Overview
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.
Description
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).
Eligibility
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.