Combination Therapy in Patients With Localized Pancreatic Ductal Adenocarcinoma

NCT ID: NCT06048484

Last Updated: 2025-02-13

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-05-10
• Study Completion Date: 2027-04-30

Brief Summary

The purpose of this study is to combine standard radiation therapy with drugs that encourages the body's immune system against cancer cells and simultaneously adding drugs which also target the pathway that the tumor uses to evade the immune system (CD73 and A2a/b). The study hopes that these drugs will work in concert with radiation therapy to kill cancer cells.

The specific goal of this study is to ensure that treatment with zimberelimab and stereotactic body radiation therapy (SBRT) alone or in combination with quemliclustat (a drug which blocks CD73), with or without etrumadenant (a drug which blocks the A2a/b) given before surgery is safe and if it can further increase the immune response against the tumor.

Detailed Description

The overall objective of this study is to combine standard radiation therapy with drugs that stimulate the body's immune system against cancer cells (by targeting the protein programmed cell death (PD-1), while adding drugs which also target the pathway that the tumor uses to evade the immune system (the CD73 and A2a/b pathways).The main goal of this study is to find out if study treatment with zimberelimab (an antibody which binds the protein PD-1) and stereotactic body radiation therapy (SBRT) alone or in combination with quemliclustat (a drug which blocks CD73), with or without etrumadenant (a drug which blocks the A2a/b) given before surgery is safe and if it can further increase the immune response against the tumor.

The study is divided into two parts (Stage 1 and Stage 2). In Stage 1 participants will undergo 5 days of SBRT and receive zimberelimab, quemliclustat and etrumadenant (Arm A) for 7 weeks before surgery. If this combination is considered safe, the study will proceed to Stage 2. In Stage 2, participants will be randomized into one of three different treatment arms (B - D). All participants will undergo SBRT and will receive either Zimberelimab alone (Arm B), a combination of zimberelimab with quemliclustat (Arm C), or will receive combination of zimberelimab, quemliclustat and etrumadenant (Arm D) for 7 weeks prior to surgery.

Conditions

Pancreatic Ductal Adenocarcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A: Safety run-in

Prior to resection: SBRT 40 Gy over 5 fractions, zimberelimab (AB122) 240 mg intravenously (IV) every 2 weeks for 7 weeks (4 doses), quemliclustat (AB680) 100 mg IV every 2 weeks for 7 weeks (4 doses) and etrumadenant (AB928) 150 mg PO daily for 7 weeks. After resection: mFOLFIRINOX (4 cycles)

Group Type: EXPERIMENTAL

Stereotactic body radiotherapy (SBRT)

Intervention Type: RADIATION

SBRT 40 gray (Gy) over 5 fractions

Zimberelimab

Intervention Type: DRUG

240 mg intravenously (IV)

Quemliclustat

Intervention Type: DRUG

100 mg IV

Etrumadenant

Intervention Type: DRUG

150 mg orally

Modified FOLFIRINOX

Intervention Type: DRUG

• Oxaliplatin 85 mg per square meter IV
• Irinotecan 150 mg per square meter IV
• Leucovorin 400 mg per square meter IV
• Fluorouracil 2400 mg per square meter IV
• Pegfilgrastim injector kit (6mg subcutaneous)

Arm B: SBRT with Zimberelimab (AB122) Alone (Control Arm)

Prior to resection: SBRT 40 Gy over 5 fractions, 240 mg IV zimberelimab (AB122) every 2 weeks for 7 weeks (4 doses) prior to surgery. After resection: mFOLFIRINOX (4 cycles)

Group Type: ACTIVE_COMPARATOR

Stereotactic body radiotherapy (SBRT)

Intervention Type: RADIATION

SBRT 40 gray (Gy) over 5 fractions

Zimberelimab

Intervention Type: DRUG

240 mg intravenously (IV)

Modified FOLFIRINOX

Intervention Type: DRUG

• Oxaliplatin 85 mg per square meter IV
• Irinotecan 150 mg per square meter IV
• Leucovorin 400 mg per square meter IV
• Fluorouracil 2400 mg per square meter IV
• Pegfilgrastim injector kit (6mg subcutaneous)

Arm C: SBRT, Zimberelimab with quemliclustat (AB680)

Prior to resection: SBRT 40 Gy over 5 fractions, 240 mg IV zimberelimab (AB122) every 2 weeks for 7 weeks (4 doses) prior to surgery in combination with quemliclustat IV at the recommended therapeutic dose (RTD)every 2 weeks for 7 weeks (4 doses) prior to surgery. After resection: mFOLFIRINOX (4 cycles)

Group Type: EXPERIMENTAL

Stereotactic body radiotherapy (SBRT)

Intervention Type: RADIATION

SBRT 40 gray (Gy) over 5 fractions

Zimberelimab

Intervention Type: DRUG

240 mg intravenously (IV)

Quemliclustat

Intervention Type: DRUG

100 mg IV

Modified FOLFIRINOX

Intervention Type: DRUG

• Oxaliplatin 85 mg per square meter IV
• Irinotecan 150 mg per square meter IV
• Leucovorin 400 mg per square meter IV
• Fluorouracil 2400 mg per square meter IV
• Pegfilgrastim injector kit (6mg subcutaneous)

Arm D: SBRT, Zimberelimab with AB680 and Etrumadenant (AB928)

Prior to resection: SBRT 40 Gy over 5 fractions, 240 mg IV zimberelimab (AB122) every 2 weeks for 7 weeks (4 doses) prior to surgery in combination with quemliclustat IV at the RTD every 2 weeks for 7 weeks (4 doses) and etrumadenant (AB928) PO at the RTD daily for 7 weeks prior to surgery. After resection: mFOLFIRINOX (4 cycles)

Group Type: EXPERIMENTAL

Stereotactic body radiotherapy (SBRT)

Intervention Type: RADIATION

SBRT 40 gray (Gy) over 5 fractions

Zimberelimab

Intervention Type: DRUG

240 mg intravenously (IV)

Quemliclustat

Intervention Type: DRUG

100 mg IV

Etrumadenant

Intervention Type: DRUG

150 mg orally

Modified FOLFIRINOX

Intervention Type: DRUG

• Oxaliplatin 85 mg per square meter IV
• Irinotecan 150 mg per square meter IV
• Leucovorin 400 mg per square meter IV
• Fluorouracil 2400 mg per square meter IV
• Pegfilgrastim injector kit (6mg subcutaneous)

Interventions

Stereotactic body radiotherapy (SBRT)

SBRT 40 gray (Gy) over 5 fractions

Intervention Type: RADIATION

Zimberelimab

240 mg intravenously (IV)

Intervention Type: DRUG

Quemliclustat

100 mg IV

Intervention Type: DRUG

Etrumadenant

150 mg orally

Intervention Type: DRUG

Modified FOLFIRINOX

• Oxaliplatin 85 mg per square meter IV
• Irinotecan 150 mg per square meter IV
• Leucovorin 400 mg per square meter IV
• Fluorouracil 2400 mg per square meter IV
• Pegfilgrastim injector kit (6mg subcutaneous)

Intervention Type: DRUG

Other Intervention Names

AB122; AB680; AB928; mFOLFIRINOX

Eligibility Criteria

Inclusion Criteria

• Histological or pathological confirmation of pancreatic adenocarcinoma Cytologic or histologic proof of pancreatic ductal adenocarcinoma (PDAC) needs to be verified by the treating institution pathologist. A pathological report from non-treating institutions is sufficient to consent and to initiate investigational therapy if tissue sample is unavailable for evaluation at time of consent or enrollment. However, in such a case, PDAC diagnosis should be confirmed by the treating institution pathologist at a later time.
• Completed 8 cycles of neoadjuvant modified FOLFIRINOX. Omission of oxaliplatin due to adverse events may be allowed in cycles 5-8 with consultation with the principal investigator.
• Patients with surgically resectable PDAC who are considered appropriate to undergo the applicable operation.
• Eligible to undergo SBRT.
• Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• No prior surgical, systemic, or radiotherapy for PDAC except for mFOLFIRINOX.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Age ≥ 18 years.
• Adequate hematological and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of investigational treatment:

Exclusion Criteria

• Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies, including but not limited to anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies.
• Patients who are receiving any other investigational agents concurrently.
• Concomitant treatment with other anti-neoplastic agents (hormonal therapy acceptable).
• Uncontrolled pleural effusion, pericardial effusion, or ascites.
• Uncontrolled hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL, or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy.
• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease (Crohn's disease or ulcerative colitis), antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis (some exceptions permissible as outlined per protocol).
• History of idiopathic pulmonary fibrosis, interstitial lung disease, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.

• History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• Positive HIV test at screening or at any time prior to screening.
• Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg) test at screening.

--Note: Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody test at screening, are eligible for the study.

• Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test followed by a positive HCV RNA test at screening. The HCV RNA test will be performed only for patients who have a positive HCV antibody test.
• Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, fatty liver disease, and inherited liver disease.
• Known active tuberculosis.
• Inability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications.
• Pregnant women are excluded from this study because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents and breastfeeding should be discontinued.
• History of allergy or hypersensitivity to oxaliplatin, irinotecan, leucovorin, fluorouracil, pegfilgrastim, or any excipients.
• History of Gilbert's disease or known genotype UGT1A1 *28/*28.
• Inflammatory disease of the colon or rectum, or severe uncontrolled diarrhea.
• Active or history of celiac disease.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Arcus Biosciences, Inc.

INDUSTRY

Sponsor Role: collaborator

Gulam Manji

OTHER

Sponsor Role: lead

Responsible Party

Gulam Manji

Associate Professor of Medicine

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Gulam Manji, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Columbia University

Locations

Northwell Health R.J. Zuckerberg Cancer Center

Lake Success, New York, United States

Site Status: RECRUITING

Columbia University Irving Medical Center

New York, New York, United States

Site Status: RECRUITING

UNC Hospitals, The University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

Site Status: RECRUITING

University of Pennsylvania, Abramson Cancer Center

Philadelphia, Pennsylvania, United States

Site Status: RECRUITING

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Research Nurse Navigator

Role: CONTACT

cancerclinicaltrials@cumc.columbia.edu

212-342-5162

Facility Contacts

Role: primary

dking14@northwell.edu

Research Nurse Navigator

Role: primary

cancerclinicaltrials@cumc.columbia.edu

212-342-5162

Ashwin Somasundaram, MD

Role: primary

919-843-7709

Mark O'Hara, MD

Role: primary

Mark.OHara@pennmedicine.upenn.edu

215-360-0919

Ben George, MD

Role: primary

bgeorge@mcw.edu

Other Identifiers

AAAU4206

Identifier Type: -

Identifier Source: org_study_id