<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/NCT03229278</url>
  </required_header>
  <id_info>
    <org_study_id>Pro20170000453</org_study_id>
    <secondary_id>NCI-2017-01155</secondary_id>
    <secondary_id>Pro20170000453</secondary_id>
    <secondary_id>051707</secondary_id>
    <secondary_id>P30CA072720</secondary_id>
    <nct_id>NCT03229278</nct_id>
  </id_info>
  <brief_title>Trigriluzole With Nivolumab and Pembrolizumab in Treating Patients With Metastatic or Unresectable Solid Malignancies or Lymphoma</brief_title>
  <official_title>A Phase I Study to Evaluate the Safety of Trigriluzole (FC-4157/BHV-4157) in Combination With PD-1 Blocking Antibodies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rutgers, The State University of New Jersey</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Rutgers, The State University of New Jersey</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>
      This phase I trial studies the best dose and side effects of trigriluzole in combination with&#xD;
      nivolumab and pembrolizumab in treating patients with solid malignancies or lymphoma that has&#xD;
      spread to other places in the body or cannot be removed by surgery. Trigriluzole may stop the&#xD;
      growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal&#xD;
      antibodies, such as nivolumab and pembrolizumab, may interfere with the ability of tumor&#xD;
      cells to grow and spread. Giving trigriluzole in combination with nivolumab and pembrolizumab&#xD;
      may work better at treating patients with solid malignancies or lymphoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. The primary objective of this study is to determine the safety of trigriluzole in&#xD;
      combination with PD-1 inhibiting antibodies, and to define a maximum tolerated dose (MTD) of&#xD;
      trigriluzole in combination therapy.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To characterize the efficacy of the combination therapy. II. To identify markers of&#xD;
      response to trigriluzole in the tumor microenvironment.&#xD;
&#xD;
      OUTLINE: This is a dose-escalation study of trigriluzole.&#xD;
&#xD;
      Patients receive trigriluzole orally (PO) every other day (QOD), twice daily (BID), every&#xD;
      morning (QAM) or every bedtime (QHS) on days -14 to -1. Patients then receive nivolumab&#xD;
      intravenously (IV) over 60 minutes every 2 weeks beginning week 1 and trigriluzole PO QOD,&#xD;
      BID, QAM or QHS. Once the MTD of trigriluzole with nivolumab is identified, patients receive&#xD;
      pembrolizumab IV over 30 minutes every 3 weeks beginning week 1 and trigriluzole PO.&#xD;
      Treatment repeats for up to 1 year in the absence of disease progression or unacceptable&#xD;
      toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 12 weeks for up to 3&#xD;
      years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 17, 2017</start_date>
  <completion_date type="Actual">January 30, 2020</completion_date>
  <primary_completion_date type="Actual">January 8, 2020</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <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>Maximum tolerated dose (MTD))/recommended phase 2 dose of trigriluzole</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>The MTD of trigriluzole in combination with nivolumab will be identified. The MTD will then be tested in combination with pembrolizumab using the same escalate/de-escalate/stay rules. Data on the adverse event type, severity and frequency will be recorded.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Adverse event (AE) type, severity and frequency</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>The frequency of AEs and serious AEs will be recorded.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response rate assessed according to Response Evaluation Criteria in Solid Tumors version 1.1</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% confidence intervals [CI]) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% CI) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Landmark survival rates</measure>
    <time_frame>1 year</time_frame>
    <description>Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% CI) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Landmark survival rates</measure>
    <time_frame>2 years</time_frame>
    <description>Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% CI) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response for responding patients</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% CI) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% CI) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to treatment failure</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% CI) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to next therapy or death</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% CI) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Freedom from new metastases</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% CI) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI).</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Change in angiogenesis markers</measure>
    <time_frame>Baseline up to 3 years</time_frame>
    <description>Treatment effect for each patient will be measured as paired differences between pre- and post- measurements of these parameters at various times. Transformation of the data will be performed if appropriate, e.g. log transformation, and hence treatment effect will be expressed on a log scale. This analysis of the data obtained in these correlative studies will be descriptive in nature.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in exosomal formation</measure>
    <time_frame>Baseline up to 3 years</time_frame>
    <description>Treatment effect for each patient will be measured as paired differences between pre- and post- measurements of these parameters at various times. Transformation of the data will be performed if appropriate, e.g. log transformation, and hence treatment effect will be expressed on a log scale. This analysis of the data obtained in these correlative studies will be descriptive in nature.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in immune cell phenotypes and gene expression</measure>
    <time_frame>Baseline up to 3 years</time_frame>
    <description>Treatment effect for each patient will be measured as paired differences between pre- and post- measurements of these parameters at various times. Transformation of the data will be performed if appropriate, e.g. log transformation, and hence treatment effect will be expressed on a log scale. This analysis of the data obtained in these correlative studies will be descriptive in nature.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in metabolic effector molecules</measure>
    <time_frame>Baseline up to 3 years</time_frame>
    <description>Treatment effect for each patient will be measured as paired differences between pre- and post- measurements of these parameters at various times. Transformation of the data will be performed if appropriate, e.g. log transformation, and hence treatment effect will be expressed on a log scale. This analysis of the data obtained in these correlative studies will be descriptive in nature.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in tumor infiltrating lymphocyte (TIL)s and PD-L1 expression</measure>
    <time_frame>Baseline up to 3 years</time_frame>
    <description>Treatment effect for each patient will be measured as paired differences between pre- and post- measurements of these parameters at various times. Transformation of the data will be performed if appropriate, e.g. log transformation, and hence treatment effect will be expressed on a log scale. This analysis of the data obtained in these correlative studies will be descriptive in nature.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">14</enrollment>
  <condition>Lymphoma</condition>
  <condition>Metastatic Malignant Solid Neoplasm</condition>
  <condition>Metastatic Melanoma</condition>
  <condition>Metastatic Renal Cell Cancer</condition>
  <condition>Recurrent Bladder Carcinoma</condition>
  <condition>Recurrent Classical Hodgkin Lymphoma</condition>
  <condition>Recurrent Head and Neck Squamous Cell Carcinoma</condition>
  <condition>Recurrent Lymphoma</condition>
  <condition>Recurrent Malignant Solid Neoplasm</condition>
  <condition>Recurrent Renal Cell Carcinoma</condition>
  <condition>Stage III Bladder Cancer</condition>
  <condition>Stage III Lymphoma</condition>
  <condition>Stage III Non-Small Cell Lung Cancer AJCC v7</condition>
  <condition>Stage III Renal Cell Cancer</condition>
  <condition>Stage III Skin Melanoma</condition>
  <condition>Stage IIIA Non-Small Cell Lung Cancer AJCC v7</condition>
  <condition>Stage IIIA Skin Melanoma</condition>
  <condition>Stage IIIB Non-Small Cell Lung Cancer AJCC v7</condition>
  <condition>Stage IIIB Skin Melanoma</condition>
  <condition>Stage IIIC Skin Melanoma</condition>
  <condition>Stage IV Bladder Cancer</condition>
  <condition>Stage IV Lymphoma</condition>
  <condition>Stage IV Non-Small Cell Lung Cancer AJCC v7</condition>
  <condition>Stage IV Renal Cell Cancer</condition>
  <condition>Stage IV Skin Melanoma</condition>
  <condition>Stage IVA Bladder Cancer</condition>
  <condition>Stage IVB Bladder Cancer</condition>
  <condition>Unresectable Head and Neck Squamous Cell Carcinoma</condition>
  <condition>Unresectable Solid Neoplasm</condition>
  <arm_group>
    <arm_group_label>Treatment (trigriluzole, nivolumab, pembrolizumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive trigriluzole PO QOD, BID, QAM or QHS on days -14 to -1. Patients then receive nivolumab IV over 60 minutes every 2 weeks beginning week 1 and trigriluzole PO QOD, BID, QAM or QHS. Once the MTD of trigriluzole with nivolumab is identified, patients receive pembrolizumab IV over 30 minutes every 3 weeks beginning week 1 and trigriluzole PO. Treatment repeats for up to 1 year in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Enzyme Inhibitor Therapy</intervention_name>
    <description>Given trigriluzole PO</description>
    <arm_group_label>Treatment (trigriluzole, nivolumab, pembrolizumab)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (trigriluzole, nivolumab, pembrolizumab)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (trigriluzole, nivolumab, pembrolizumab)</arm_group_label>
    <other_name>BMS-936558</other_name>
    <other_name>MDX-1106</other_name>
    <other_name>NIVO</other_name>
    <other_name>ONO-4538</other_name>
    <other_name>Opdivo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (trigriluzole, nivolumab, pembrolizumab)</arm_group_label>
    <other_name>Keytruda</other_name>
    <other_name>Lambrolizumab</other_name>
    <other_name>MK-3475</other_name>
    <other_name>SCH 900475</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have histologically confirmed solid malignancy or lymphoma that is&#xD;
             metastatic or unresectable&#xD;
&#xD;
          -  There is reasonable expectation of response to pembrolizumab or nivolumab, and one of&#xD;
             the drugs is available from the commercial supply; this includes (but is not limited&#xD;
             to) the following tumor types: melanoma, non-small cell lung cancer, renal cell&#xD;
             carcinoma, squamous cell carcinoma of the head and neck, bladder cancer, and classic&#xD;
             Hodgkin lymphoma&#xD;
&#xD;
          -  The patient must have failed at least one line of standard treatment, with the&#xD;
             following exceptions in which a PD-1 antibody is Food and Drug Administration (FDA)&#xD;
             approved in the first-line setting:&#xD;
&#xD;
               -  Melanoma patients&#xD;
&#xD;
               -  Non-small cell lung cancer patients without EGFR or ALK genomic tumor aberrations&#xD;
                  whose tumors have high PD-L1 expression (tumor proportion score [TPS] &gt;= 50%) as&#xD;
                  determined by an FDA-approved test&#xD;
&#xD;
          -  Patients must give informed consent&#xD;
&#xD;
          -  Prior chemotherapy, immunotherapy, radiotherapy or major surgery (including radiation&#xD;
             therapy or surgery for treatment of brain metastases) must be completed at least 3&#xD;
             weeks before study entry; prior PD-1 or PD-L1 therapy is acceptable&#xD;
&#xD;
          -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =&lt;&#xD;
             2&#xD;
&#xD;
          -  Hemoglobin &gt; 8.0 mg/dL (without transfusion in the preceding 7 days)&#xD;
&#xD;
          -  Platelets &gt;= 70,000 /uL&#xD;
&#xD;
          -  Total bilirubin within normal institutional limits (patients with Gilbert's syndrome&#xD;
             must have a total bilirubin &lt; 3.0 mg/dL)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =&lt; 2&#xD;
             X institutional upper limit of normal (ULN)&#xD;
&#xD;
          -  Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =&lt; 2 X&#xD;
             institutional ULN&#xD;
&#xD;
          -  Patients must have measurable disease, defined as at least one lesion that can be&#xD;
             accurately measured in at least one dimension (longest diameter to be recorded) as &gt;=&#xD;
             10 mm by computed tomography (CT) scan, positron emission tomography (PET)/CT scan,&#xD;
             magnetic resonance imaging (MRI) or caliper/ruler measurement by clinical exam; lymph&#xD;
             nodes: to be considered pathologically enlarged and measurable, a lymph node must be&#xD;
             &gt;= 15 mm in short axis when assessed by CT scan; lesions that have been radiated in&#xD;
             the advanced setting cannot be included as sites of measurable disease unless clear&#xD;
             tumor progression has been documented in these lesions since the end of radiation&#xD;
             therapy&#xD;
&#xD;
          -  Ability to swallow pills&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Systemic immunosuppressive medications such as steroids; the following steroid&#xD;
             formulations are permitted: intranasal, intra-articular, and inhaled steroids&#xD;
&#xD;
          -  History of immune-related adverse event from prior immunotherapy treatment that has&#xD;
             not improved to grade 0-1; subjects with grade 2 hypothyroidism and grade 2 adrenal&#xD;
             insufficiency requiring continued medical treatment may enroll provided that they are&#xD;
             asymptomatic and stable on their dose of hormone replacement&#xD;
&#xD;
          -  Serious concomitant systemic disorders (including active infections) that would&#xD;
             compromise the safety of the patient or compromise the patient?s ability to complete&#xD;
             the study, at the discretion of the investigator, including active autoimmune disease&#xD;
             requiring treatment within the past 30 days&#xD;
&#xD;
          -  Any condition requiring systemic treatment with either corticosteroids (&gt; 10 mg daily&#xD;
             prednisone equivalents) or other systemic immunosuppressive medications within 14 days&#xD;
             of study drug administration; inhaled or topical steroids and adrenal replacement&#xD;
             doses &lt; 10 mg daily prednisone equivalents are permitted in the absence of active&#xD;
             autoimmune disease; patients are permitted to use topical, ocular, intra-articular,&#xD;
             intranasal, and inhalational corticosteroids (with minimal systemic absorption)'&#xD;
             physiologic replacement doses of systemic corticosteroids are permitted, even if &lt; 10&#xD;
             mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis&#xD;
             (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g.,&#xD;
             delayed-type hypersensitivity reaction caused by contact allergen) is permitted&#xD;
&#xD;
          -  Second primary malignancy, except those second primary malignancies that are not&#xD;
             considered to be competing causes of death in the opinion of the treating&#xD;
             investigator; examples include: in situ carcinoma of the cervix, adequately treated&#xD;
             non-melanoma carcinoma of the skin, or other malignancy treated at least 5 years&#xD;
             previously with no evidence of recurrence&#xD;
&#xD;
          -  Patients with active, untreated central nervous system (CNS) metastases will be&#xD;
             excluded from this clinical trial; patients who have brain metastases that been&#xD;
             treated with radiation therapy or surgery will be required to have a washout period of&#xD;
             at least 3 weeks prior to study entry, must be neurologically asymptomatic, and must&#xD;
             not require systemic steroids&#xD;
&#xD;
          -  Women of child-bearing potential and men must agree to use adequate contraception&#xD;
             prior to the start of treatment, for the duration of treatment, and for 5 months after&#xD;
             last dose of study treatment&#xD;
&#xD;
          -  Patients with immune deficiency have impaired immune responses, therefore, known human&#xD;
             immunodeficiency virus (HIV)-positive patients are excluded from the study&#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>Biren Saraiya</last_name>
    <role>Principal Investigator</role>
    <affiliation>Rutgers Cancer Institute of New Jersey</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Rutgers Cancer Institute of New Jersey</name>
      <address>
        <city>New Brunswick</city>
        <state>New Jersey</state>
        <zip>08903</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>July 18, 2017</study_first_submitted>
  <study_first_submitted_qc>July 21, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 25, 2017</study_first_posted>
  <last_update_submitted>November 16, 2022</last_update_submitted>
  <last_update_submitted_qc>November 16, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 21, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Rutgers Cancer Institute of New Jersey</investigator_affiliation>
    <investigator_full_name>Biren Saraiya, MD</investigator_full_name>
    <investigator_title>Assistant Professor, Medical Oncology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Lung Neoplasms</mesh_term>
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
    <mesh_term>Melanoma</mesh_term>
    <mesh_term>Carcinoma, Squamous Cell</mesh_term>
    <mesh_term>Urinary Bladder Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Renal Cell</mesh_term>
    <mesh_term>Squamous Cell Carcinoma of Head and Neck</mesh_term>
    <mesh_term>Skin Neoplasms</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Enzyme Inhibitors</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>October 4, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/78/NCT03229278/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <pending_results>
    <submitted>September 14, 2023</submitted>
  </pending_results>
  <!-- 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/NCT03229278
org study id: Pro20170000453
secondary id: NCI-2017-01155
secondary id: Pro20170000453
secondary id: 051707
secondary id: P30CA072720
nct id: NCT03229278
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase I trial studies the best dose and side effects of trigriluzole in combination with
      nivolumab and pembrolizumab in treating patients with solid malignancies or lymphoma that has
      spread to other places in the body or cannot be removed by surgery. Trigriluzole may stop the
      growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal
      antibodies, such as nivolumab and pembrolizumab, may interfere with the ability of tumor
      cells to grow and spread. Giving trigriluzole in combination with nivolumab and pembrolizumab
      may work better at treating patients with solid malignancies or lymphoma.
PRIMARY OBJECTIVES:

      I. The primary objective of this study is to determine the safety of trigriluzole in
      combination with PD-1 inhibiting antibodies, and to define a maximum tolerated dose (MTD) of
      trigriluzole in combination therapy.

      SECONDARY OBJECTIVES:

      I. To characterize the efficacy of the combination therapy. II. To identify markers of
      response to trigriluzole in the tumor microenvironment.

      OUTLINE: This is a dose-escalation study of trigriluzole.

      Patients receive trigriluzole orally (PO) every other day (QOD), twice daily (BID), every
      morning (QAM) or every bedtime (QHS) on days -14 to -1. Patients then receive nivolumab
      intravenously (IV) over 60 minutes every 2 weeks beginning week 1 and trigriluzole PO QOD,
      BID, QAM or QHS. Once the MTD of trigriluzole with nivolumab is identified, patients receive
      pembrolizumab IV over 30 minutes every 3 weeks beginning week 1 and trigriluzole PO.
      Treatment repeats for up to 1 year in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients are followed up every 12 weeks for up to 3
      years.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose (MTD))/recommended phase 2 dose of trigriluzole
time frame: Up to 3 years
description: The MTD of trigriluzole in combination with nivolumab will be identified. The MTD will then be tested in combination with pembrolizumab using the same escalate/de-escalate/stay rules. Data on the adverse event type, severity and frequency will be recorded.
measure: Adverse event (AE) type, severity and frequency
time frame: Up to 3 years
description: The frequency of AEs and serious AEs will be recorded.
measure: Objective response rate assessed according to Response Evaluation Criteria in Solid Tumors version 1.1
time frame: Up to 3 years
description: Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% confidence intervals [CI]) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI).
measure: Overall survival
time frame: Up to 3 years
description: Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% CI) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI).
measure: Landmark survival rates
time frame: 1 year
description: Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% CI) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI).
measure: Landmark survival rates
time frame: 2 years
description: Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% CI) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI).
measure: Duration of response for responding patients
time frame: Up to 3 years
description: Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% CI) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI).
measure: Progression-free survival
time frame: Up to 3 years
description: Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% CI) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI).
measure: Time to treatment failure
time frame: Up to 3 years
description: Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% CI) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI).
measure: Time to next therapy or death
time frame: Up to 3 years
description: Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% CI) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI).
measure: Freedom from new metastases
time frame: Up to 3 years
description: Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% CI) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI).
measure: Change in angiogenesis markers
time frame: Baseline up to 3 years
description: Treatment effect for each patient will be measured as paired differences between pre- and post- measurements of these parameters at various times. Transformation of the data will be performed if appropriate, e.g. log transformation, and hence treatment effect will be expressed on a log scale. This analysis of the data obtained in these correlative studies will be descriptive in nature.
measure: Change in exosomal formation
time frame: Baseline up to 3 years
description: Treatment effect for each patient will be measured as paired differences between pre- and post- measurements of these parameters at various times. Transformation of the data will be performed if appropriate, e.g. log transformation, and hence treatment effect will be expressed on a log scale. This analysis of the data obtained in these correlative studies will be descriptive in nature.
measure: Change in immune cell phenotypes and gene expression
time frame: Baseline up to 3 years
description: Treatment effect for each patient will be measured as paired differences between pre- and post- measurements of these parameters at various times. Transformation of the data will be performed if appropriate, e.g. log transformation, and hence treatment effect will be expressed on a log scale. This analysis of the data obtained in these correlative studies will be descriptive in nature.
measure: Change in metabolic effector molecules
time frame: Baseline up to 3 years
description: Treatment effect for each patient will be measured as paired differences between pre- and post- measurements of these parameters at various times. Transformation of the data will be performed if appropriate, e.g. log transformation, and hence treatment effect will be expressed on a log scale. This analysis of the data obtained in these correlative studies will be descriptive in nature.
measure: Change in tumor infiltrating lymphocyte (TIL)s and PD-L1 expression
time frame: Baseline up to 3 years
description: Treatment effect for each patient will be measured as paired differences between pre- and post- measurements of these parameters at various times. Transformation of the data will be performed if appropriate, e.g. log transformation, and hence treatment effect will be expressed on a log scale. This analysis of the data obtained in these correlative studies will be descriptive in nature.
arm group label: Treatment (trigriluzole, nivolumab, pembrolizumab)
arm group type: Experimental
description: Patients receive trigriluzole PO QOD, BID, QAM or QHS on days -14 to -1. Patients then receive nivolumab IV over 60 minutes every 2 weeks beginning week 1 and trigriluzole PO QOD, BID, QAM or QHS. Once the MTD of trigriluzole with nivolumab is identified, patients receive pembrolizumab IV over 30 minutes every 3 weeks beginning week 1 and trigriluzole PO. Treatment repeats for up to 1 year in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Enzyme Inhibitor Therapy
description: Given trigriluzole PO
arm group label: Treatment (trigriluzole, nivolumab, pembrolizumab)
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Treatment (trigriluzole, nivolumab, pembrolizumab)
intervention type: Biological
intervention name: Nivolumab
description: Given IV
arm group label: Treatment (trigriluzole, nivolumab, pembrolizumab)
other name: BMS-936558
other name: MDX-1106
other name: NIVO
other name: ONO-4538
other name: Opdivo
intervention type: Biological
intervention name: Pembrolizumab
description: Given IV
arm group label: Treatment (trigriluzole, nivolumab, pembrolizumab)
other name: Keytruda
other name: Lambrolizumab
other name: MK-3475
other name: SCH 900475
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Biren Saraiya
role: Principal Investigator
affiliation: Rutgers Cancer Institute of New Jersey
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Rutgers Cancer Institute of New Jersey
investigator full name: Biren Saraiya, MD
investigator title: Assistant Professor, Medical Oncology
mesh term: Lymphoma
mesh term: Carcinoma
mesh term: Lung Neoplasms
mesh term: Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Melanoma
mesh term: Carcinoma, Squamous Cell
mesh term: Urinary Bladder Neoplasms
mesh term: Carcinoma, Renal Cell
mesh term: Squamous Cell Carcinoma of Head and Neck
mesh term: Skin Neoplasms
mesh term: Recurrence
mesh term: Pembrolizumab
mesh term: Nivolumab
mesh term: Enzyme Inhibitors
sharing ipd: No
provided document: 
submitted: September 14, 2023