Defactinib + Radiotherapy for Pancreatic Cancer

Not currently recruiting at 1 trial location

Overseen By Hyun Kim

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

Must not be taking: FAK inhibitors, Immunotherapy

Disqualifiers: Other malignancy, Immunodeficiency, Autoimmune, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for advanced pancreatic cancer. It compares standard chemotherapy and precise radiation therapy (Stereotactic Body Radiotherapy) with and without an added drug called defactinib, which might improve outcomes like survival and cancer control. The trial seeks patients with pancreatic cancer that cannot be easily removed by surgery and who have completed three months of chemotherapy without disease progression. Participants will help researchers determine if adding defactinib offers better results and manageable side effects. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you require continued use of warfarin and cannot switch to another anticoagulant. Also, you should not have taken any investigational agents within 4 weeks before the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that defactinib, when used with other treatments, has generally been well-tolerated. In combination with drugs like pembrolizumab and gemcitabine, defactinib showed promising results without major safety issues, suggesting it might be safe to use, although side effects can still occur.

For stereotactic body radiotherapy (SBRT), previous studies have shown mixed results. Some studies report it is very safe with no severe side effects, while others found that up to 34% of patients experienced more serious side effects. This indicates that while SBRT can be safe, there remains a chance of serious side effects.

Overall, both defactinib and SBRT have shown potential in studies, but there is always a possibility of side effects. It is important for patients to discuss the risks and benefits with their doctors. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining Defactinib with Stereotactic Body Radiotherapy (SBRT) for pancreatic cancer because it offers a novel approach compared to traditional chemotherapy or surgery. Defactinib works by targeting cancer stem cells, a unique mechanism that could potentially prevent tumor regrowth after radiation. Additionally, the use of magnetic resonance adaptive SBRT allows for precise targeting of cancer cells, potentially reducing damage to surrounding healthy tissues. This combination aims to enhance the effectiveness of radiation therapy and improve patient outcomes in a condition that is notoriously difficult to treat.

What evidence suggests that this trial's treatments could be effective for pancreatic cancer?

Research has shown that defactinib, a type of drug, might enhance the effectiveness of pancreatic cancer treatments. In studies, when combined with other treatments, defactinib allowed patients to live without cancer progression for about 5 months and survive overall for about 8.3 months. In this trial, some participants will receive defactinib with stereotactic body radiotherapy (SBRT). SBRT alone has proven effective for pancreatic cancer, with patients living about 14 months on average and achieving cancer control in 85% of cases after one year. These findings suggest that using defactinib with SBRT, as tested in this trial, could potentially improve outcomes for pancreatic cancer patients. ^{2 3 6 7 8}

Who Is on the Research Team?

Carl DeSelm, M.D., Ph.D.

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

Adults over 18 with advanced pancreatic adenocarcinoma that's borderline resectable or unresectable, who've had at least 3 months of chemo without disease progression. Participants must have a life expectancy over 3 months, adequate organ function, and agree to use effective contraception. Excluded are those with other recent cancers, certain health conditions like uncontrolled hypertension or active infections, prior FAK inhibitor treatment, known allergies to study drugs' components, or inability to swallow pills.

Inclusion Criteria

My bone marrow and organs are functioning normally.

Your corrected QT interval is less than 480 milliseconds.

My blood clotting time is normal or managed with medication.

Exclusion Criteria

I have had pneumonitis treated with steroids or have it now.

Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry

I haven't needed systemic treatment for an autoimmune disease in the last 2 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy

Participants receive standard of care chemotherapy

Estimated 12 weeks

Radiation

Participants receive 5 fractions of magnetic resonance adaptive stereotactic body radiation therapy (SBRT)

1 week

Treatment with Defactinib

Participants in the experimental arm receive 17 cycles of defactinib, each cycle lasting 21 days

Approximately 12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

What Are the Treatments Tested in This Trial?

Interventions

• Defactinib
• Stereotactic Body Radiotherapy

Trial Overview The trial is testing if adding the drug defactinib to standard chemotherapy and stereotactic body radiotherapy (SBRT) improves survival in patients with advanced pancreas cancer compared to SBRT alone. Patients will be randomly assigned in a ratio of 6:1 to either the experimental group receiving defactinib or the control group not receiving it.

How Is the Trial Designed?

Group I: Adaptive SBRT + Defactinib Experimental Treatment 4 Interventions

* Participants in this study will receive 5 fractions of magnetic resonance adaptive stereotactic body radiation therapy (SBRT) and seventeen 21-day cycles of defactinib (beginning on Day 2 of radiation). * Participants 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 (+/- 1 week). These participants will discontinue defactinib the day prior to the operation and will resume taking it for the remainder of the 17 cycles 4 to 6 weeks after surgery. Participants who are not candidates for surgical resection will continue to receive defactinib uninterrupted. All participants should receive 17 cycles of defactinib unless they experience disease progression or intolerable toxicity.

Group II: Adaptive SBRT Active Control 2 Interventions

-Participants in this study will receive 5 fractions of magnetic resonance adaptive stereotactic body radiation therapy (SBRT)

Stereotactic Body Radiotherapy is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Stereotactic Body Radiation Therapy for:

• Lung cancer
• Liver cancer
• Spine tumors
• Pancreatic cancer
• Prostate cancer

Approved in United States as Stereotactic Body Radiation Therapy for:

• Early-stage lung cancer
• Liver cancer
• Spine tumors
• Pancreatic cancer
• Prostate cancer

Approved in Canada as Stereotactic Body Radiation Therapy for:

• Lung cancer
• Liver cancer
• Spine tumors
• Pancreatic cancer
• Prostate cancer

Approved in Japan as Stereotactic Body Radiation Therapy for:

• Lung cancer
• Liver cancer
• Spine tumors
• Pancreatic cancer
• Prostate cancer

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Verastem, Inc.

Industry Sponsor

Trials

42

Recruited

2,800+

Published Research Related to This Trial

Stereotactic ablative radiotherapy (SABR) shows promise as a treatment for inoperable pancreatic cancer, with only 8.1% of patients experiencing significant acute toxicities and a median overall survival of 8.4 months.

The study suggests that increasing the radiation dose (biological effective dose) could improve patient outcomes, but careful planning is necessary to minimize the risk of severe gastrointestinal toxicity, especially in patients with larger tumor volumes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic ablative radiotherapy (SABR) as primary, adjuvant, consolidation and re-treatment option in pancreatic cancer: scope for dose escalation and lessons for toxicity. Goldsmith, C., Plowman, PN., Green, MM., et al.[2018]

In a phase 2 study involving 26 patients with refractory pancreatic cancer, the combination of ipilimumab, nivolumab, tocilizumab, and stereotactic body radiotherapy (SBRT) did not result in any objective responses, indicating limited efficacy for this treatment regimen.

While 19% of patients achieved stable disease, the median overall survival was only 5.3 months, and 73% experienced treatment-related adverse events, highlighting safety concerns associated with this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study of ipilimumab, nivolumab, and tocilizumab combined with stereotactic body radiotherapy in patients with refractory pancreatic cancer (TRIPLE-R). Chen, IM., Donia, M., Chamberlain, CA., et al.[2023]

The use of neoadjuvant stereotactic body radiation therapy (SBRT) for pancreatic cancer is on the rise, increasing from 0% in 2004 to 9.5% in 2015, particularly in patients with more advanced disease.

Patients receiving neoadjuvant chemo-SBRT showed improved overall survival rates and higher rates of R0 resection compared to those receiving chemotherapy or conventional radiation therapy, suggesting that SBRT may offer significant benefits in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant stereotactic body radiation therapy for nonmetastatic pancreatic adenocarcinoma. Jiang, W., Haque, W., Verma, V., et al.[2023]

In a phase 2 clinical trial involving 35 patients with borderline resectable (BR) and locally advanced (LA) pancreatic cancer, the combination of induction chemotherapy (gemcitabine and capecitabine) followed by stereotactic ablative radiation therapy (SABR) showed high rates of successful surgical resection, with 91.7% of surgeries resulting in R0 resection.

The treatment was well-tolerated, with no severe toxicities observed from SABR, and the study demonstrated promising overall survival rates, particularly for BR patients who underwent surgery, highlighting the potential efficacy of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a prospective phase 2 clinical trial of induction gemcitabine/capecitabine followed by stereotactic ablative radiation therapy in borderline resectable or locally advanced pancreatic adenocarcinoma. Quan, K., Sutera, P., Xu, K., et al.[2023]

Stereotactic ablative radiation therapy (SABR) for metastatic pancreatic cancer showed significant effectiveness in reducing abdominal pain and decreasing the need for opioids, with a 46% relative reduction in opioid use after treatment.

In a study of 27 patients, SABR was found to be safe, with only 7% experiencing severe toxicity, and it resulted in a median overall survival of 7 months, indicating its potential as a palliative treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Utility of Stereotactic Ablative Radiation Therapy for Palliation of Metastatic Pancreatic Adenocarcinoma. Koong, AJ., Toesca, DAS., Baclay, JRM., et al.[2023]

The PANCOSAR trial is investigating the effectiveness of stereotactic ablative body radiotherapy (SABR) in improving overall survival and quality of life for patients with localized pancreatic ductal adenocarcinoma (PDAC) who are unfit for surgery or chemotherapy, involving a multicenter approach with a focus on patient-reported outcomes.

The study will compare the outcomes of patients receiving SABR combined with best supportive care against those receiving only best supportive care, assessing factors like pain relief, quality of life, and treatment-related toxicity over a 12-month period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic ablative radiotherapy or best supportive care in patients with localized pancreatic cancer not receiving chemotherapy and surgery (PANCOSAR): a nationwide multicenter randomized controlled trial according to a TwiCs design. Doppenberg, D., Besselink, MG., van Eijck, CHJ., et al.[2023]

In a study of 74 patients with locally advanced pancreatic cancer (LAPC) treated with chemotherapy followed by stereotactic ablative radiation therapy (SABR), the median overall survival was 19.6 months from diagnosis and 12.1 months from the start of SABR, indicating promising efficacy of this treatment approach.

SABR was found to be well-tolerated, with only a 2.7% rate of severe fatigue and late gastrointestinal toxicity, and better outcomes were associated with patients who had a Karnofsky Performance Status (KPS) score of ≥90, were younger than 70 years, and had no pain prior to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing patient selection for stereotactic ablative radiotherapy in patients with locally advanced pancreatic cancer after initial chemotherapy - a single center prospective cohort. Doppenberg, D., Lagerwaard, FJ., van Dieren, S., et al.[2023]

Stereotactic body radiotherapy (SBRT) offers a promising alternative to conventional radiotherapy for patients with locally advanced unresectable pancreatic cancer, potentially improving local control and disease outcomes due to its ability to deliver high doses of radiation in a shorter treatment time.

Current research is exploring the advantages of SBRT in terms of quality of life and cost-effectiveness, indicating a shift towards more effective management strategies for pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic body radiotherapy in the treatment of pancreatic cancer. Trakul, N., Koong, AC., Chang, DT.[2022]

The SPARC study aims to determine the maximum tolerated dose of margin-intensive stereotactic radiotherapy for patients with borderline-resectable pancreatic cancer, with a focus on improving resection rates and local disease control.

Up to 24 patients will be recruited, and the study will assess not only the safety of the treatment but also secondary outcomes like resection margin status and overall survival, providing valuable insights into the efficacy of this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase-I trial of pre-operative, margin intensive, stereotactic body radiation therapy for pancreatic cancer: the 'SPARC' trial protocol. Holyoake, DL., Ward, E., Grose, D., et al.[2022]

In a study of 18 patients with locally recurrent or oligometastatic pancreatic cancer, the simultaneous integrated protection (SIP) approach for stereotactic body radiotherapy (SBRT) showed a favorable toxicity profile, with only one patient experiencing significant acute toxicity.

Both treatment approaches (with and without SIP) resulted in similar local control rates, and the median overall survival was 13.2 months, indicating that SIP does not compromise treatment efficacy while potentially reducing harm to surrounding organs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic body radiotherapy (SBRT) in recurrent or oligometastatic pancreatic cancer : A toxicity review of simultaneous integrated protection (SIP) versus conventional SBRT. Gkika, E., Adebahr, S., Kirste, S., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36228156/

A Phase I Dose Escalation and Expansion Study - PubMed - NIH The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated and safe, had promising preliminary efficacy, and showed biomarker activity.

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e16403

Avutometinib/defactinib and gemcitabine/nab-paclitaxel ... Results: At data cutoff (03Jan2025), 54 pts were enrolled and included in the safety analysis: 46% men, median age 59 years (range, 36-79), and ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03875820?term=VS-6063&rank=9

NCT03875820 | Phase I Trial of Defactinib and VS-6766. This is a multi-centre, investigator-initiated, dose escalation, Phase I trial of the combination of the FAK inhibitor, Defactinib ( VS-6063 ), and the dual ...

4. letswinpc.org letswinpc.org/research/more-effective-radiotherapy-advanced-pancreatic-cancer/

More Effective Radiotherapy for Advanced Pancreatic ... This phase II trial for patients with advanced pancreatic cancer will test if the FAK inhibitor defactinib can enhance the response to radiotherapy.

5. aacrjournals.org aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-22-0308/709765/am/Defactinib-pembrolizumab-and-gemcitabine-in

Defactinib, pembrolizumab, and gemcitabine in patients with ... The median PFS and OS on study treatment were 5.0 months and 8.3 months, respectively. Conclusions: The combination of defactinib, pembrolizumab, and ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9772237/

Defactinib, pembrolizumab, and gemcitabine in patients ... The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated and safe, had promising preliminary efficacy and showed biomarker activity in ...

7. investor.verastem.com investor.verastem.com/news-releases/news-release-details/verastem-oncology-announces-positive-updated-results-ramp-205

Press Release - Verastem, Inc. Selected recommended Phase 2 dose: Dose level 1 demonstrated an ORR of 83% (10/12) in frontline metastatic pancreatic ductal adenocarcinoma.

8. nature.com nature.com/articles/s41591-025-03763-y

Defactinib with avutometinib in patients with solid tumors Key findings include an objective response rate of 42.3% (11 of 26; 95% confidence interval 23.4–63.1) and a median progression-free survival of ...