception is a brief (≤10 days) course of antibiotics to be completed before initiation of treatment), symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements, as determined the treating investigator. Pregnant or nursing women due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants. • Breastfeeding should be discontinued prior to study enrollment. Has a diagnosis of primary immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. • Chronic steroids equivalent to ≤ 10mg prednisone are permitted. Has active autoimmune disease that has required systemic treatment in the past 1 year (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). • Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is permitted. Has a known additional malignancy that is progressing and requires active treatment. • Exceptions include: basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical or anal cancer, prostate cancer on stable dose of hormonal therapy without rising PSA, and breast cancer treated with curative intent now on hormonal 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 is not in the best interest of the subject to participate, in the opinion of the treating Investigator. HIV positive with detectable viral load, or anyone not on stable anti-viral (HAART) regimen, or with \<200 CD4+ T cells/microliter in the peripheral blood. HIV testing is mandatory for patients with no known history of HIV. For such patients, HIV testing will be considered SOC. Has known active Hepatitis B (e.g., HBV detected by PCR (\>200 IU/ml) or known active Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). • Subjects who started antiviral therapy \>/=14days from baseline are permitted. History of allogeneic hematopoietic cell transplantation or solid organ transplantation. Documented allergic or hypersensitivity response to any protein therapeutics (e.g., recombinant proteins, vaccines, intravenous immune globulins, monoclonal antibodies, receptor traps) Principle investigator believes that for one or multiple reasons the subject will be unable to comply with all study visits, or if they believe the trial is not clinically in the best interest of the subject.