Testing the Safety and Effectiveness of Combining Two Drugs, PLX2853 and Trametinib in the Treatment of Advanced Uveal Melanoma

This phase I/II trial tests the safety, side effects, and best dose of PLX2853 in combination with trametinib in treating patients with uveal (eye) melanoma that has spread to other places in the body (metastatic) or nearby tissues or lymph nodes (locally advanced), or that cannot be removed by surgery (unresectable). PLX2853 works by targeting and inhibiting certain activities within cells that promote tumor growth. By inhibiting these activities, PLX2853 may help to stabilize or reduce the growth of tumor cells. Trametinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals tumor cells to multiply. This helps stop the spread of tumor cells. Giving PLX2853 in combination with trametinib may help to shrink and stabilize tumor cells in patients with advanced uveal melanoma.

CO-PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose(s) (MTD(s)) and recommended phase II dose. (Phase I) II. To evaluate whether combination BRD4 inhibitor PLX2853 (PLX2853) and trametinib demonstrate clinical activity in advanced uveal melanoma (UM), as determined by a best response rate of 25% compared to a historical rate of 10%. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the overall response rate (ORR) associated with combination PLX2853 and trametinib.

II. To evaluate the progression-free survival (PFS) associated with combination PLX2853 and trametinib.

III. To evaluate the overall survival (OS) associated with combination PLX2853 and trametinib.

IV. To characterize the adverse event profile associated with combination PLX2853 and trametinib.

PHARMACOKINETICS SECONDARY OBJECTIVE:

I. To evaluate the pharmacokinetic profile of combination PLX2853 and trametinib.

OUTLINE: This is a phase I dose-escalation study of PLX2853 and trametinib followed by a phase II study.

Patients receive PLX2853 orally (PO) in combination with trametinib PO throughout the study. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) with contrast and collection of blood at screening and on study.

Eligibility Criteria:
Inclusion Criteria:

* Patients must have histologically documented advanced uveal melanoma. Pathology review and confirmation of diagnosis will occur at the site enrolling the patient on this study. Patients must have locally advanced unresectable or metastatic uveal melanoma (UM).
* Patients must have at least one lesion which is measurable according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Measurable disease is not required in the phase I portion
* Patients may be treatment-naïve or have received any number of prior systemic or liver-directed therapies for advanced UM. There are no maximum number of prior therapies received
* There is no specified washout time for prior therapies however patients must have fully recovered from acute toxicities related to prior anti-cancer therapies including

  \* Cytotoxic therapies, immunotherapy, small molecule targeted agents, cell therapy, liver-directed therapy, or radiation therapy
* Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative pregnancy test done =\< 7 days prior to registration is required
* Age \>= 18 years
* Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
* Absolute neutrophil count (ANC) \>= 1000/mm\^3
* Hemoglobin \>= 9g/dL (transfusions to achieve this level are allowed)
* Platelet count \>= 100,000/mm\^3
* Creatinine clearance \>= 45 mL/minute (per Cockcroft-Gault equation)
* Total bilirubin =\<1.5 x upper limit of normal (ULN)
* Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) =\< 3 x upper limit of normal (ULN)
* Prothrombin time (PT)/international normalized ratio (INR) =\< 1.5 x upper limit of normal (ULN)
* No history of any medical condition such as uncontrolled infection (including hepatitis B \[HepB\], hepatitis C \[HepC\]), uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient
* Patients who are human immunodeficiency virus (HIV)-infected on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible
* Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible
* Patients with a new or progressive brain metastases (active brain metastases) or leptomeningeal disease if the treating physician determines that immediate central nervous system (CNS) specific treatment is not required and is unlikely to be required during the first cycle of therapy are eligible
* Patients with a known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification with a class 2B or better are eligible
* Patients must be able to obtain confirmation of payment coverage (insurance or other) for trametinib \* Trametinib will not be provided by the Alliance and must be obtained through commercial or other mechanisms independent of the clinical trial. Confirmation of payment coverage or medication access must be obtained by treating physician prior to registration

Exclusion Criteria

* Patients must not have received prior treatment with a BET or MEK inhibitor
* No patients who cannot swallow oral formulations of the agent(s)
* Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study