Stereotactic Body Radiotherapy Plus FAK and RAF/MEK Inhibition in Advanced Pancreatic Adenocarcinoma

NCT07126158 | Recruiting Phase 2 DMC FDA Drug FDA Device

• 1 other identifier: 202602073
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

Advanced pancreatic cancer patients receiving treatment of adaptive stereotactic body radiotherapy (SBRT) with concurrent and adjuvant defactinib plus avutometinib will have increased progression-free survival (PFS) compared to historical PFS rates for patients receiving adaptive SBRT alone.

Conditions

Pancreatic Adenocarcinoma; Cancer of the Pancreas; Pancreas Cancer; Pancreatic Cancer

Keywords

Pancreas cancer; SBRT; FAK; MEK

Outcome Measures

Primary Outcomes (1)

• Progression-free survival (PFS) - Experimental Arm Only

  Defined as the days from the date of standard of care (SOC) chemotherapy treatment start to progression or death.

  Through completion of follow-up (up to 2 years)

Secondary Outcomes (6)

• Number of patients with acute toxicity - Experimental Arm Only

  From start of treatment through 90 days

• Number of patients with late toxicity - Experimental Arm Only

  From day 91 through 2 years

• Local control - Experimental Arm Only

  At 12 months

• Distant metastasis progression-free survival (DM-PFS) - Experimental Arm Only

  Through completion of follow-up (up to 2 years)

• Cumulative incidence of objective response (CI-OR) - Experimental Arm Only

  At 12 weeks post-adaptive SBRT (estimated to be 13 weeks)

Study Arms (2)

Experimental Arm: SBRT + Defactinib + Avutometinib

EXPERIMENTAL

Participants will receive approximately 12 months of treatment on study with 5 fractions of adaptive SBRT with 12 cycles of oral defactinib + avutometinib beginning on Day 2 of radiation. Cycles are 28 days in length. Defactinib is dosed twice a day and avutometinib is dosed twice a week (e.g. Monday and Thursday, Tuesday and Friday, etc.) on a 3 weeks on, 1 week off schedule. The first 6 participants will be enrolled in the Safety Lead-In cohort to monitor for dose-limiting toxicities. Patients who are candidates for surgical resection will undergo standard of care surgery at 2 weeks post-end of SBRT (+/- 1 weeks) or 12 weeks post-end of SBRT (+/- 2 weeks). These patients will discontinue defactinib and avutometinib the day prior to the operation and will resume taking it 4 to 6 weeks after surgery for the remainder of the 12 cycles. Patients who are not candidates for surgical resection will continue to receive defactinib plus avutometinib uninterrupted.

Radiation: Stereotactic body radiotherapy; Drug: Defactinib; Drug: Avutometinib

Control Arm: SBRT

ACTIVE COMPARATOR

Participants will receive 5 fractions of adaptive SBRT.

Radiation: Stereotactic body radiotherapy

Interventions

Stereotactic body radiotherapy RADIATION

MRIdian and Ethos (adaptive radiation platforms)

Also known as: SBRT

Control Arm: SBRT; Experimental Arm: SBRT + Defactinib + Avutometinib

Defactinib DRUG

Taken with 30 minutes of a meal

Experimental Arm: SBRT + Defactinib + Avutometinib

Avutometinib DRUG

Can be taken without regard to food.

Experimental Arm: SBRT + Defactinib + Avutometinib

Eligibility Criteria

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

You may qualify if:

• Histologically or cytologically confirmed advanced pancreatic adenocarcinoma that is considered borderline resectable or locally advanced per institutional standardized criteria of unresectability or medical inoperability (NCCN guidelines 2.2021 PANC-C 1 of 2).
• Patients with locoregional adenopathy are eligible as long as all suspicious lymph nodes are deemed to be adjacent to the primary tumor as per radiation oncologist assessment.
• Patients must have received at least 2 months of systemic chemotherapy, such as FOLFOX, FOLFIRINOX, gemcitabine, nab-paclitaxel, cisplatin, or other regimens, for this disease without progression of local or systemic disease. Newly diagnosed patients may be screened for enrollment in this study and can be enrolled once they have completed 2 months of systemic chemotherapy (and still meet all eligibility criteria) prior to randomization. The last dose of chemotherapy must be ≥ 2 weeks prior to randomization.
• At least 18 years of age.
• ECOG performance status ≤ 1.
• Life expectancy \> 3 months
• Adequate bone marrow and organ function as defined below:
• Absolute neutrophil count ≥ 1.5 K/cumm
• Platelets ≥ 100 K/cumm
• Hemoglobin ≥ 9.0 g/dL without transfusion in the preceding 14 days.
• Total bilirubin ≤ 1.5 x IULN; no prior history of Gilbert's syndrome
• AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN or ≤ 5.0 x IULN if due to liver involvement by tumor
• Creatinine clearance ≤ 1.5 x IULN or glomerular filtration rate of ≥ 60 mL/min
• INR ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR or PTT is within therapeutic range of intended use of anticoagulants
• aPTT ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR or PTT is within therapeutic range of intended use of anticoagulants

You may not qualify if:

• A history of other malignancy with the exception of prior or concurrent malignancies whose natural history is unlikely to interfere with the safety or efficacy of the investigational regimen (in the opinion of the treating physician).
• Clinically evident ascites or pleural effusion that requires therapeutic paracentesis or thoracentesis.
• Prior treatment with a drug of the FAK inhibitor or RAF/MEK inhibitor class, or with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
• Prior anti-human antibody response (AHA or ADA).
• Currently receiving any other investigational agents or has received any other investigational agents within 4 weeks or 5 half-lives, whichever is shorter, of randomization.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to defactinib, avutometinib, or other agents used in the study, or a history of hypersensitivity to any of the inactive ingredients (hydroxypropylmethylcellulose, mannitol, magnesium stearate) of the investigational product.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy not routinely associated with chemotherapeutic regimen.
• Requires continued use of warfarin for anticoagulation and cannot stop warfarin or be safely switched to another anticoagulant or direct oral anticoagulant.
• Has an active autoimmune disease requiring systemic treatment with use of disease modifying agents, corticosteroids, or immunosuppressive drugs within the past 2 years. Replacement therapy such as thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc. is not considered a form of systemic treatment.
• Received a live vaccine within 30 days prior to randomization. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. FluMist) are live attenuated vaccines and are not allowed.
• Known history of hepatitis B (defined as hepatitis B surface antigen \[HBsAg\] reactive) or known active hepatitis C virus (defined as HCV RNA \[qualitative\] is detected).
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Has a known history of active TB (bacillus tuberculosis).
• Major surgery within 28 days prior to randomization.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of randomization.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Verastem, Inc.: collaborator
• The Foundation for Barnes-Jewish Hospital: collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

RECRUITING

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Pancreatic Neoplasms

Interventions

Radiosurgery; defactinib

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Patrick Grierson, M.D., Ph.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Patrick Grierson, M.D., Ph.D.

CONTACT

314-747-7689; grierson@wustl.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients will be randomized on a 5:1 basis to the Experimental Arm or the Control arm. The first 6 patients randomized and treated on the Experimental Arm will be considered the safety lead-in. Following completion of the safety lead-in, additional patients will be accrued in order to reach a total of 30 patients on the Experimental arm (inclusive of the safety lead-in cohort) and 6 on the Control arm.

Study Record Dates

• First Submitted: August 10, 2025
• First Posted: August 17, 2025
• Study Start: April 10, 2026
• Primary Completion (Estimated): April 30, 2030
• Study Completion (Estimated): April 30, 2030
• Last Updated: April 15, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)