A Phase I-II Study to Test the Safety and Efficacy of PD1 (AB122) and Adenosine Receptor (AB928) Antagonists With Chemotherapy After Short-Course Radiation for Rectal Cancer.

Study Overview
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Brief Summary
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Enrolled patients will receive upfront (week 1) short-course radiotherapy to gross pelvic disease (25Gy in 5fx) in combination with AB928 (150 mg orally, once daily as part of a continuous dose regimen). This will be followed by consolidation chemotherapy (weeks 3-20) with mFOLFOX x9 cycles in combination with AB928 and AB122.

Detailed Description
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Enrolled patients will receive upfront (week 1) short-course radiotherapy to gross pelvic disease (25Gy in 5fx) in combination with AB928 (150 mg orally, once daily as part of a continuous dose regimen). This will be followed by consolidation chemotherapy (weeks 3-20) with mFOLFOX x9 cycles in combination with AB928 and AB122. Patients will thereafter be assessed for therapeutic responses (week 22-24) with a digital rectal examination, pelvic MRI, and endoscopy. Each case will be reviewed by the Weill Cornell Medicine Colorectal Multidisciplinary Tumor Board for consensus agreement regarding clinical treatment response. The patients thereafter will proceed with total mesorectal excision (TME, week 24) by transabdominal resection for pathologic evaluation (primary tumor and pelvic lymph nodes will be examined).

Official Title
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A Phase I-II Study to Test the Safety and Efficacy of PD1 (AB122) and Adenosine Receptor (AB928) Antagonists With Chemotherapy After Short-Course Radiation for Rectal Cancer.

Conditions
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Rectal Cancer

Intervention / Treatment
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* Drug: Etrumadenant (AB928)
* Radiation: Radiation therapy
* Drug: FOLFOX regimen
* Drug: Zimberelimab (AB122)


Participation Criteria
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Eligibility Criteria
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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 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 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, 90 days after the last dose of zimberelimab, whichever is longer 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). ≥4 regional lymph nodes each ≥10 mm on pelvic MRI Suspected T4 tumor 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 or 5 half-lives of the drug (whichever is shorter) prior to initiation of study treatment 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 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiation therapy and etrumadenant (AB928)<br>Enrolled patients will receive Radiation therapy of 25 Gy in 5 fractions along with etrumadenant 150mg oral drug taken once daily. this will then be followed by 9 cycles of FOLFOX in combination of etrumadenant and zimberelimab investigational drugs. | Drug: Etrumadenant (AB928)<br>* Patients will receive a radiation therapy dose of 25Gy in 5 fractions in combination with etrumadenant 150 mg orally, once daily as part of a continuous dose regimen.<br>Radiation: Radiation therapy<br>* Patients will receive a radiation therapy dose of 25Gy in 5fx<br>Drug: FOLFOX regimen<br>* After completing the radiation therapy, patients will receive FOLFOX regimen for 9 cycles in combination with etrumadenant and zimberelimab. All patients will be offered adjuvant zimberelimab for up to one year.<br>Drug: Zimberelimab (AB122)<br>* After completing the radiation therapy, patients will receive FOLFOX regimen for 9 cycles in combination with etrumadenant and zimberelimab. All patients will be offered adjuvant zimberelimab for up to one year.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of treated patients who achieve complete pathologic response | The primary endpoint is the proportion of treated rectal cancer patients who achieve a complete pathologic response. All patients will be offered surgical resection however those who achieve a clinical CR at the time of clinical response assessment may choose a non-operative management approach. Due to practicality the latter will be included as complete responders at the time of analysis for this trial. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients who experience treatment-related adverse events | Number of patients with treatment-related early and late adverse events as assessed by the CTCAE version 5.0 | Day 5 of radiation therapy | 
| Number of patients who experience treatment-related adverse events | Number of patients with treatment-related early and late adverse events as assessed by the CTCAE version 5.0 | 3 months | 
| Number of patients who experience treatment-related adverse events | Number of patients with treatment-related early and late adverse events as assessed by the CTCAE version 5.0 | 6 months | 
| Number of patients who experience treatment-related adverse events | Number of patients with treatment-related early and late adverse events as assessed by the CTCAE version 5.0 | 12 months | 
| Number of patients who experience treatment-related adverse events | Number of patients with treatment-related early and late adverse events as assessed by the CTCAE version 5.0 | 60 months | 
| Progression free survival | PFS is defined as the duration of time from start of treatment to time of progression. | 36 months | 
| Overall survival | Overall Survival is defined as the duration of time from start of treatment until death. | 60 months |