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.

Weill Medical College of Cornell University3 sites in 1 country43 target enrollmentMarch 31, 2022

Overview

Brief Summary

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

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).

Registry

clinicaltrials.gov

Start Date

March 31, 2022

End Date

December 1, 2030

Last Updated

8 months ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

Weill Medical College of Cornell University

Responsible Party

Sponsor

Eligibility Criteria

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

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

Arms & Interventions

Radiation therapy and etrumadenant (AB928)

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.

Intervention: Etrumadenant (AB928)

Radiation therapy and etrumadenant (AB928)

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.

Intervention: Radiation therapy

Radiation therapy and etrumadenant (AB928)

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.

Intervention: FOLFOX regimen

Radiation therapy and etrumadenant (AB928)

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.

Intervention: Zimberelimab (AB122)

Outcomes

Primary Outcomes

Number of treated patients who achieve complete pathologic response

Time Frame: Week 24

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.