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Trial record 1 of 1 for:    NCT02546531
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Defactinib Combined With Pembrolizumab and Gemcitabine in Patients With Advanced Cancer

This study is currently recruiting participants.
See Contacts and Locations
Verified July 2017 by Washington University School of Medicine
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT02546531
First received: August 14, 2015
Last updated: July 20, 2017
Last verified: July 2017
  Purpose
In pancreatic cancer, targeting the tumor microenvironment has become a promising therapeutic strategy. Focal adhesion kinase (FAK) pathway activation is essential for promoting a fibrotic and inflammatory tumor microenvironment, and FAK inhibitors have demonstrated reasonable anti-tumor activity in the preclinical setting. Furthermore, a maximal synergetic effect was achieved when a FAK inhibitor was given in combination with a PD-1 antagonist and chemotherapy in multiple pancreas tumor animal models. This supports the concept of using FAK inhibitors to reduce stromal fibrosis during checkpoint immunotherapeutic treatment. Therefore, these robust preclinical findings will be tested in the proposed phase I trial.

Condition Intervention Phase
Advanced Solid Tumors Solid Tumors Pancreatic Cancer Biological: Defactinib Biological: Pembrolizumab Drug: Gemcitabine Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Defactinib Combined With Pembrolizumab and Gemcitabine in Patients With Advanced Cancer

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • Recommended phase II dose [ Time Frame: Completion of the first cycle of all patients enrolled (approximately 25 months) ]
    • The recommended phase II dose will be determined from the maximum tolerated dose (MTD) found in the dose escalation cohort.
    • The maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity during the first cycle (21 days). Dose escalations will proceed until the MTD has been reached or the completion of cycle 5.


Secondary Outcome Measures:
  • Safety and toxicity as measured by NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 [ Time Frame: 30 days after completion of treatment (estimated average of 7 months) ]
  • Objective response rate (ORR) in dose escalation cohort [ Time Frame: Up to 2 years after completion of treatment (estimated average to be 36 months) ]
    • The definition of ORR is the proportion of patients who achieved a complete response or a partial response
    • The definition of complete response (CR) is the disappearance of all target lesions, non-target lesions, and no new lesions
    • The definition of partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions and no new lesions

  • Objective response rate (ORR) in dose expansion cohort [ Time Frame: Up to 2 years after completion of treatment (estimated average to be 36 months) ]
    • The definition of ORR is the proportion of patients who achieved a complete response or a partial response
    • The definition of complete response (CR) is the disappearance of all target lesions, non-target lesions, and no new lesions
    • The definition of partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions and no new lesions

  • Treatment duration in dose escalation cohort [ Time Frame: Completion of treatment (estimated average of 6 months) ]
  • Treatment duration in dose expansion cohort [ Time Frame: Completion of treatment (estimated average of 6 months) ]
  • Progression-free survival (PFS) in dose escalation cohort [ Time Frame: Up to 2 years after completion of treatment (estimated average to be 36 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, appearance of one more new lesions

  • Progression-free survival in dose expansion cohort [ Time Frame: Up to 2 years after completion of treatment (estimated average to be 36 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, appearance of one more new lesions

  • Overall survival (OS) in dose escalation cohort [ Time Frame: Up to 2 years after completion of treatment (estimated average to be 36 months) ]
    -OS: duration of time from start of treatment to time of death from any cause

  • Overall survival in dose expansion cohort [ Time Frame: Up to 2 years after completion of treatment (estimated average to be 36 months) ]
    -OS: duration of time from start of treatment to time of death from any cause

  • Immune-related PFS in dose escalation cohort [ Time Frame: Up to 2 years after completion of treatment (estimated average to be 36 months) ]
  • Immune-related PFS in dose expansion cohort [ Time Frame: Up to 2 years after completion of treatment (estimated average to be 36 months) ]

Estimated Enrollment: 50
Actual Study Start Date: February 3, 2016
Estimated Study Completion Date: July 31, 2020
Estimated Primary Completion Date: July 31, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dose escalation (defactinib, pembrolizumab, gemcitabine)
  • Defactinib is an oral drug which will be administered on an outpatient basis at the prescribed dose twice a day daily during each 21-day cycle.
  • Pembrolizumab is an intravenous (IV) drug which will be administered on an outpatient basis over 30 minutes (-5/+10) at a dose of 200 mg on Day 1 of each 21-day cycle.
  • Gemcitabine is an IV drug which will be administered on an outpatient basis over 30 minutes at the prescribed dose on Days 1 and 8 of each 21-day cycle.
  • Participants enrolled in Dose Level 1 and 2 will not receive gemcitabine.
Biological: Defactinib
Other Name: VS-6063
Biological: Pembrolizumab
Other Names:
  • Keytruda
  • MK-3475
Drug: Gemcitabine
Other Name: Gemzar
Experimental: Dose expansion (defactinib, pembrolizumab, gemcitabine)
  • Defactinib is an oral drug which will be administered on an outpatient basis at the prescribed dose twice a day daily during each 21-day cycle.
  • Pembrolizumab is an intravenous (IV) drug which will be administered on an outpatient basis over 30 minutes (-5/+10) at a dose of 200 mg on Day 1 of each 21-day cycle.
  • Gemcitabine is an IV drug which will be administered on an outpatient basis over 30 minutes at the prescribed dose on Days 1 and 8 of each 21-day cycle.
  • Participants enrolled in Dose Level 1 and 2 will not receive gemcitabine.
Biological: Defactinib
Other Name: VS-6063
Biological: Pembrolizumab
Other Names:
  • Keytruda
  • MK-3475
Drug: Gemcitabine
Other Name: Gemzar

  Eligibility

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

Inclusion Criteria:

  • Dose escalation cohort: Histologically or cytologically confirmed diagnosis of advanced solid tumor for which standard curative or palliative measures do not exist or are no longer effective.
  • Expansion cohort: Histologically or cytologically confirmed diagnosis of advanced pancreatic cancer. Patients may be stable on front-line therapy (defined as at least 4 months stable disease on nab-paclitaxel / gemcitabine) or may have failed or could not tolerate at least one line of chemotherapy indicated for advanced pancreatic cancer. There should be 2-4 weeks break between the last dose of nab-paclitaxel/gemzar and the three drugs regimen. No more than two lines of prior systemic therapy allowed.
  • Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan or MRI, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam.
  • 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
    • AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN, or ≤ 5.0 x IULN if due to liver involvement by tumor
    • Creatinine ≤ 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
  • Corrected QT interval (QTc) < 480 ms (as calculated by the Fridericia correction formula).
  • 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.
  • 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 ≤ 2 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix.
  • No clinically evident ascites that requires therapeutic paracentesis.
  • At risk of bowel perforation
  • 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 treatment with systemic gemcitabine less than 6 months
  • Currently receiving any other investigational agents
  • Known brain metastases. Patients with known brain metastases must be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
  • A history of allergic reactions attributed to compounds of similar chemical or biologic composition to defactinib, pembrolizumab, gemcitabine, or other agents used in the study.
  • Received a live vaccine within 30 days prior to the first study treatment.
  • Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of pembrolizumab.
  • Has an active autoimmune disease requiring systemic treatment within the past 2 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidisms stable on hormone replacement or Sjorgen's syndrome would not e excluded from the study.
  • Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
  • Major surgery within 28 days prior to the first study treatment.
  • History or evidence of cardiac risk including any of the following: history or evidence of current clinically significant uncontrolled arrhythmias or arrhythmia requiring treatment with the exceptions of atrial fibrillation and paroxysmal supraventricular tachycardia; history of acute coronary syndromes within 6 months prior to the first dose of study therapy (including myocardial infarction and unstable angina, coronary angioplasty, or stenting); or any history of congestive heart failure with most recent ejection fraction < 45% (screening LVEF assessment without history of CHF is not required).
  • Known active hepatitis B (e.g. HBsAg reactive) or hepatitis C (e.g. HCV RNA [qualitative] is detected)
  • 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, immunosuppression, autoimmune conditions, underlying pulmonary disease, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
  • Known HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with pembrolizumab and/or defactinib. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02546531

Contacts
Contact: Andrea Wang-Gillam, M.D., Ph.D. 314-362-5740 awang-gillam@wustl.edu

Locations
United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Andrea Wang-Gillam, M.D., Ph.D.    314-362-5740    awang-gillam@wustl.edu   
Principal Investigator: Andrea Wang-Gillam, M.D., Ph.D.         
Sub-Investigator: Manik Amin, M.D.         
Sub-Investigator: David G DeNardo, Ph.D.         
Sub-Investigator: Eric Knoche, M.D.         
Sub-Investigator: Kian-Huat Lim, M.D., Ph.D.         
Sub-Investigator: Joel Picus, M.D.         
Sub-Investigator: Alex Politsmakher, M.D.         
Sub-Investigator: Caron Rigden, M.D.         
Sub-Investigator: Preet Singh, M.D.         
Sub-Investigator: Rama Suresh, M.D.         
Sub-Investigator: Benjamin Tan, M.D.         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
Principal Investigator: Andrea Wang-Gillam, M.D., Ph.D. Washington University School of Medicine
  More Information

Additional Information:
Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT02546531     History of Changes
Other Study ID Numbers: 201510157
Study First Received: August 14, 2015
Last Updated: July 20, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Pancreatic Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Gemcitabine
Pembrolizumab
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 21, 2017