Stereotactic Body Radiotherapy and Focal Adhesion Kinase Inhibitor in Advanced Pancreas Adenocarcinoma

• ClinicalTrials.gov Identifier: NCT04331041
• Recruitment Status: Recruiting
• First Posted: April 2, 2020
• Last Update Posted: January 31, 2023
• Sponsor: Washington University School of Medicine
• Collaborators: National Cancer Institute (NCI); Verastem, Inc.
• Information provided by (Responsible Party): Washington University School of Medicine

Study Description

Brief Summary:

Patients with advanced pancreas adenocarcinoma will be randomized on a 6:1 basis to receive standard of care chemotherapy followed by 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.

Hypothesis: locally advanced pancreas cancer patients treated with SBRT and concurrent plus adjuvant defactinib will have increased PFS compared to historical rates for patients receiving SBRT alone.

Condition or disease	Intervention/treatment	Phase
Pancreas Cancer; Cancer of the Pancreas; Pancreas Adenocarcinoma	Device: MR-guided stereotactic body radiation therapy; Drug: Defactinib; Procedure: Tumor biopsy; Procedure: Research blood draw	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Stereotactic Body Radiotherapy and Focal Adhesion Kinase Inhibitor in Advanced Pancreas Adenocarcinoma
• Actual Study Start Date: July 21, 2021
• Estimated Primary Completion Date: June 30, 2026
• Estimated Study Completion Date: June 30, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: MR-guided SBRT + Defactinib; Participants in this study will receive 5 fractions of magnetic resonance (MR)-guided 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.	Device: MR-guided stereotactic body radiation therapy; Will be administered using MRIdian or MRIdian Linac system; 50 Gy in 5 fractions; Other Name: MR-guided SBRT; Drug: Defactinib; -Oral drug 400 mg twice a day; Other Names: VS-6063; PF-04554878; Procedure: Tumor biopsy; -Baseline and 12-14 weeks after end of SBRT (or at time of surgery); Procedure: Research blood draw; -Baseline, 6-8 weeks after the end of SBRT, and 12-14 weeks after the end of SBRT
Active Comparator: MR-guided SBRT; -Participants in this study will receive 5 fractions of magnetic resonance (MR)-guided stereotactic body radiation therapy (SBRT)	Device: MR-guided stereotactic body radiation therapy; Will be administered using MRIdian or MRIdian Linac system; 50 Gy in 5 fractions; Other Name: MR-guided SBRT; Procedure: Research blood draw; -Baseline, 6-8 weeks after the end of SBRT, and 12-14 weeks after the end of SBRT

Outcome Measures

Primary Outcome Measures :

1. Progression-free survival (PFS) [ Time Frame: Through completion of follow-up (estimated to be 24 months) ]
   • PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first
   • Progressive disease: At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

Secondary Outcome Measures :

1. Safety and toxicity profile of the regimen as measured by incidence of acute adverse events [ Time Frame: From start of SBRT through 90 days ]
   -The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.
2. Safety and toxicity profile of the regimen as measured by incidence of late adverse events [ Time Frame: From 91 days through completion of follow-up (estimated to be 24 months) ]
   -The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.
3. Overall survival [ Time Frame: Through completion of follow-up (estimated to be 24 months) ]
   -Overall survival as defined as the time from the date of treatment until death; censored at last follow-up if death is not observed
4. Distant metastasis progression-free survival [ Time Frame: Through completion of follow-up (estimated to be 24 months) ]
   -Defined as the days from the date of the treatment to distant metastasis progression or death
5. Objective response rate [ Time Frame: 12-14 weeks post-radiation therapy ]
   -Objective response rate as determined by RECIST 1.1 criteria
6. Local control [ Time Frame: Through completion of follow-up (estimated to be 24 months) ]
   -Local control as defined by no progression of the primary tumor by RECIST 1.1 criteria

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Histologically or cytologically confirmed locally advanced pancreas adenocarcinoma that is considered borderline resectable or unresectable 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.
• At least 3 months of systemic chemotherapy 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 3 months of systemic chemotherapy (and still meet all eligibility criteria) prior to the start of study treatment.
• At least 18 years of age.
• ECOG performance status ≤ 1
• Life expectancy > 3 months

• Normal bone marrow and organ function within 21 days of randomization as defined below:

  • Absolute neutrophil count ≥ 1,500/mcL
  • Platelets ≥ 100,000/mcL
  • Hemoglobin ≥ 9.0 g/dL
  • 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
  • Albumin ≥ 2.5 mg/dL
• Corrected QT interval (QTc) < 480 ms (as calculated by the Fridericia correction formula).
• The effects of defactinib on the developing human fetus are unknown. For this reason and because radiation therapy is known to be teratogenic, women of childbearing potential and men must agree to use highly effective contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and 120 days after completion of the study
• Ability to understand and willingness to sign an IRB approved written informed consent document

Exclusion Criteria:

• A history of other malignancy with the exception of malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease.
• Clinical evident ascites or pleural effusion that requires therapeutic paracentesis or thoracentesis.
• Prior treatment with a drug of the FAK 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 receive any other investigational agents within 4 weeks or 5 half-lives or planned first dose of study agents.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to defactinib or other agents used in the study.
• 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
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, hypertension, immunosuppression, autoimmune conditions, or underlying pulmonary disease.
• Has an active autoimmune disease requiring systemic treatment within the past 2 years (i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., 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 the first study treatment. 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 the first study treatment.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
• Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended.
• Known SARS-Cov2 infection ≤28 days prior to first dose of study therapy.
• Exposure to P-glycoprotein (P-gp) inhibitors or inducers within 14 days prior to the first dose and during the course of therapy.
• Subjects with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease.
• Subjects with a history of hypersensitivity to any of the inactive ingredients (hydroxypropylmethylcellulose, mannitol, magnesium stearate) of the investigational product.

Contacts and Locations

Contacts

Contact: Hyun Kim, M.D.; 314-362-8502; kim.hyun@wustl.edu

Locations

United States, Missouri

Washington University School of Medicine; Recruiting

Saint Louis, Missouri, United States, 63110

Contact: Hyun Kim, M.D. 314-362-8502 kim.hyun@wustl.edu

Principal Investigator: Hyun Kim, M.D.

Sub-Investigator: Julie Schwarz, M.D., Ph.D.

Sub-Investigator: David DeNardo, Ph.D.

Sub-Investigator: Shahed Badiyan, M.D.

Sub-Investigator: Pamela Samson, M.D.

Sub-Investigator: Carl DeSelm, M.D., Ph.D.

Sub-Investigator: William Hawkins, M.D.

Sub-Investigator: Ryan Fields, M.D.

Sub-Investigator: Chet Hammill, M.D.

Sub-Investigator: Steven Strasberg, M.D.

Sub-Investigator: Majella Doyle, M.D.

Sub-Investigator: Adeel Khan, M.D.

Sub-Investigator: William Chapman, M.D.

Sub-Investigator: Dominic Sanford, M.D.

Sub-Investigator: Kian-Huat Lim, M.D., Ph.D.

Sub-Investigator: Katrina Pedersen, M.D.

Sub-Investigator: Benjamin Tan, M.D.

Sub-Investigator: Rama Suresh, M.D.

Sub-Investigator: Patrick Grierson, M.D.

Sub-Investigator: Nikolaos Trikalinos, M.D.

Sub-Investigator: Vladimir Kushnir, M.D.

Sub-Investigator: Gabriel Lang, M.D.

Sub-Investigator: Dan Mullady, M.D.

Sub-Investigator: Natalie Cosgrove, M.D.

Sub-Investigator: Koushik Das, M.D.

Sub-Investigator: Eugene Koay, M.D., Ph.D.

Sub-Investigator: Esther Lu, Ph.D.

Sub-Investigator: Olivia Aranha, M.D.

Sponsors and Collaborators

Washington University School of Medicine

National Cancer Institute (NCI)

Verastem, Inc.

Investigators

• Principal Investigator: Hyun Kim, M.D.; Washington University School of Medicine

More Information

Additional Information:

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

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT04331041
• Other Study ID Numbers: 202106061; R01CA248917-01 ( U.S. NIH Grant/Contract )
• First Posted: April 2, 2020
• Last Update Posted: January 31, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Sharing of individual participant data that underlie the results reported in the article after deidentification (text, tables, figures, and appendices) for individual participant data meta-analysis.
• Supporting Materials: Study Protocol
• Time Frame: Beginning 9 months and ending 36 months following article publication.
• Access Criteria: Investigators who proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Adenocarcinoma; Pancreatic Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases