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.
Inclusion Criteria:
Patients must have histologically confirmed pancreas ductal adenocarcinoma
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
Patients must have resectable/borderline-resectable disease
Patients must be treatment-naïve and clinically fit and eligible for either FOLFIRINOX or gemcitabine/nab-paclitaxel chemotherapy regimens (per treating physician's determination)
Patients must be ≥ 18 years of age
Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
Patients must have adequate organ and bone marrow function as determined by the treating physician to be considered to be clinically fit for the physician-determined chemotherapy regimen
Patients must agree to use adequate contraception: (e.g. hormonal or barrier method of birth control for a patient of child-bearing potential (POCBP), prior to study entry, and for the duration of study participation. Should a female patient, or a female partner of a patient become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician and study doctor immediately. Male patients with a female partner(s) of childbearing potential must agree to use highly effective contraceptive measures throughout the study starting with the screening visit through the time period indicated for standard of care drugs , after the last dose of study treatment is received. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner. Note: A POCBP is any patient (regardless of gender, sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) with an egg-producing reproductive tract who meets the following criteria:
POCBP must have a negative pregnancy test prior to registration on study
Patients must have the ability to understand and the willingness to sign a written informed consent document and comply with the study requirements
Exclusion Criteria:
Patients with the presence of any of the following genetic or molecular abnormalities:
Patients who are currently participating in another study and receiving a study drug
Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia, neuropathy and other non-significant adverse events per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 6.0
Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen (per treating physician's determination)
Patients who are pregnant or nursing
Patients who have an uncontrolled intercurrent illness (as determined by treating physician), including, but not limited to any of the following:
Patient with presence of any concurrent medical or psychiatric condition/social situations which would make them inappropriate candidates for entry into this study or that would limit compliance with study requirements, or would compromise the patient's safety or study endpoints, in the treating investigator's judgment
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Patients receive gemcitabine and nab-paclitaxel with or without radiation therapy per SOC. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. After 8 week restaging, patients may continue to receive treatment for up to 16 or 24 weeks at the discretion of the multidisciplinary tumor board. Starting 21 days after last dose of chemotherapy, patients undergo surgical resection. Additionally, patients undergo blood sample collection and CT or MRI as clinically indicated throughout the study.
Patients receive either physicians choice of either fluorouracil, leucovorin, irinotecan, and oxaliplatin or gemcitabine and nab-paclitaxel with or without radiation therapy per SOC. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. After 8 week restaging, patients may continue to receive treatment for up to 16 or 24 weeks at the discretion of the multidisciplinary tumor board. Starting 21 days after last dose of chemotherapy, patients undergo surgical resection. Additionally, patients undergo blood sample collection and CT or MRI as clinically indicated throughout the study.
Gemcitabine, Nab-paclitaxel, Durvalumab, and Oleclumab Before Surgery for the Treatment of in Resectable/Borderline Resectable Primary Pancreatic Cancer
Personalize (Signature Driven) Neoadjuvant Chemotherapy Trial for Patients With Resectable Borderline Pancreatic Ductal Adenocarcinoma.
Perioperative Therapy for Resectable and Borderline-Resectable Pancreatic Adenocarcinoma With Molecular Correlates
Gemcitabine, Cisplatin and Nab-Paclitaxel as Neoadjuvant Treatment for Patients With Resectable or Borderline Resectable Pancreatic Cancer
NeoOPTIMIZE: Early Switching of mFOLFIRINOX or Gemcitabine/Nab-Paclitaxel Before Surgery for the Treatment of Resectable, Borderline Resectable, or Locally-Advanced Unresectable Pancreatic Cancer
Neoadjuvant Chemotherapy for Borderline Resectable and Locally Advanced Pancreatic Adenocarcinoma
New and Emerging Therapies for the Treatment of Resectable, Borderline Resectable, or Locally Advanced Pancreatic Cancer, PIONEER-Panc Study