This phase II trial tests the impact of using SMAD4-mutant status to personalize chemotherapy in treating patients with pancreatic ductal adenocarcinoma (PDAC) that can be removed by surgery (resectable) or that may be between resectable and unresectable (borderline resectable) before undergoing surgery (neoadjuvant). PDAC is one of the most aggressive and fastest growing tumors. SMAD4, a tumor suppressor gene, acts like a brake on cell growth and helps to prevent tumor cells from growing. However, losing it makes the tumor more aggressive and often resistant to standard of care (SOC) treatments regimens, such as gemcitabine with nab-paclitaxel and fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). Gemcitabine is a chemotherapy drug that blocks the cells from making deoxyribonucleic (DNA) and may kill tumor cells. Paclitaxel is in a class of medications called antimicrotubule agents. It stops tumor cells from growing and dividing and may kill them. Nab-paclitaxel is an albumin-stabilized nanoparticle formulation of paclitaxel which may have fewer side effects and work better than other forms of paclitaxel. Fluorouracil, a type of antimetabolite, stops cells from making DNA and it may kill tumor cells. Leucovorin is a form of folic acid. It is a type of chemoprotective agent and a type of chemosensitizing agent. Irinotecan is in a class of antineoplastic medications called topoisomerase I inhibitors. It blocks a certain enzyme needed for cell division and DNA repair and may kill tumor cells. Oxaliplatin is in a class of medications called platinum-containing antineoplastic agents. It damages the cell's DNA and may kill tumor cells. Instead of a one-sized fits all treatment approach with SOC therapies, matching therapy based on SMAD4 mutation status may use this specific genetic weakness against the tumor. This approach to neoadjuvant therapy may dramatically alter the path of treatment and improve outcomes, including complete resection rates, in patients with resectable or borderline resectable PDAC.
Patients must have histologically confirmed pancreas ductal adenocarcinoma
Most recent cross-sectional imaging of the chest, abdomen and pelvis will be used to rule out distant metastases (this will have been completed within standard of care timelines which will typically fall within 90 days of registration)
Patients must have undergone next generation sequencing (NGS) testing on the pre-treatment tumor tissue and must have either SMAD4 mutant or SMAD4 wild-type mutation identified before consenting for this study
Note: Before consenting to this study, standard of care NGS procedure will be performed on pre-treatment tumor biopsies that are routinely collected through endoscopic biopsy specimens (in-house Oncomine Precision NGS). The results will be documented for this study from clinic notes
Mismatch repair (MMR)-deficiency/Lynch syndrome
High-frequency microsatellite instability (MSI-H)
Homologous recombination deficiency (HRD)
Patients who are currently participating in another study and receiving a study drug
Parallel
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Computed Tomography
Procedure/SurgeryUndergo CT
Electronic Health Record Review
Other interventionAncillary studies
Fluorouracil
DrugGiven fluorouracil
Gemcitabine
DrugGiven gemcitabine
Irinotecan
DrugGiven irinotecan
Leucovorin
DrugGiven leucovorin
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Nab-paclitaxel
DrugGiven nab-paclitaxel
Oxaliplatin
DrugGiven oxaliplatin
Radiation Therapy
RadiationUndergo radiation therapy
Surgical Procedure
Procedure/SurgeryUndergo surgical resection
Proportion of patients who achieve R0/R1 surgical resection (Cohort A)
Successful surgical resection is defined as macroscopically complete removal of the primary pancreatic tumor, classified as R0 or R1. Will follow the Simon's minimax two-stage design decision rule. The observed R0/R1 resection rate will be summarized descriptively and reported with an exact (Clopper-Pearson) binomial confidence interval.
Trial participation rate
Will be defined as the proportion of patients who consent and enroll among all patients who are approached and eligible for trial participation. Will be summarized using proportions with exact confidence intervals. Feasibility monitoring will occur on an ongoing basis during accrual (e.g. monthly or after every 20 approached eligible patients, whichever occurs first) using cumulative participation rate.
Proportion of patients who achieve R0/R1 surgical resection rate (Cohort B)
Among participants who undergo R0/R1 surgical resection, the proportion achieving R0 resection will be summarized.
Proportion of patients who achieve R0/R1 surgical resection rate (Cohort A)
Among participants who undergo R0/R1 surgical resection, the proportion achieving R0 resection will be summarized.
Pathologic response rates
Pathology reports will be reviewed to determine the College of American Pathologists (CAP) tumor regression score, categorized from 0 (complete response) to 3 (poor or no response). CAP tumor regression scores will be summarized descriptively as frequencies and percentages across categories. The distribution of reasons for failure to reach surgical resection will be summarized descriptively using frequencies and percentages. These summaries may be further stratified by baseline resectability status and SMAD4 mutation status to provide clinical context and inform future trial design.
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Northwestern University
Lead sponsor
National Cancer Institute (NCI)
Collaborator
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