Phase II Open-label Trial of Neoadjuvant Immunochemotherapy for Resectable Non-metastatic Colon cancER: NICER

Eligibility Criteria

• * Signed Informed Consent Form
• * Age \>18 years at time of signing Informed Consent Form
• * Ability to comply with the study protocol
• * MSS or pMMR tumor determined by local CLIA-certified PCR or IHC testing respectively.
• * Histologically or cytologically confirmed resectable non-metastatic adenocarcinoma of the colon (stages I-III)
• * The distal extent of the tumor must be ≥12 cm from the anal verge on pre-surgical endoscopy and/or imaging (i.e., excluding rectal adenocarcinomas warranting treatment with chemoradiation). If the patient did not undergo a pre-surgical endoscopy, then the distal extent of the tumor must be ≥12 cm from the anal verge as determined by surgical examination or pre-operative imaging.
• * Availability of a representative tumor specimen (preop biopsy or surgical tissue specimen) for ctDNA assay design from tumor sample and for exploratory biomarker research determination.
• * One or more of the following high-risk features:
• * High CEA levels (\>5 ng/ml in non-smoker patients , \>10ng/ml in smoker patients)
• * Low Lymphocyte-to-monocyte Ratio (\<2.38)
• * Poor grade of tumor differentiation
• * Evidence of Lymphovascular Invasion
• * Evidence of Perineural Invasion
• * CT evidence of T3 orT4 disease w/ ≥4 cm tumor longitudinal diameter
• * CT evidence of regional lymphadenopathy
• * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
• * Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment:
• * ANC ≥ 1.5 x 10\*9/L (1500/mL) without granulocyte colony-stimulating factor support
• * Lymphocyte count ≥ 0.5 x 10\*9/L (500/µL)
• * Platelet count ≥100 x 10\*9/L (100,000/µL) without transfusion
• * Hemoglobin ≥ 9 g/L (9 g/dL) Patients may be transfused to meet this criterion.
• * AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN)
• * Serum bilirubin ≤ 1.5 x ULN with the following exception:
• * Serum creatinine ≤1.5 x ULN or Creatinine clearance ≥ 50 mL/min (calculated using the Cockcroft-Gault formula)
• * Serum albumin ≥ 25 g/L (2.5 g/dL)
• * For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN
• * For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
• * Negative hepatitis B surface antigen (HBsAg) test at screening
• * Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening The HCV RNA test must be performed for patients who have a positive HCV antibody test.
• * Negative HIV test at screening
• * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating eggs, as defined below:
• * Symptomatic, untreated, or any site actively progressing metastatic disease.
• * History of leptomeningeal disease
• * Uncontrolled tumor-related pain Patients requiring pain medication must be on a stable regimen at study entry. Presence of any metastatic effusion (pleural, pericardial, ascites)
• * Uncontrolled or symptomatic hypercalcemia (ionized calcium \> 1.5 mmol/L, calcium \> 12 mg/dL or corrected serum calcium \> ULN)
• * Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis (see Appendix 11 for a more comprehensive list of autoimmune diseases and immune deficiencies), with the following exceptions:
• * Rash must cover \< 10% of body surface area
• * Disease is well controlled at baseline and requires only low-potency topical corticosteroids
• * There has been no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
• * History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• * Active tuberculosis
• * Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
• * Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
• * History of malignancy other than colon adenocarcinoma within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate \> 90%), such as adequately treated carcinoma in situ of the cervix, non melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, Stage I uterine cancer or colonic polyps
• * Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that could impact patient safety
• * Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
• * Prior allogeneic stem cell or solid organ transplantation
• * Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
• * Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab
• * Current treatment with anti-viral therapy for HBV
• * Synchronous primary rectal and/ or colon cancers or history of prior invasive colon malignancy, regardless of disease-free interval.
• * Treatment with investigational therapy within 28 days prior to initiation of study treatment
• * Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
• * Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 \[IL-2\]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
• * Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF- agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:
• * History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• * Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
• * Known allergy or hypersensitivity to any component of the CAPEOX or mFOLFOX6 chemotherapy formulations
• * Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months for Atezolizumab and 6 months for any chemotherapy regimen after the final dose of study treatment Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.