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. (PANTHER)

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.

Study Overview

• Status: Recruiting
• Conditions: Rectal Cancer
• Intervention / Treatment: Drug: Etrumadenant (AB928); Radiation: Radiation therapy; Drug: FOLFOX regimen; Drug: Zimberelimab (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).

• Study Type: Interventional
• Enrollment (Estimated): 43
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Pragya Yadav, Ph.D.; Phone Number: 646-962-2196; Email: pry2003@med.cornell.edu
• Study Contact Backup: Name: Sharanya Chandrasekhar, M.S.; Phone Number: 646- 962-3110; Email: shc2043@med.cornell.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Weill Cornell Medical College
      • Principal Investigator: Pashtoon Kasi, M.D.
      • Contact: Encouse Golden, M.D.,Ph.D.; Phone Number: 212-746-3650; Email: eng2003@med.cornell.edu
      • Principal Investigator: Encouse Golden, M.D., Ph.D.
      • Contact: Sharanya Chandrasekhar, M.S.; Phone Number: 646-962-3110; Email: shc2043@med.cornell.edu
    • New York, New York, United States, 11355
      • Recruiting
      • New York Presbyterian Hospital - Queens
      • Contact: Pragya Yadav, Ph.D; Phone Number: 6469622196; Email: pry2003@med.cornell.edu
      • Contact: Hina Ali, M.D.; Phone Number: 718-670-1541; Email: hia4002@med.cornell.edu
      • Principal Investigator: Andrew Brandmaier, M.D.
    • New York, New York, United States, 11215
      • Not yet recruiting
      • Brooklyn Methodist Hospital - NewYork Presbyterian
      • Contact: Pragya Yadav, Ph.D.; Phone Number: 6469622196; Email: pry2003@med.cornell.edu
      • Contact: Mary Palmer, M.S.; Email: map9505@med.cornell.edu
      • Principal Investigator: Hani Ashamalla, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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.

Drug: Etrumadenant (AB928); 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.; Radiation: Radiation therapy; Patients will receive a radiation therapy dose of 25Gy in 5fx; Drug: FOLFOX regimen; 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.; Drug: Zimberelimab (AB122); 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Collaborators: Arcus Biosciences, Inc.
• Investigators: Principal Investigator: Encouse Golden, M.D., Ph.D., Weill Medical College of Cornell University

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2022
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: August 20, 2021
• First Submitted That Met QC Criteria: August 26, 2021
• First Posted (Actual): August 27, 2021

Study Record Updates

• Last Update Posted (Actual): October 31, 2023
• Last Update Submitted That Met QC Criteria: October 27, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms
• Other Study ID Numbers: 21-02023289

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No