Clinical Trials /

Trigriluzole With Nivolumab and Pembrolizumab in Treating Patients With Metastatic or Unresectable Solid Malignancies or Lymphoma

NCT03229278

Description:

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.

Related Conditions:
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trigriluzole With Nivolumab and Pembrolizumab in Treating Patients With Metastatic or Unresectable Solid Malignancies or Lymphoma
  • Official Title: A Phase I Study to Evaluate the Safety of Trigriluzole (FC-4157/BHV-4157) in Combination With PD-1 Blocking Antibodies

Clinical Trial IDs

  • ORG STUDY ID: 051707
  • SECONDARY ID: NCI-2017-01155
  • SECONDARY ID: Pro20170000453
  • SECONDARY ID: 051707
  • SECONDARY ID: P30CA072720
  • NCT ID: NCT03229278

Conditions

  • Lymphoma
  • Metastatic Malignant Solid Neoplasm
  • Metastatic Melanoma
  • Metastatic Renal Cell Cancer
  • Recurrent Bladder Carcinoma
  • Recurrent Classical Hodgkin Lymphoma
  • Recurrent Head and Neck Squamous Cell Carcinoma
  • Recurrent Lymphoma
  • Recurrent Malignant Solid Neoplasm
  • Recurrent Renal Cell Carcinoma
  • Stage III Bladder Cancer
  • Stage III Lymphoma
  • Stage III Non-Small Cell Lung Cancer AJCC v7
  • Stage III Renal Cell Cancer
  • Stage III Skin Melanoma
  • Stage IIIA Non-Small Cell Lung Cancer AJCC v7
  • Stage IIIA Skin Melanoma
  • Stage IIIB Non-Small Cell Lung Cancer AJCC v7
  • Stage IIIB Skin Melanoma
  • Stage IIIC Skin Melanoma
  • Stage IV Bladder Cancer
  • Stage IV Lymphoma
  • Stage IV Non-Small Cell Lung Cancer AJCC v7
  • Stage IV Renal Cell Cancer
  • Stage IV Skin Melanoma
  • Stage IVA Bladder Cancer
  • Stage IVB Bladder Cancer
  • Unresectable Head and Neck Squamous Cell Carcinoma
  • Unresectable Solid Neoplasm

Interventions

DrugSynonymsArms
Enzyme Inhibitor TherapyTreatment (trigriluzole, nivolumab, pembrolizumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (trigriluzole, nivolumab, pembrolizumab)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (trigriluzole, nivolumab, pembrolizumab)

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (trigriluzole, nivolumab, pembrolizumab)ExperimentalPatients 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.
  • Enzyme Inhibitor Therapy
  • Nivolumab
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed solid malignancy or lymphoma that is
             metastatic or unresectable

          -  There is reasonable expectation of response to pembrolizumab or nivolumab, and one of
             the drugs is available from the commercial supply; this includes (but is not limited
             to) the following tumor types: melanoma, non-small cell lung cancer, renal cell
             carcinoma, squamous cell carcinoma of the head and neck, bladder cancer, and classic
             Hodgkin lymphoma

          -  The patient must have failed at least one line of standard treatment, with the
             following exceptions in which a PD-1 antibody is Food and Drug Administration (FDA)
             approved in the first-line setting:

               -  Melanoma patients

               -  Non-small cell lung cancer patients without EGFR or ALK genomic tumor aberrations
                  whose tumors have high PD-L1 expression (tumor proportion score [TPS] >= 50%) as
                  determined by an FDA-approved test

          -  Patients must give informed consent

          -  Prior chemotherapy, immunotherapy, radiotherapy or major surgery (including radiation
             therapy or surgery for treatment of brain metastases) must be completed at least 3
             weeks before study entry; prior PD-1 or PD-L1 therapy is acceptable

          -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =<
             2

          -  Hemoglobin > 8.0 mg/dL (without transfusion in the preceding 7 days)

          -  Platelets >= 70,000 /uL

          -  Total bilirubin within normal institutional limits (patients with Gilbert's syndrome
             must have a total bilirubin < 3.0 mg/dL)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 2
             X institutional upper limit of normal (ULN)

          -  Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 X
             institutional ULN

          -  Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded) as >=
             10 mm by computed tomography (CT) scan, positron emission tomography (PET)/CT scan,
             magnetic resonance imaging (MRI) or caliper/ruler measurement by clinical exam; lymph
             nodes: to be considered pathologically enlarged and measurable, a lymph node must be
             >= 15 mm in short axis when assessed by CT scan; lesions that have been radiated in
             the advanced setting cannot be included as sites of measurable disease unless clear
             tumor progression has been documented in these lesions since the end of radiation
             therapy

          -  Ability to swallow pills

        Exclusion Criteria:

          -  Systemic immunosuppressive medications such as steroids; the following steroid
             formulations are permitted: intranasal, intra-articular, and inhaled steroids

          -  History of immune-related adverse event from prior immunotherapy treatment that has
             not improved to grade 0-1; subjects with grade 2 hypothyroidism and grade 2 adrenal
             insufficiency requiring continued medical treatment may enroll provided that they are
             asymptomatic and stable on their dose of hormone replacement

          -  Serious concomitant systemic disorders (including active infections) that would
             compromise the safety of the patient or compromise the patient?s ability to complete
             the study, at the discretion of the investigator, including active autoimmune disease
             requiring treatment within the past 30 days

          -  Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily
             prednisone equivalents) or other systemic immunosuppressive medications within 14 days
             of study drug administration; inhaled or topical steroids and adrenal replacement
             doses < 10 mg daily prednisone equivalents are permitted in the absence of active
             autoimmune disease; patients are permitted to use topical, ocular, intra-articular,
             intranasal, and inhalational corticosteroids (with minimal systemic absorption)'
             physiologic replacement doses of systemic corticosteroids are permitted, even if < 10
             mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis
             (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g.,
             delayed-type hypersensitivity reaction caused by contact allergen) is permitted

          -  Second primary malignancy, except those second primary malignancies that are not
             considered to be competing causes of death in the opinion of the treating
             investigator; examples include: in situ carcinoma of the cervix, adequately treated
             non-melanoma carcinoma of the skin, or other malignancy treated at least 5 years
             previously with no evidence of recurrence

          -  Patients with active, untreated central nervous system (CNS) metastases will be
             excluded from this clinical trial; patients who have brain metastases that been
             treated with radiation therapy or surgery will be required to have a washout period of
             at least 3 weeks prior to study entry, must be neurologically asymptomatic, and must
             not require systemic steroids

          -  Women of child-bearing potential and men must agree to use adequate contraception
             prior to the start of treatment, for the duration of treatment, and for 5 months after
             last dose of study treatment

          -  Patients with immune deficiency have impaired immune responses, therefore, known human
             immunodeficiency virus (HIV)-positive patients are excluded from the study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD))/recommended phase 2 dose of trigriluzole
Time Frame:Up to 3 years
Safety Issue:
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.

Secondary Outcome Measures

Measure:Adverse event (AE) type, severity and frequency
Time Frame:Up to 3 years
Safety Issue:
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
Safety Issue:
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
Safety Issue:
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
Safety Issue:
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
Safety Issue:
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
Safety Issue:
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
Safety Issue:
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
Safety Issue:
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
Safety Issue:
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
Safety Issue:
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).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Rutgers, The State University of New Jersey

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