<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03291054</url>
  </required_header>
  <id_info>
    <org_study_id>AAAR1581</org_study_id>
    <nct_id>NCT03291054</nct_id>
  </id_info>
  <brief_title>Epacadostat and Pembrolizumab in Patients With GIST</brief_title>
  <official_title>A Phase II Study of Epacadostat and Pembrolizumab in Patients With Imatinib Refractory Advanced Gastrointestinal Stromal Tumors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Richard D. Carvajal</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Columbia University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Primary objective is to assess the efficacy of combined IDO and PD-1 inhibition in a single&#xD;
      arm phase II trial of epacadostat and pembrolizumab in patients with advanced&#xD;
      imatinib-refractory GIST, using a primary endpoint of overall response rate.&#xD;
&#xD;
      Secondary objectives are to evaluate the progression free survival (PFS), the overall&#xD;
      survival (OS), the response rate and to evaluate the safety and tolerability of combined&#xD;
      epacadostat and pembrolizumab treatment.&#xD;
&#xD;
      The investigator hypothesizes that treatment with epacadostat and pembrolizumab will increase&#xD;
      the response rate compared to what has been historically achieved with salvage tyrosine&#xD;
      kinase inhibitors.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      While targeted therapy with imatinib has significantly improved survival for patients with&#xD;
      inoperable and metastatic gastrointestinal stromal tumors (GIST), the majority will&#xD;
      eventually progress after a median of 20-26 months. Standard second-line treatment with&#xD;
      sunitinib has a response rate of 7%, and third-line treatment with regorafenib has a response&#xD;
      rate of only 5%. More effective treatments for imatinib-refractory GIST are needed.&#xD;
&#xD;
      This study aims to assess the efficacy of combined IDO and PD-1 inhibition with epacadostat&#xD;
      (IDO inhibitor) and pembrolizumab (anti-PD-1 antibody) in patients with imatinib-refractory&#xD;
      GIST.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 28, 2018</start_date>
  <completion_date type="Actual">August 19, 2020</completion_date>
  <primary_completion_date type="Actual">August 19, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall Response Rate</measure>
    <time_frame>within the first 24 weeks of the start of study therapy</time_frame>
    <description>The primary endpoint is the overall response rate as defined as the best response using RECIST v1.1 criteria. A standard way to measure how well a cancer patient responds to treatment. It is based on whether tumors shrink, stay the same, or get bigger. To use RECIST, there must be at least one tumor that can be measured on x-rays, CT scans, or MRI scans. The types of response a patient can have are a complete response (CR), a partial response (PR), progressive disease (PD), and stable disease (SD). Also called Response Evaluation Criteria In Solid Tumors.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>time from registration up to 2 years</time_frame>
    <description>The length of time from the start of treatment that patients diagnosed with the disease are still alive.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">1</enrollment>
  <condition>Gastrointestinal Stromal Tumors</condition>
  <arm_group>
    <arm_group_label>Epacadostat and pembrolizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive epacadostat and pembrolizumab</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Subjects will receive pembrolizumab 200 mg (flat dose) IV every 3 weeks on day 1 of a 21 day cycle.</description>
    <arm_group_label>Epacadostat and pembrolizumab</arm_group_label>
    <other_name>Keytruda</other_name>
    <other_name>Anti-PD-1 antibody</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Epacadostat</intervention_name>
    <description>Epacadostat will be dosed at 100 mg PO twice a day (BID) daily. Doses should be taken twice daily, in the morning and evening, approximately 12 hours apart, without regard to food.Doses will be self-administered, except on Cycle 2 Day 1, when the morning dose will be given at the study site clinic. Subjects will be required to keep a pill diary that will be provided to them.</description>
    <arm_group_label>Epacadostat and pembrolizumab</arm_group_label>
    <other_name>INCB024360</other_name>
    <other_name>IDO inhibitor</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically confirmed diagnosis of GIST.&#xD;
&#xD;
          -  Unresectable or metastatic GIST&#xD;
&#xD;
          -  Allowable prior therapies:&#xD;
&#xD;
               1. Subjects must have had clinical or radiographic progression on imatinib. Those&#xD;
                  who were taken off of imatinib for intolerance must have progressed on at least&#xD;
                  one other tyrosine kinase inhibitor (TKI).&#xD;
&#xD;
               2. Subjects must have received ≥ 1 prior systemic therapy (including imatinib). A&#xD;
                  maximum of 4 prior therapies for metastatic disease are allowed.&#xD;
&#xD;
          -  Male or female subjects, age 18 years or older.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1&#xD;
&#xD;
          -  Life expectance of ≥ 3 months.&#xD;
&#xD;
          -  Laboratory and medical history parameters within the following Protocol-defined range.&#xD;
&#xD;
        All screening laboratory tests should be performed within 28 days of treatment initiation&#xD;
        and must be independent of hematopoietic growth factor support.&#xD;
&#xD;
          -  Absolute neutrophil count ≥ 1.5 x 109/L.&#xD;
&#xD;
          -  Platelets ≥ 100 x 109/L.&#xD;
&#xD;
          -  Hemoglobin ≥ 9 g/dL (transfusion is acceptable to meet this criteria)&#xD;
&#xD;
          -  Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN) OR calculated&#xD;
             creatinine clearance ≥ 50 mL/min for subjects with creatinine levels &gt; 1.5 x&#xD;
             institutional ULN.&#xD;
&#xD;
          -  Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase ≤ 2.5 x&#xD;
             ULN, or ≤ 5 x ULN in subjects with liver metastases.&#xD;
&#xD;
          -  Total bilirubin ≤ 1.5 x ULN&#xD;
&#xD;
             o Note: patients with hyperbilirubinemia clinically consistent with an inherited&#xD;
             disorder of bilirubin metabolism (eg, Gilbert syndrome) will be eligible at the&#xD;
             discretion of the principal investigator.&#xD;
&#xD;
          -  International normalized ratio (INR) or prothrombin time (PT) &lt; 1.5x ULN unless&#xD;
             subject is receiving anticoagulation therapy as long as PT or INR is within&#xD;
             therapeutic range of intended use of anticoagulant.&#xD;
&#xD;
          -  Activated partial thromboplastin time (aPTT) &lt; 1.5 x ULN unless subject is receiving&#xD;
             anticoagulant therapy, as long as PTT is within therapeutic range of intended use of&#xD;
             anticoagulants.&#xD;
&#xD;
               -  Presence of baseline measureable disease by RECIST v1.1 for solid tumors, defined&#xD;
                  as at least one lesion that can be accurately measured in at least one dimension&#xD;
                  (longest diameter to be recorded for non-nodal lesions and short axis for nodal&#xD;
                  lesions) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT&#xD;
                  scan, MRI, or calipers by clinical exam. (See Section 15.4 for the evaluation of&#xD;
                  measurable disease).&#xD;
&#xD;
               -  The effects of pembrolizumab and epacadostat on the developing human fetus are&#xD;
                  unknown, and thus female subjects of childbearing potential (defined as women who&#xD;
                  have not undergone surgical sterilization with a hysterectomy and/or bilateral&#xD;
                  oophorectomy, and are not postmenopausal (defined as ≥ 12 months of amenorrhea))&#xD;
                  must have a negative pregnancy test at screening and must agree to use adequate&#xD;
                  contraception (complete abstinence, or two methods of birth control (Appendix B))&#xD;
                  prior to study entry and until at least 4 months after the last dose of study&#xD;
                  treatment. Should a woman become pregnant or suspect she is pregnant while she or&#xD;
                  her partner is participating in this study, she should inform her treating&#xD;
                  physician immediately.&#xD;
&#xD;
               -  Fertile men must also agree to use adequate contraception (2 barrier methods or&#xD;
                  abstinence) during the study and for up to 4 months after the last dose of study&#xD;
                  drug.&#xD;
&#xD;
               -  All subjects must agree to pre- and on-treatment tumor biopsies. Subjects in whom&#xD;
                  biopsy is technically not feasible or in whom would result in unacceptable risk,&#xD;
                  in the opinion of the investigator, may be exempted from the biopsy requirement&#xD;
                  with discussion with the principal investigator. Use of outside archived tumor&#xD;
                  tissue for a baseline biopsy is not permitted.&#xD;
&#xD;
               -  Willingness and ability to provide written informed consent prior to any&#xD;
                  study-related procedures and to comply with all study requirements.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Treatment with chemotherapy (not including Tyrosine Kinase Inhibitors) or radiotherapy&#xD;
             within 4 weeks (6 weeks from nitrosoureas or mitomycin C), or treatment with&#xD;
             monoclonal antibody therapy within 4 weeks prior to start of study treatment. Note: No&#xD;
             minimum washout period is required for tyrosine kinase inhibitor therapy (eg, imatinib&#xD;
             or sunitinib).&#xD;
&#xD;
          -  Patients must have recovered from adverse events (greater than grade 1) due to prior&#xD;
             anticancer therapy, except for stable chronic toxicities such as alopecia.&#xD;
&#xD;
          -  Participation in any other clinical study with investigational drug received within 28&#xD;
             days or 5 half lives (whichever is longer) before first dose.&#xD;
&#xD;
          -  Subjects who have received prior anti-PD-1 or anti-PD-L1 antibody, or an IDO&#xD;
             inhibitor.&#xD;
&#xD;
          -  Subjects who have received experimental vaccines or other immune therapies should be&#xD;
             discussed with the principal investigator to confirm eligibility.&#xD;
&#xD;
          -  Any prior ≥ Grade 3 immune-related adverse event (irAE) while receiving immunotherapy,&#xD;
             or any unresolved irAE &gt; grade 1.&#xD;
&#xD;
          -  Subjects receiving immunologically based treatment for any reason, including chronic&#xD;
             steroids or prednisone (at dose &gt;10 mg/day of prednisone) within 14 day prior to first&#xD;
             study treatment. Inhaled or topical steroids or systemic steroids (at dose ≤10 mg/day&#xD;
             of prednisone) is permitted.&#xD;
&#xD;
          -  Subjects with any active or inactive autoimmune process (eg, rheumatoid arthritis,&#xD;
             moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease) or who&#xD;
             are receiving systemic therapy for an autoimmune disease. Exceptions include vitiligo,&#xD;
             hypothyroidism controlled on hormone replacement, type I diabetes, Grave's disease,&#xD;
             adrenal insufficiency on stable replacement doses of steroids (prednisone ≤10 mg/day&#xD;
             or equivalent), or with principal investigator approval.&#xD;
&#xD;
          -  No prior organ allograft or allogenic bone marrow transplantation.&#xD;
&#xD;
          -  History of (noninfectious) pneumonitis that require steroids or current pneumonitis.&#xD;
&#xD;
          -  A diagnosis of another active malignancy with the following exceptions: basal or&#xD;
             squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, isolated&#xD;
             elevation of prostate-specific antigen, indolent secondary malignancies not requiring&#xD;
             active therapy, or with the approval of the principal investigator. Subjects with a&#xD;
             completely treated prior malignancy and no evidence of disease for ≥ 2 years are&#xD;
             eligible.&#xD;
&#xD;
          -  Subjects with known active hepatitis B (HBV) or hepatitis C (HCV) infection as defined&#xD;
             by the following (Hepatitis screening studies are required:&#xD;
&#xD;
               -  Positive test for hepatitis B surface antigen&#xD;
&#xD;
               -  Positive test for hepatitis C antibody and/ or hepatitis C quantitative viral&#xD;
                  load (Note: Subjects with a positive hepatitis C antibody and negative&#xD;
                  quantitative hepatitis C polymerase chain reaction (PCR) viral load are eligible)&#xD;
&#xD;
          -  Subjects with a known history of HIV, including patients with controlled disease on&#xD;
             antiretroviral therapy. HIV testing is not required as part of screening for this&#xD;
             study.&#xD;
&#xD;
          -  Subjects receiving monoamine oxidase (MAO) inhibitors within 21 days of study&#xD;
             enrollment (epacadostat increases serotonin levels, theoretically increasing the risk&#xD;
             of serotonin syndrome, although this has not been reported in any ongoing clinical&#xD;
             studies to date).&#xD;
&#xD;
          -  Any history of serotonin syndrome (SS) after receiving 1 or more serotonergic drugs.&#xD;
&#xD;
          -  Current pregnancy or breast feeding. Pregnant women are excluded from this study&#xD;
             because the teratogenicity of epacadostat and pembrolizumab are unknown. Because there&#xD;
             is an unknown but potential risk for adverse events in nursing infants secondary to&#xD;
             treatment of the mother with pembrolizumab and/or epacadostat, breastfeeding should be&#xD;
             discontinued in all female subjects.&#xD;
&#xD;
          -  Receipt of live attenuated vaccines (including, but not limited to: intranasal&#xD;
             influenza vaccine (FluMist), measles, mumps, rubella, chicken pox, yellow fever,&#xD;
             rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine) within 30 days before the&#xD;
             first dose of study treatment.&#xD;
&#xD;
          -  Concurrent use of any medication that is an inhibitor of UGT1A9 during the screening&#xD;
             or treatment period.&#xD;
&#xD;
          -  Major surgical procedure or significant traumatic injury within 14 days of initiating&#xD;
             study drug or anticipation of the need for major surgery during the study.&#xD;
&#xD;
          -  Inability to swallow capsules, or refractory nausea and vomiting, malabsorption, an&#xD;
             external biliary shunt, or significant bowel resection that would preclude adequate&#xD;
             absorption.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, active liver disease, symptomatic congestive heart failure, unstable angina&#xD;
             pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would&#xD;
             limit compliance with study requirements.&#xD;
&#xD;
          -  History of current evidence of any condition, therapy, or laboratory abnormality that&#xD;
             might confound the results of the study, or interfere with the subject's participation&#xD;
             for the full duration of the study.&#xD;
&#xD;
          -  Known allergy or reaction to any component of either study drug formulation.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Richard D Carvajal, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Columbia University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>U-M Comprehensive Cancer Center</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109-0944</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Columbia University Medical Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>September 20, 2017</study_first_submitted>
  <study_first_submitted_qc>September 20, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 25, 2017</study_first_posted>
  <last_update_submitted>March 18, 2021</last_update_submitted>
  <last_update_submitted_qc>March 18, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 19, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Columbia University</investigator_affiliation>
    <investigator_full_name>Richard D. Carvajal</investigator_full_name>
    <investigator_title>Associate Professor of Medicine at the Columbia University Medical Center</investigator_title>
  </responsible_party>
  <keyword>Gastrointestinal Stromal Tumors</keyword>
  <keyword>GIST</keyword>
  <keyword>Pembrolizumab</keyword>
  <keyword>Epacadostat</keyword>
  <keyword>Columbia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Gastrointestinal Stromal Tumors</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03291054
org study id: AAAR1581
nct id: NCT03291054
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Primary objective is to assess the efficacy of combined IDO and PD-1 inhibition in a single
      arm phase II trial of epacadostat and pembrolizumab in patients with advanced
      imatinib-refractory GIST, using a primary endpoint of overall response rate.

      Secondary objectives are to evaluate the progression free survival (PFS), the overall
      survival (OS), the response rate and to evaluate the safety and tolerability of combined
      epacadostat and pembrolizumab treatment.

      The investigator hypothesizes that treatment with epacadostat and pembrolizumab will increase
      the response rate compared to what has been historically achieved with salvage tyrosine
      kinase inhibitors.
While targeted therapy with imatinib has significantly improved survival for patients with
      inoperable and metastatic gastrointestinal stromal tumors (GIST), the majority will
      eventually progress after a median of 20-26 months. Standard second-line treatment with
      sunitinib has a response rate of 7%, and third-line treatment with regorafenib has a response
      rate of only 5%. More effective treatments for imatinib-refractory GIST are needed.

      This study aims to assess the efficacy of combined IDO and PD-1 inhibition with epacadostat
      (IDO inhibitor) and pembrolizumab (anti-PD-1 antibody) in patients with imatinib-refractory
      GIST.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall Response Rate
time frame: within the first 24 weeks of the start of study therapy
description: The primary endpoint is the overall response rate as defined as the best response using RECIST v1.1 criteria. A standard way to measure how well a cancer patient responds to treatment. It is based on whether tumors shrink, stay the same, or get bigger. To use RECIST, there must be at least one tumor that can be measured on x-rays, CT scans, or MRI scans. The types of response a patient can have are a complete response (CR), a partial response (PR), progressive disease (PD), and stable disease (SD). Also called Response Evaluation Criteria In Solid Tumors.
measure: Overall Survival
time frame: time from registration up to 2 years
description: The length of time from the start of treatment that patients diagnosed with the disease are still alive.
arm group label: Epacadostat and pembrolizumab
arm group type: Experimental
description: Subjects will receive epacadostat and pembrolizumab
intervention type: Drug
intervention name: Pembrolizumab
description: Subjects will receive pembrolizumab 200 mg (flat dose) IV every 3 weeks on day 1 of a 21 day cycle.
arm group label: Epacadostat and pembrolizumab
other name: Keytruda
other name: Anti-PD-1 antibody
intervention type: Drug
intervention name: Epacadostat
description: Epacadostat will be dosed at 100 mg PO twice a day (BID) daily. Doses should be taken twice daily, in the morning and evening, approximately 12 hours apart, without regard to food.Doses will be self-administered, except on Cycle 2 Day 1, when the morning dose will be given at the study site clinic. Subjects will be required to keep a pill diary that will be provided to them.
arm group label: Epacadostat and pembrolizumab
other name: INCB024360
other name: IDO inhibitor
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Richard D Carvajal, MD
role: Principal Investigator
affiliation: Columbia University
facility: 
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Columbia University
investigator full name: Richard D. Carvajal
investigator title: Associate Professor of Medicine at the Columbia University Medical Center
mesh term: Gastrointestinal Stromal Tumors
mesh term: Pembrolizumab
sharing ipd: No