Testing a new treatment for rectal cancer using radiation and specific medications

Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen should be included.

Inclusion Criteria:

* Histologically confirmed diagnosis of adenocarcinoma of the rectum
* Age ≥ 18 years
* ECOG performance status 0-1
* cT3N0 or cT1-3N1 or cT4 or cN2
* 5cm from the anal verge
* Rectal cancer amenable to total mesorectal excision
* No evidence of distant metastases
* No prior pelvic radiation therapy
* No prior chemotherapy or surgery for rectal cancer
* No infections requiring systemic antibiotic treatment
* Hgb \>8.0 gm/dL, PLT \> 150,000/mm3, total bilirubin ≤ 1.5x upper limit of normal, AST ≤ upper limit of normal, ALT ≤ 3x upper limit of normal
* Patients must read, agree to, and sign a statement of informed consent prior to participation in this study. Patients who do not read or understand English or eligible but must have the consent form bread to them in its entirety by an official translator. Informed consent for non-literate or non-English speaking patients may not be obtained by using a relative or a member of the patient's clinical team as a translator
* Female participants or reproductive potential, defined as not surgically sterilized and between menarche and 1 year post menopause, must have a negative serum pregnancy test within 4 weeks prior to initiation of study treatment
* Female participants of reproductive potential and male participants with female partners of reproductive potential must remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive measures from the start of study treatment until 30 days after the last dose of Etrumadenant, -120 days after the last dose of Zimberelimab, whichever is longer and duration of contraception to follow oxaliplatin should be at least 9 months after the last dose for women and 6 months after the last dose for men)
* Women with childbearing potential who are negative for pregnancy (urine or blood) and who agree to use effective contraceptive methods. A woman of childbearing potential is defined by one who is biologically capable of becoming pregnant. Reliable contraception should be used from trial screening and must be continued throughout the study.
* Male subjects must also agree to use effective contraception.

Exclusion Criteria:

* Recurrent rectal cancer
* Primary unresectable rectal cancer is defined as a primary rectal tumor which, on the basis of either physical exam or pelvic MRI, is demed to be adherent or fixed to adjacent pelvic structures (en bloc resection wll not be achieved with negative margins).
* Involved radial margin
* Serum creatinine level \>1.5x the upper limit of normal
* Patients who have received prior pelvic radiotherapy
* QTc ≥480 msec using Fredericia's QT correction formula
* Due to the potential risk for drug-drug interactions with etrumadenant, participants must not have had:

  * Treatment with known BCRP substrates with a narrow therapeutic window, administered orally (e.g., prazosin, rosuvastatin) within 4 weeks or 5 half-lives of the drug (whichever is shorter) prior to initiation of and throughout study treatment
  * Treatment with known P-gp substrates with a narrow therapeutic window, administered orally (e.g., digoxin) within 4 weeks or 5 half-lives of the drug (whichever is shorter) prior to initiation of study treatment
  * Treatment with known strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, and St. John's Wort) and strong CYP3A4 inhibitors (e.g., clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole) within 4 weeks (for investigational drugs when half- life is unknown or not accurately determined) or 5 drug-elimination half-lives of the drug (when half-life is determined), whichever is longer, or if it is a marketed drug, then 5 drug-elimination half-lives of the drug, prior to initiation of study treatment
  * Refer to the following for more examples of relevant substrates, inhibitors, and inducers with the potential for drug-drug interactions with Etrumadenant: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug- interactions-table-substrates-inhibitors-and- Inducers
  * Patients receiving herbal and natural remedies. Concomitant use of therapies that contain cannabinoids may be permitted based on the Investigator's discretion.
  * Sensitive substrates of BSEP, MATE1and OCT2.
* Any gastrointestinal condition that would preclude the use of oral medications (e.g., difficulty swallowing, nausea, vomiting, or malabsorption)
* Prior treatment with an agent targeting the adenosine pathway
* Patients with prior allogenic stem cell or solid organ transplantation
* Any active autoimmune disease or a documented history of autoimmune disease or syndrome that required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs), except for vitiligo or resolved childhood asthma/atopy
* Patients with history of idiopathic pulmonary fibrosis, pneumonitis, or interstitial lung disease
* Patients receiving treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor-α agents) administered at \>10 mg/day prednisone or equivalent within 2 weeks prior to initiation of study treatment
* Patients who received a live vaccine within 30 days
* Patients who are known to have dihydropyrimidine dehydrogenase (DPD) deficiency
* Patients with peripheral neuropathy Grade ≥ 2
* History of severe allergic reactions to chimeric or humanized antibodies or fusion proteins
* Patients with a history of any arterial thrombitic event within the past 6 months,
* Patients with any other concurrent medical or psychiatric condition or disease which, in the investigator's judgment would make them inappropriate candidates for entry into this study
* Patients with a history of prior malignancy within the past 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer.
* Patients with a history of thrombotic episodes, such as deep venous thrombosis, pulmonary embolus, MI or CVA occurring more than 6 months prior to enrollment may be considered for protocol participation, provided they are on stable doses of anticoagulant therapy. Patients who are anticoagulated for atrial fibrillation or other conditions may participate, provided they are on stable doses of anticoagulant therapy.
* Patients receiving other anticancer or experimental therapy. No other experimental therapies (including chemotherapy, radiation, hormonal treatment, antibodiy therapy, immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, matrix metalloprotease inhibitors, thalidomide, anti-VEGF/Flk-1 monoclonal antibody, or other experimental drugs) of any kind are permitted while the patient is receiving study treatment.
* Women who are pregnant or breastfeeding. Women of childbearing potential who are unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study period and for up to four weeks after the study.