Metastatic Pancreatic Adenocarcinoma, Metastatic Pancreatic Cancer, Pancreatic Cancer
Conditions
Keywords
Pancreatic Cancer, Metastatic Pancreatic Cancer, Metastatic Pancreatic Adenocarcinoma, ASP3082, setidegrasib, KRAS G12D, PDAC, mFOLFIRINOX, NALIRIFOX
Brief 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.
Interventions
DRUGSetidegrasib
Intravenous infusion
DRUGOxaliplatin
Intravenous infusion
DRUGLeucovorin
Intravenous infusion
DRUGIrinotecan
Intravenous infusion
DRUGfluorouracil
Intravenous infusion
DRUGliposomal irinotecan
Intravenous infusion
DRUGPlacebo
Intravenous Infusion
Sponsors
Astellas Pharma Global Development, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to 3.5 years | OS is defined as the time from the date of randomization until the date of death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) per RECIST v1.1. as assessed by the investigator. | Up to 3.5 years | 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 to Improvement in Pancreatic Pain (TIPP) measured by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-PAN26). | Up to 3.5 years | 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 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). | Up to 3.5 years | 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. |
| Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, | Up to 3.5 years | 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. |
| Number of Participants with Adverse Events (AEs) | Up to 3.5 years | 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. |
| Number of Participants with Serious Adverse Events (SAEs) | Up to 3.5 years | 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. |
| Number of Participants with laboratory value abnormalities and/or AEs | Up to 3.5 years | Number of participants with potentially clinically significant laboratory values. |
| Number of Participants with electrocardiogram (ECG) abnormalities and/or AEs. | Up to 3.5 years | Number of participants with potentially clinically significant ECG values. |
| Number of Participants with vital sign abnormalities and/or AEs. | Up to 3.5 years | Number of participants with potentially clinically significant vital sign values. |
| Number of Participants with Eastern Cooperative Oncology Group (ECOG) performance status. | Up to 3.5 years | 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. |
| Pharmacokinetics (PK) of setidegrasib End-of-Infusion (EOI) concentration | Up to 9 months | EOI Concentration will be recorded from plasma samples collected. |
| PK of setidegrasib in plasma: concentration immediately prior to dosing at multiple dosing (Ctrough) | Up to 9 months | Ctrough will be recorded from plasma samples collected. |
| Change from baseline in EORTC QLQ-PAN26 | Up to 3.5 years | 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. |
| Change from baseline in EORTC QLQ-C30 | Up to 3.5 years | 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. |
| Change from baseline in EuroQol 5-dimensional 5-level version (EQ-5D-5L) | Up to 3.5 years | 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. |
| Change from baseline in Patient Global Impression of Change (PGIC). | Up to 3.5 years | 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. |
| Change from baseline in Patient Global Impression of Severity PGIS | Up to 3.5 years | 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. |
Countries
China, Japan, United States
Contacts
CONTACTAstellas Pharma Global Development, Inc.
STUDY_DIRECTORMedical Director
Astellas Pharma Global Development, Inc.
Outcome results
None listed