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A Phase 3, Double-blind, Placebo-controlled, Randomized Study to Assess the Efficacy and Safety of ASP3082 in Combination with mFOLFIRINOX or NALIRIFOX as First-line Treatment in Participants with KRAS G12D-mutated Metastatic Pancreatic Adenocarcinoma

A study to evaluate the effectiveness and safety of setidegrasib, given with either mFOLFIRINOX or NALIRIFOX chemotherapies, in people with pancreatic cancer

Fujii Hisaki

Astellas Pharma Inc.

2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo

clinicaltrialregistration@astellas.com

Medical Information Center

Astellas Pharma Inc.

2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo

+81-120-189-371

clinicaltrialregistration@astellas.com

Recruiting

Mar. 13, 2026

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1. 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).
2. Participant has no option for surgical resection or radiotherapy with curative intent.
3. 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.
4. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 within 7 days prior to randomization.
5. 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.
6. 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).

1. Participant has neuroendocrine, acinar pancreatic carcinoma or pancreatic cancer with squamous/adenosquamous features.
2. 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.
3. Participant has chronic inflammatory bowel disease, bowel obstruction and/or severe uncontrolled diarrhea.
4. Participant has peripheral sensory neuropathy with functional impairment.
5. Participant has ascites and/or pleural effusion that require invasive interventions within 30 days prior to randomization or have an indwelling drainage catheter.
6. Participant has symptomatic pulmonary embolism or pulmonary embolism not being treated with anticoagulation.
7. Participant has a history of interstitial lung disease or pulmonary fibrosis.
8. Participant has uncontrolled seizure disorder or refractory to antiepileptics.
9. Participant has known homozygous or compound heterozygous uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism.
10. 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.
11. 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).
12. Participant has had prior treatment with a KRAS G12D targeted agent.
13. Participant has a corrected QT interval by Fridericia (QTcF) (single electrocardiograms [ECG]) > 470 msec during the screening period.

Both

KRAS G12D-mutated Metastatic Pancreatic Adenocarcinoma

In this study, people are given either setidegrasib with mFOLFIRINOX or NALIRIFOX chemotherapy, or a placebo with mFOLFIRINOX or NALIRIFOX chemotherapy.
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.

Overall survival (OS), defined as the time from the date of randomization until the date of death from any cause

- Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, as assessed by the investigator
- Time to improvement in pancreatic pain (TIPP) measured by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Pancreatic Cancer Module (EORTC QLQ-PAN26)
- Time to worsening of General Health Status/Quality of Life (GHS/QoL) (TWGQ) measured by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30)
- Objective response rate (ORR) per RECIST v1.1, as assessed by the investigator
- Safety and tolerability evaluated via the following: adverse events (AEs), serious AE (SAEs), laboratory test results, ECGs, vital signs and ECOG PS
- End of infusion (EOI) concentration and observed trough concentration Ctrough
- Change from baseline in EORTC QLQ PAN26, EORTC QLQ-C30, EuroQol 5-dimensional 5-level version (EQ-5D-5L), Patient Global Impression of Change (PGIC) and Patient Global Impression of Severity (PGIS)

+81-3-5800-8743

Feb. 19, 2026

Yes

Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as products terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/. Study-related supporting documentation is redacted and provided if available, such as the protocol and amendments, statistical analysis plan and clinical study report. Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data. Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.

United States