Defactinib + Radiotherapy for Pancreatic Cancer

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

42 Participants Needed

Trial Summary

What is the purpose of this trial?

Patients with advanced pancreas adenocarcinoma will be randomized on a 6:1 basis to receive standard of care chemotherapy followed by adaptive stereotactic body radiotherapy (SBRT) with concurrent and adjuvant FAK inhibitor defactinib (experimental arm) or standard of care chemotherapy followed by SBRT (control arm). Patients enrolled to the experimental arm will be assessed for clinical outcomes such as progression free survival (PFS), local control, distant control, and toxicity. The first 6 patients randomized to the experimental arm will be considered the safety lead-in and will be assessed for dose-limiting toxicities (DLTs). The 6 patients randomized to the control arm will be evaluated for correlatives but will not be included in the analysis for primary and secondary endpoints.

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.

What data supports the effectiveness of the treatment Defactinib + Radiotherapy for Pancreatic Cancer?

Research suggests that stereotactic ablative radiotherapy (SABR) can be a promising treatment for pancreatic cancer, offering high-dose, precise radiation that may improve disease control and quality of life for patients who cannot undergo surgery. This type of radiotherapy has shown potential benefits in local control and disease outcomes, making it a valuable option for those with locally advanced pancreatic cancer. ^{1 2 3 4 5}

Is the combination of Defactinib and Stereotactic Body Radiotherapy safe for humans?

Stereotactic Ablative Radiotherapy (SABR) is generally considered safe, but gastrointestinal (GI) toxicity is a concern, meaning it can cause issues in the stomach and intestines. The safety of Defactinib specifically in combination with SABR for pancreatic cancer isn't detailed in the provided research, but SABR alone has been studied for its safety in pancreatic cancer treatment. ^{1 2 3 6 7}

How is the treatment of Defactinib + Stereotactic Body Radiotherapy (SBRT) for pancreatic cancer different from other treatments?

The combination of Defactinib with Stereotactic Body Radiotherapy (SBRT) for pancreatic cancer is unique because SBRT delivers high-dose, precise radiation over a short period, potentially improving disease control and quality of life for patients who cannot undergo surgery or chemotherapy. This approach is particularly beneficial for those with localized pancreatic cancer, offering a novel option compared to traditional treatments. ^{1 3 8 9 10}

Research Team

Hyun Kim

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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]

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]

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]

References

1. England 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. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

The Utility of Stereotactic Ablative Radiation Therapy for Palliation of Metastatic Pancreatic Adenocarcinoma. [2023]

3. United States 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. [2023]

4. Switzerland 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. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Stereotactic body radiotherapy in the treatment of pancreatic cancer. [2022]

6. England 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. [2018]

7. Germany 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. [2022]

8. England 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). [2023]

9. England pubmed.ncbi.nlm.nih.gov

Neoadjuvant stereotactic body radiation therapy for nonmetastatic pancreatic adenocarcinoma. [2023]

10. England 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. [2022]