Neoadjuvant Avutometinib/Defactinib and mFOLFIRINOX Combination Therapy in Pancreatic Adenocarcinoma

NCT07824960 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 302740
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this study is to find out if taking two oral study drugs (avutometinib and defactinib) are safe for patients with pancreatic ductal adenocarcinoma (PDAC). Researchers also want to see if the drugs can slow down tumor growth and shrink tumors for possible surgery. These drugs are approved by the FDA to treat a certain kind of ovarian cancer. This study has two parts:

• Part A is for patients whose cancer has spread to other parts of the body.
• Part B is for patients whose cancer has not spread, but who cannot have surgery. Participants will take both drugs as told by their doctor with their regular cancer medicine. Participants will also give blood samples throughout the study. These samples will help researchers learn about how participants respond to treatment and about their pancreatic cancer.

Conditions

PDAC - Pancreatic Ductal Adenocarcinoma; Pancreatic Cancer; Metastatic Pancreatic Carcinoma; Locally Advanced Pancreatic Cancer

Keywords

avutometinib; defactinib; PDAC; pancreatic cancer; dual RAF/MEK inhibitor; RAF inhibitor; MEK inhibitor

Outcome Measures

Primary Outcomes (2)

• Dose limiting toxicities (DLTs) - Part A

  For each participant, we will determine DLTs during first cycle of neoadjuvant therapy

  1 cycle (28 days)

• Objective response (OR) - Part B

  PR (partial response) or CR (complete response) per RECIST criteria

  through 6 cycles (each cycle is 28 days)

Secondary Outcomes (3)

• TRAEs (Treatment-related adverse events)

  Up to 30 days after completion of study treatment (average of 6 months)

• (Part B only): Surgical resection rate

  after all participants complete up to 6 cycles (each cycle is 28 days)

• EFS (event free-survival)

  through study completion (an average of a year)

Study Arms (1)

Neoadjuvant avutometinib + defactinib with standard of care chemotherapy

EXPERIMENTAL

Avutometinib and defactinib will be taken for 3 weeks, followed by a 1-week rest period in each 4 week cycle.

Drug: Avutometinib (VS-6766) + Defactinib (VS-6063)

Interventions

Avutometinib (VS-6766) + Defactinib (VS-6063) DRUG

Participants will receive avutometinib and defactinib in combination with mFOLFIRINOX (standard of care chemotherapy) in 28-day cycles for up to 6 cycles.

Neoadjuvant avutometinib + defactinib with standard of care chemotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed and dated informed consent form.
• Individuals ≥ 18 years of age.
• Stated willingness to comply with all study procedures and availability for the duration of the study.
• Ability to take oral medication and be willing to adhere to the study intervention regimen.
• Ability to receive mFOLFIRINOX.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Adenocarcinoma of the pancreas, confirmed by histology or cytology.
• Part A: Metastatic pancreatic cancer
• Part B: Borderline resectable or locally advanced PDAC not eligible for primary surgical resection per institutional standards and following a multidisciplinary discussion at local tumor board
• No prior systemic or localized treatment for PDAC.
• Radiographically measurable disease of at least one site by computed tomography (CT) or magnetic resonance (MR) imaging, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• Individuals must have adequate organ function defined by the following laboratory parameters:
• Absolute neutrophil count (ANC): ≥ 1500/mm3 Platelets: ≥100,000/mm3 Hemoglobin: ≥9 g/dL Serum Creatinine: ≤ 1.5 x ULN or creatinine clearance rate of ≥ 50 mL/min as calculated by the Cockcroft-Gault formula Bilirubin: ≤ 1.5 x ULN (except in patients with Gilbert's disease, where bilirubin to 3x ULN is allowed).
• AST and ALT: ≤ 2.5 x ULN or ≤ 5 x ULN for patients with liver metastasis INR: ≤ 1.5 x ULN in the absence of anticoagulation or therapeutic levels in the presence of anticoagulation Creatine phosphokinase (CPK): ≤ 2.5 x ULN
• Baseline corrected QT interval (QTc) interval ≤ 480 millisecond (ms) (CTCAE v5.0, Grade 0-1) using Fridericia's QT correction formula.

You may not qualify if:

• Patients with pancreatic neuroendocrine tumors (PNET), islet cell tumors, mucinous cystic, acinar or squamous (≥ 50%) histology are excluded.
• Prior treatment for pancreatic ductal adenocarcinoma.
• Presence of distant metastases (Part B only).
• Presence of symptomatic ascites or the need for paracentesis within 2 weeks prior to registration.
• Major surgery within 4 weeks (excluding placement of vascular access) of registration.
• Patients with a prior or concurrent malignancy within past 5 years whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Examples of malignancies that may be permitted include non-melanoma skin cancer, localized prostate cancer treated with curative intent or under active surveillance, localized thyroid cancer (papillary or follicular), non-muscle invasive low-grade bladder cancer, resected gastrointestinal stromal tumor, stage I testicular cancer post orchiectomy, WHO (World Health Organization) grade 1 meningioma.
• Prior treatment with either inhibitors of the RAS/MAPK pathway \[e.g., MEK inhibitors\] or inhibitors of FAK within the last 6 months.
• Patients on treatment with warfarin within 5 days of registration. Patients on warfarin for deep vein thrombosis or pulmonary embolism can be converted to low-molecular-weight heparin or direct oral anticoagulants (DOACs).
• Participants requiring medications or supplements with potential for drug-drug interactions, specifically strong CYP3A4 or CYP2C9 inhibitors or inducers (Table 7). Participants must be off these medications for 7 days prior to the first dose of study intervention(s). These substances should also be avoided during the course of therapy.
• Patients with known UGT1A1 deficiency based on genetic analysis of the UGT1A1 gene.
• Receipt of live vaccines (not limited to the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG) within 30 days of registration. Seasonal influenza vaccines for injection are generally killed virus vaccines and are permitted. However, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not permitted.
• Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
• Active Human Immunodeficiency Virus (HIV) infection, unless patient is on effective anti-retroviral therapy and was shown to have a negative viral load within 6 months of registration.
• Active Hepatitis B Virus (HBV) or Hepatitis C (HCV) infection, unless patient is on antiviral therapy and was shown to have a negative viral load test within 6 months of registration.
• Active skin disorder that requires current systemic therapy.

Sponsors & Collaborators

• University of Virginia: lead
• Verastem, Inc.: collaborator

Study Sites (1)

University of Virginia Health System

Charlottesville, Virginia, 22908, United States

Location

MeSH Terms

Conditions

Pancreatic Neoplasms

Interventions

defactinib

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Study Officials

• Matthew Reilley, MD

  University of Virginia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Amanda Neider

CONTACT

434-566-6768; ALN4K@uvahealth.org

Kristen Harris

CONTACT

(434) 297-5724; KAH2GV@uvahealth.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor; Principal Investigator

Study Record Dates

• First Submitted: September 2, 2026
• First Posted: September 17, 2026
• Study Start: October 1, 2026
• Primary Completion (Estimated): April 1, 2029
• Study Completion (Estimated): April 1, 2030
• Last Updated: September 17, 2026

Record last verified: 2026-09

Locations

US (1)