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

Lymphoma Clinical Trial

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 Details — Status: Completed

Administrative data

• NCT number: NCT03229278
• Other study ID #: 051707
• Secondary ID: NCI-2017-01155Pr
• Status: Completed
• Phase: Phase 1
• Start date: October 3, 2017
• Est. completion date: October 30, 2022

Study information

• Verified date: November 2023
• Source: Rutgers, The State University of New Jersey
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 14
• Est. completion date: October 30, 2022
• Est. primary completion date: October 20, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Non-Small-Cell Lung
• Carcinoma, Renal Cell
• Carcinoma, Squamous Cell
• Lung Neoplasms
• Lymphoma
• Melanoma
• Metastatic Malignant Solid Neoplasm
• Metastatic Melanoma
• Metastatic Renal Cell Cancer
• Neoplasms
• Recurrence
• Recurrent Bladder Carcinoma
• Recurrent Classical Hodgkin Lymphoma
• Recurrent Head and Neck Squamous Cell Carcinoma
• Recurrent Lymphoma
• Recurrent Malignant Solid Neoplasm
• Recurrent Renal Cell Carcinoma
• Skin Neoplasms
• Squamous Cell Carcinoma of Head and Neck
• 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
• Urinary Bladder Neoplasms

Intervention

Drug:
• Enzyme Inhibitor Therapy
Given trigriluzole PO

Other:
• Laboratory Biomarker Analysis
Correlative studies

Biological:
• Nivolumab
Given IV
• Pembrolizumab
Given IV

Locations

Country	Name	City	State
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey

Sponsors (2)

Lead Sponsor	Collaborator
Rutgers, The State University of New Jersey	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Tolerated Dose (MTD))/Recommended Phase 2 Dose of Trigriluzole	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.	Four weeks
Secondary	Number of Participants Who Experienced Dose-Limiting Toxicities (DLT)	A DLT was any Grade 3 or 4 adverse event (AE) using the Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE 3.0) that was possibly Trigriluzole or Nivolumab related. CTCAE 3.0 Grade 3 is a severe AE and Grade 4 is a life- threatening or disabling AE. DLTs were collected to determine the Maximum-Tolerated Dose (MTD), which is defined as the dose level below the dose at which 33% of participants experienced a DLT.	Four weeks
Secondary	Objective Response Rate Assessed According to Response Evaluation Criteria in Solid Tumors Version 1.1	Continuous variables will be presented by summary statistics (such as mean, median, standard error and 95% confidence intervals [CI]) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 95% CI).	Up to 3 years
Secondary	Overall Survival	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).	Up to 3 years
Secondary	Time to Next Therapy or Death	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).	Up to 3 years
Secondary	Freedom From New Metastases	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).	Up to 3 years
Secondary	Landmark Survival Rates at 1 Year	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).	1 year
Secondary	Landmark Survival Rate at 2 Years	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).	2 years
Secondary	Duration of Response for Responding Patients	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).	Up to 3 years
Secondary	Progression Free Survival	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).	Up to 3 years
Secondary	Time to Treatment Failure	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).	Up to 3 years