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

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ClinicalTrials.gov Identifier: NCT04331041
Recruitment Status : Not yet recruiting
First Posted : April 2, 2020
Last Update Posted : January 20, 2021
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine

Brief Summary:

Patients with advanced pancreas adenocarcinoma will be treated with standard of care chemotherapy followed by stereotactic body radiotherapy (SBRT) concurrent with the FAK inhibitor defactinib. Patients will be assessed for clinical outcomes such as progression free survival (PFS), local control, distant control, and toxicity. A safety lead-in of 6 patients will be treated and assessed for DLT; if no DLTs are observed, 30 additional patients will be enrolled to phase II of the study.

Hypothesis: defactinib given concurrently with SBRT will increase the PFS of advanced pancreas tumor primaries compared to historical rates of 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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: N/A
Intervention Model: Single Group 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
Estimated Study Start Date : June 30, 2021
Estimated Primary Completion Date : June 30, 2025
Estimated Study Completion Date : June 30, 2025

Resource links provided by the National Library of Medicine


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 two 21-day cycles of defactinib (beginning on Day 2 of radiation).
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, daily, for 2 21-day cycles

Procedure: Tumor biopsy
-Baseline and 12 weeks after end of SBRT (or at time of surgery)

Procedure: Research blood draw
-Baseline, at the end of cycle 2 (6 weeks after the end of SBRT), and 12 weeks after the end of SBRT




Primary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: 12 months post radiation therapy ]
    • 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 radiation therapy 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 90 days through completion of follow-up (estimated to be 2 years) ]
    -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: 12 months post radiation therapy ]
    -Overall survival as defined by from date of diagnosis until death; censored at last follow-up if death is not observed

  4. Distant metastasis progression-free survival [ Time Frame: 12 months post radiation therapy ]
  5. Objective response rate [ Time Frame: 3 months post radiation therapy ]
    -Objective response rate as determined by RECIST 1.1 criteria

  6. Local control [ Time Frame: 12 months post radiation therapy ]
    -Local control as defined by no progression of the primary tumor by RECIST 1.1 criteria



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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.
  • 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
  • At least 18 years of age.
  • ECOG performance status ≤ 1
  • Life expectancy > 3 months
  • Normal bone marrow and organ function 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
  • 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 adequate 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 (or that of legally authorized representative, if applicable).

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.
  • Gastrointestinal condition that could interfere with the swallowing or absorption of study medication.
  • 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.
  • A history of allergic reactions attributed to compounds of similar chemical or biologic composition to defactinib, gemcitabine, or other agents used in the study.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04331041


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

Locations
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United States, Missouri
Washington University School of Medicine
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: Lauren Henke, M.D.         
Sub-Investigator: Andrea Wang-Gillam, M.D., Ph.D.         
Sub-Investigator: Yi Huang         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
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Principal Investigator: Hyun Kim, M.D. Washington University School of Medicine
Additional Information:
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT04331041    
Other Study ID Numbers: 19-x506
First Posted: April 2, 2020    Key Record Dates
Last Update Posted: January 20, 2021
Last Verified: January 2021
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.

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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:
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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