Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Eye Diseases

Rare Diseases

Melanoma

Uveal Neoplasms

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Eye Neoplasms

Uveal Diseases

Intraocular Melanoma

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Trametinib

Protein Kinase Inhibitors

Enzyme Inhibitors

Patients receive PLX2853 PO in combination with trametinib PO throughout the study. Patients also undergo collection of blood at screening and on study. Patients also undergo CT or MRI with contrast and collection of blood at screening and on study.

BRD4 Inhibitor PLX2853

Computed Tomography

Magnetic Resonance Imaging

Biospecimen collection

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.

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

Phase I/II Study of BET and MEK Inhibition in Advanced Uveal Melanoma

Will be found using a Keyboard design which will be the dose with an estimated dose-limiting toxicity (DLT) rate closest to 25% (the target DLT rate).

Defined as the number of patients that achieve a best response of PR or better divided by the total number of evaluable patients. Will be evaluated using a Simon two-stage mini-max design using a historical response rate of 10% based on some prior work in this disease population with chemotherapy and targeted therapy. A 95% confidence interval for this estimate will also be calculated based on properties of the binomial distribution.

The Kaplan-Meier (KM) method will be used to estimate the median PFS time. A 95% confidence interval for the median PFS time will also be calculated using KM methodology.

Will be estimated using Kaplan-Meier method, and a 95% confidence interval will also be calculated using KM methodology.

The Kaplan-Meier method will be used to estimate the median PFS time. A 95% confidence interval for the median PFS time will also be calculated using KM methodology.

Adverse events will be recorded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 for each patient. Frequency tables and summary statistics will be used and with the appropriate methods of evaluating categorical and continuous data.

Systemic exposure to trametinib and PLX2853 will be assessed by determining trough plasma concentrations (Ctrough, Cmin), which is the concentration in a sample collected immediately prior to a next dose. Ctrough will be determined throughout the first two treatment cycles on day 1 and day 15. Ctrough of trametinib and PLX2853 will be summarized using descriptive statistics. Dose dependency of Ctrough in phase 1 will be investigated using exploratory statistics. Potential changes in systemic exposure to either trametinib and/or PLX2853 over time will be explored by investigating changes in Ctrough during the two cycles. In addition, will use population PK models combined with the Ctroughs to describe the full PK of trametinib and PLX2853.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Testing the Safety and Effectiveness of Combining Two Drugs, PLX2853 and Trametinib in the Treatment of Advanced Uveal Melanoma	NCT05677373	Advanced Uveal ... Metastatic Uvea... Unresectable Uv...	BRD4 Inhibitor ... Trametinib Computed Tomogr... Magnetic Resona... Biospecimen col... Biospecimen col...	18 Years -	Alliance for Clinical Trials in Oncology
Testing the Safety and Effectiveness of Combining Two Drugs, PLX2853 and Trametinib in the Treatment of Advanced Uveal Melanoma	NCT05677373	Advanced Uveal ... Metastatic Uvea... Unresectable Uv...	BRD4 Inhibitor ... Trametinib Computed Tomogr... Magnetic Resona... Biospecimen col... Biospecimen col...	18 Years -	Alliance for Clinical Trials in Oncology

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