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NCT07409272PHASE3Recruiting

A Study to Evaluate the Effectiveness and Safety of Setidegrasib, Given With Either mFOLFIRINOX or NALIRIFOX Chemotherapies, in People With Pancreatic Cancer

Astellas Pharma Global Development, Inc.

Start Date

2/17/2026

Completion Date

8/31/2029

Summary

Pancreatic cancer is difficult to diagnose early. By the time people have been diagnosed, the cancer has usually spread to other parts of the body (metastatic). The standard treatment is chemotherapy, but other treatments are needed to improve outcomes in people with pancreatic cancer. The first treatment that people usually receive is chemotherapy. At the time this study started, some of the main standard chemotherapies for pancreatic cancer were mFOLFIRINOX or NALIRIFOX. Genes give your body instructions on how to make proteins. Proteins are needed to keep the body working properly. Many types of cancer are caused by changes in certain genes, making them faulty. Many people with pancreatic cancer have a faulty KRAS gene. One such change in the KRAS gene is called a G12D mutation. Researchers are looking for ways to stop the actions of abnormal proteins made from the KRAS G12D mutation. This study is about setidegrasib given with chemotherapy in people with pancreatic cancer who have the KRAS G12D mutation. Before setidegrasib can become an approved treatment, clinical studies need to be completed to understand how it works and how safe it is. The main aim is to learn if people who are given setidegrasib with chemotherapy live for longer than people who are given placebo with chemotherapy. Other aims are to learn if setidegrasib delays the cancer and symptoms returning, how the body processes setidegrasib, and its safety, when given with chemotherapy. People in this study will be adults with metastatic pancreatic cancer with the G12D mutation in their KRAS gene. Surgery or radiotherapy will not be an option to cure their cancer. People cannot take part if the cancer cells have spread to the thin tissue covering the brain and spinal cord (leptomeningeal disease), have symptoms of cancer in the brain or nervous system, or have recently had some other cancers that required treatment. In this study, people are given either setidegrasib with mFOLFIRINOX or NALIRIFOX chemotherapy, or a placebo with mFOLFIRINOX or NALIRIFOX chemotherapy. Whether people receive setidegrasib or placebo is decided by chance. The study doctor decides which chemotherapy (mFOLFIRINOX or NALIRIFOX) people receive. People will only receive NALIRIFOX chemotherapy (with setidegrasib or placebo) after the safety of setidegrasib with NALIRIFOX chemotherapy has been confirmed in another ongoing setidegrasib study. All of the study treatments are given slowly through a tube into a vein (infusion). People will continue to receive study treatment until their cancer gets worse, they can't tolerate the study treatment, they start other cancer treatment, they or the doctor decides the person should stop receiving study treatment, or sadly they pass away. There will be safety checks at each visit, and the doctors will continue to check for medical problems and people's wellbeing throughout the study.

Eligibility Criteria

Age Range: 18 years to No maximum

Inclusion Criteria: * Participant has histologically confirmed metastatic pancreatic ductal adenocarcinoma (PDAC) with documented Kirsten rat sarcoma viral oncogene homolog (KRAS) G12D mutation based on local or central testing (confirmation of a participant's positive KRAS G12D mutation result must be available prior to randomization). * Participant has no option for surgical resection or radiotherapy with curative intent. * Participant consents to and provides a baseline tumor tissue specimen for the study during screening. The sample must meet the requirements described in the laboratory manual and the tumor sample guidance. * Participant has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 within 7 days prior to randomization. * Participant has adequate organ function as indicated by the following laboratory values within 7 days prior to randomization (if a participant has received a recent blood transfusion, the latest laboratory tests must be obtained ≥ 14 days after any blood transfusion). The laboratory values prior to the initiation of the first dose of setidegrasib/placebo (or mFOLFIRINOX/NALIRIFOX, if chemotherapy is administered during the screening period) should be used to determine eligibility. Participants who receive mFOLFIRINOX/NALIRIFOX during the screening period must meet these criteria within 7 days prior to the start of on-treatment chemotherapy (i.e., C1D1). * Participant agrees not to participate in another interventional study while receiving study intervention in the present study (participant who is currently in the follow-up period of an interventional clinical trial is allowed). Exclusion Criteria: * Participant has neuroendocrine, acinar pancreatic carcinoma or pancreatic cancer with squamous/adenosquamous features. * Participant has another prior malignancy active (i.e., requiring treatment, including hormonal therapies, or intervention) within the previous 2 years different from the primary malignancy for this study, except for local malignancies that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast, which are allowed. * Participant has chronic inflammatory bowel disease, bowel obstruction and/or severe uncontrolled diarrhea. * Participant has peripheral sensory neuropathy with functional impairment. * Participant has ascites and/or pleural effusion that require invasive interventions within 30 days prior to randomization or have an indwelling drainage catheter. * Participant has symptomatic pulmonary embolism or pulmonary embolism not being treated with anticoagulation. * Participant has a history of interstitial lung disease or pulmonary fibrosis. * Participant has uncontrolled seizure disorder or refractory to antiepileptics. * Participant has known homozygous uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism. * Participant has had a myocardial infarction, unstable angina or coronary artery bypass surgery within 6 months prior to randomization or currently has an uncontrolled illness including but not limited to symptomatic congestive heart failure, clinically significant cardiac disease (e.g., cardiomyopathy, infiltrative cardiac disease, etc.), unstable angina pectoris, cardiac arrhythmia, obligate use of a cardiac pacemaker or long QT interval (QT) syndrome. * Participant has received any prior systemic therapy for their metastatic PDAC (except with up to 2 doses \[i.e., 28 days; 1 cycle\] of mFOLFIRINOX or NALIRIFOX during the screening period. If a participant received \[neo\]adjuvant chemotherapy, tumor recurrence or disease progression must have occurred ≥ 6 months after completing the last dose of the \[neo\]adjuvant therapy). * Participant has had prior treatment with a KRAS G12D-targeted agent. * Participant has a corrected QT interval by Fridericia (QTcF) (single electrocardiogram \[ECG\]) \> 470 msec during the screening period.

Interventions

DRUG

Setidegrasib

DRUG

Oxaliplatin

DRUG

Leucovorin

DRUG

Irinotecan

DRUG

fluorouracil

DRUG

liposomal irinotecan

DRUG

Placebo

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Conditions

Pancreatic CancerMetastatic Pancreatic CancerMetastatic Pancreatic Adenocarcinoma

Locations

University of Arizona Cancer Center - North Campus

Tucson, Arizona 85719

United States

Mercy Cancer Center

Fort Smith, Arkansas 72903

United States

Crosson Cancer Institute at Providence St. Jude Medical Center in Fullerton

Fullerton, California 92835

United States

Cedars-Sinai - Cedars-Sinai Medical Center

Los Angeles, California 90048

United States

Hoag Mem Hosp Presbyterian

Newport Beach, California 92663

United States

Hartford Healthcare

Hartford, Connecticut 06016

United States

Baptist MD Anderson Cancer Institute

Jacksonville, Florida 32207

United States

Baptist Health Medical Group Oncology

Miami, Florida 33176

United States

Mount Sinai Medical Center - Miami Beach

Miami Beach, Florida 33140

United States

Indiana University Health - Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Indianapolis, Indiana 46202

United States

Saint Elizabeth Medical Center, Inc. DBA St. Elizabeth Health Care

Edgewood, Kentucky 41017

United States

University of Maryland School - Division of Hematology/Oncology

Baltimore, Maryland 21201

United States

University of Michigan Health - University of Michigan Medical Center

Ann Arbor, Michigan 48109

United States

Allina Health Cancer Institute - Hematology Cancer Care Services

Minneapolis, Minnesota 55407

United States

HealthPartners Frauenshuh Cancer Center

Saint Louis Park, Minnesota 55426

United States

HealthPartners Cancer Center at Regions Hospital

Saint Paul, Minnesota 55101

United States

Mercy CH Chub O'Reilly Cancer Center

Springfield, Missouri 65804

United States

The Alvin J. Siteman Cancer Center - Center for Advanced Med

St Louis, Missouri 63110

United States

Mercy David C. Pratt Cancer Center - St. - Mercy Research - David C. Pratt Cancer Center

St Louis, Missouri 63141

United States

Saint Joseph Hospital - Cancer Centers - St. Vincent Frontier Cancer Center

Billings, Montana 59102

United States

Dartmouth Hitchcock Medical Center

Lebanon, New Hampshire 03756

United States

Atlantic Health - Overlook Medical Center

Morristown, New Jersey 07962

United States

NYU Long Island Mineola

Mineola, New York 11501

United States

Laura and Isaac Perlmutter Cancer Center at NYU Langone

New York, New York 10016

United States

Memorial Sloan Kettering Cancer Center - Main Campus

New York, New York 10065

United States

University of Rochester

Rochester, New York 14611

United States

White Plains Hospital Center for Cancer Care - Oncology

White Plains, New York 10601

United States

Facilities Design and Construction - Energy Advancement and Innovation Center

Columbus, Ohio 43210

United States

Mercy Hospital Oklahoma City - Mercy Coletta Cancer Center - Oklahoma City

Oklahoma City, Oklahoma 73120

United States

AGH Singer Research Institute

Pittsburgh, Pennsylvania 15212

United States

Brown University Health Cancer Institute - Division of Hematology/Oncology

Providence, Rhode Island 02906

United States

UT Southwestern Medical Center at Dallas

Dallas, Texas 75390

United States

Houston Methodist Office of Graduate - Houston Methodist Neal Cancer Center at Texas Medical Center

Houston, Texas 77030

United States

Utah Cancer Specialists

Salt Lake City, Utah 84106

United States

UVA Emily Couric Cancer Center

Charlottesville, Virginia 22903

United States

Inova Schar Cancer Institute Clinical Trials

Fairfax, Virginia 22031

United States

Virginia Cancer Specialists

Fairfax, Virginia 22031

United States

Virginia Mason Franciscan Health - Virginia Mason Medical Center

Seattle, Washington 98101

United States

Fred Hutchinson Cancer Center - Advanced Cancer Research Group

Seattle, Washington 98109

United States

National Cancer Center Hospital East

Kashiwa, Chiba

Japan

Chugoku-Shikoku Group - Shikoku Cancer Center

Matsuyama, Ehime

Japan

Kyushu Group - Kyushu Cancer Center

Fukuoka, Fukuoka

Japan

Nara Medical University Hospital

Kashihara-shi, Nara

Japan

The University of Osaka Hospital

Suita, Osaka

Japan

The University of Tokyo Hospital

Bunkyo-ku, Tokyo

Japan

Japanese Foundation for Cancer Research - The Cancer Institute Hospital of JFCR

Koto, Tokyo

Japan

Yamaguchi University Hospital

Ube-shi, Yamaguchi

Japan

Osaka Prefectural Hospital Organization - Osaka International Cancer Institute

Osaka,

Japan