Clinical Trials /

Defactinib Combined With Pembrolizumab and Gemcitabine in Patients With Advanced Cancer

NCT02546531

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
  • Pancreatic Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Defactinib Combined With Pembrolizumab and Gemcitabine in Patients With Advanced Cancer
  • Official Title: Phase I Study of Defactinib Combined With Pembrolizumab and Gemcitabine in Patients With Advanced Cancer

Clinical Trial IDs

  • ORG STUDY ID: 201510157
  • NCT ID: NCT02546531

Conditions

  • Advanced Solid Tumors
  • Solid Tumors
  • Pancreatic Cancer

Interventions

DrugSynonymsArms
DefactinibVS-6063Dose escalation (defactinib, pembrolizumab, gemcitabine)
PembrolizumabKeytruda, MK-3475Dose escalation (defactinib, pembrolizumab, gemcitabine)
GemcitabineGemzarDose escalation (defactinib, pembrolizumab, gemcitabine)

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.

Trial Arms

NameTypeDescriptionInterventions
Dose escalation (defactinib, pembrolizumab, gemcitabine)ExperimentalDefactinib 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.
  • Gemcitabine
Dose expansion (defactinib, pembrolizumab, gemcitabine)ExperimentalDefactinib 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.
  • Gemcitabine

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase II dose
Time Frame:Completion of the first cycle of all patients enrolled (approximately 25 months)
Safety Issue:
Description: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

Measure: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)
Safety Issue:
Description:
Measure:Objective response rate (ORR) in dose escalation cohort
Time Frame:Up to 2 years after completion of treatment (estimated average to be 36 months)
Safety Issue:
Description: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
Measure:Objective response rate (ORR) in dose expansion cohort
Time Frame:Up to 2 years after completion of treatment (estimated average to be 36 months)
Safety Issue:
Description: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
Measure:Treatment duration in dose escalation cohort
Time Frame:Completion of treatment (estimated average of 6 months)
Safety Issue:
Description:
Measure:Treatment duration in dose expansion cohort
Time Frame:Completion of treatment (estimated average of 6 months)
Safety Issue:
Description:
Measure:Progression-free survival (PFS) in dose escalation cohort
Time Frame:Up to 2 years after completion of treatment (estimated average to be 36 months)
Safety Issue:
Description: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
Measure:Progression-free survival in dose expansion cohort
Time Frame:Up to 2 years after completion of treatment (estimated average to be 36 months)
Safety Issue:
Description: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
Measure:Overall survival (OS) in dose escalation cohort
Time Frame:Up to 2 years after completion of treatment (estimated average to be 36 months)
Safety Issue:
Description:-OS: duration of time from start of treatment to time of death from any cause
Measure:Overall survival in dose expansion cohort
Time Frame:Up to 2 years after completion of treatment (estimated average to be 36 months)
Safety Issue:
Description:-OS: duration of time from start of treatment to time of death from any cause
Measure:Immune-related PFS in dose escalation cohort
Time Frame:Up to 2 years after completion of treatment (estimated average to be 36 months)
Safety Issue:
Description:
Measure:Immune-related PFS in dose expansion cohort
Time Frame:Up to 2 years after completion of treatment (estimated average to be 36 months)
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Washington University School of Medicine

Last Updated

February 22, 2017