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

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.

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