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

Phase 3RecruitingNCT07409272

Astellas Pharma Global Development, Inc.614 enrolled

Overview

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. 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.

Study Type

Interventions

SetidegrasibDRUG

Intravenous infusion

OxaliplatinDRUG

Intravenous infusion

LeucovorinDRUG

Intravenous infusion

IrinotecanDRUG

Intravenous infusion

fluorouracilDRUG

Intravenous infusion

liposomal irinotecanDRUG

Intravenous infusion

PlaceboDRUG

Intravenous Infusion

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (13)

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

Fullerton, California, United States

RECRUITING

Baptist MD Anderson Cancer Institute

Jacksonville, Florida, United States

RECRUITING

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

Edgewood, Kentucky, United States

RECRUITING

HealthPartners Frauenshuh Cancer Center

Saint Louis Park, Minnesota, United States

RECRUITING

HealthPartners Cancer Center at Regions Hospital

Saint Paul, Minnesota, United States

RECRUITING

NYU Long Island Mineola

Mineola, New York, United States

RECRUITING

Laura and Isaac Perlmutter Cancer Center at NYU Langone

New York, New York, United States

RECRUITING

White Plains Hospital Center for Cancer Care - Oncology

White Plains, New York, United States

RECRUITING

Utah Cancer Specialists

Salt Lake City, Utah, United States

RECRUITING

UVA Emily Couric Cancer Center

Charlottesville, Virginia, United States

RECRUITING

...and 3 more locations

Outcomes

Primary Outcomes

Overall Survival (OS)

OS is defined as the time from the date of randomization until the date of death from any cause.

Time frame: Up to 3.5 years

Secondary Outcomes

Progression-Free Survival (PFS) per RECIST v1.1. as assessed by the investigator.

PFS is defined as the time from the start of randomization until the date of documented radiological disease progression per RECIST v1.1 as assessed by the investigator or until death for any cause, whichever comes first.

Time frame: Up to 3.5 years

Time to Improvement in Pancreatic Pain (TIPP) measured by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-PAN26).

EORTC-QLQ-PAN26 is a 26-item questionnaire that evaluates pancreatic cancer-specific symptoms such as pain, dietary changes, jaundice, altered bowel habits, and emotional problems. Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." For symptom scales/items, higher scores indicate worse symptoms.

Time frame: Up to 3.5 years

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).

The EORTC-QLQ-C30 is a 30-item cancer-specific instrument consisting of 5 functional scales (physical, role, emotional, social and cognitive), 9 symptom scales/items (fatigue, nausea/vomiting, general pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status scale. Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." For functional scales, higher scores indicate better functioning, while for symptom scales/items, higher scores indicate worse symptoms.

Time frame: Up to 3.5 years

Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1,

ORR is defined as the proportion of participants whose best overall response is rated as complete response (CR) or partial response (PR) per RECIST v1.1. as assessed by the investigator.

Time frame: Up to 3.5 years

Number of Participants with Adverse Events (AEs)

An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.

Time frame: Up to 3.5 years

Number of Participants with Serious Adverse Events (SAEs)

An SAE is defined as any untoward medical occurrence that, at any dose: Results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and other medically important events.

Time frame: Up to 3.5 years

Number of Participants with laboratory value abnormalities and/or AEs

Number of participants with potentially clinically significant laboratory values.

Time frame: Up to 3.5 years

Number of Participants with electrocardiogram (ECG) abnormalities and/or AEs.

Number of participants with potentially clinically significant ECG values.

Time frame: Up to 3.5 years

Number of Participants with vital sign abnormalities and/or AEs.

Number of participants with potentially clinically significant vital sign values.

Time frame: Up to 3.5 years

Number of Participants with Eastern Cooperative Oncology Group (ECOG) performance status.

The ECOG scale will be used to assess performance status. Grades range from 0 (fully active) to 5 (dead). Negative change scores indicate an improvement. Positive scores indicate a decline in performance.

Time frame: Up to 3.5 years

Pharmacokinetics (PK) of setidegrasib End-of-Infusion (EOI) concentration

EOI Concentration will be recorded from plasma samples collected.

Time frame: Up to 9 months

PK of setidegrasib in plasma: concentration immediately prior to dosing at multiple dosing (Ctrough)

Ctrough will be recorded from plasma samples collected.

Time frame: Up to 9 months

Change from baseline in EORTC QLQ-PAN26

Time frame: Up to 3.5 years

Change from baseline in EORTC QLQ-C30

Time frame: Up to 3.5 years

Change from baseline in EuroQol 5-dimensional 5-level version (EQ-5D-5L)

The EQ-5D-5L is a standardized instrument for use as a measure of health outcome consisting of 6 items that cover 5 main domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a general visual analog scale for health status. Each domain comprises 5 severity levels (no problems, slight problems, moderate problems, severe problems, extreme problems). The general visual analog scale records the respondent's self-rated health status on a vertical graduated (0 = the worst health a participant can imagine to 100 = the best health a participant can imagine) visual analogue scale. Responses to the 5 items will also be converted to a weighted health state index (utility score) based on values derived from general population samples.

Time frame: Up to 3.5 years

Change from baseline in Patient Global Impression of Change (PGIC).

The PGIC is a single-item questionnaire that asks participants to provide the overall self-assessment of change in their disease on a 7-point scale ranging from "very much worse" to "very much better" as compared to the participant starting the study treatment. Only PGIC questions assessing pain and overall status will be collected.

Time frame: Up to 3.5 years

Change from baseline in Patient Global Impression of Severity PGIS

The PGIS is a single-item questionnaire that asks participants to provide the overall self-assessment of their disease severity on a 4-point scale for the past week, with 1 as "None" and 4 as "Severe". Only PGIS questions assessing pain and overall status will be collected.

Time frame: Up to 3.5 years

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

Overview

Conditions

Interventions

Eligibility

Locations (13)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts