PRIMARY OBJECTIVES:~I. To determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of tazemetostat and belinostat in combination in patients with relapsed or refractory lymphoma (Phase I: Dose escalation).~II. Evaluate the safety and toxicity of the combination tazemetostat and belinostat (Phase I: Dose escalation).~III. Assess the safety and tolerability of tazemetostat and belinostat in patients with germinal-center derived aggressive B-cell lymphoma (transformed disease, diffuse large B-cell lymphoma germinal center B-cell type [GC-DLBCL] defined by Hans criteria) (Phase I: Dose expansion).~IV. Assess the impact of EZH2, CREBBP, and EP300 mutations on response to dual epigenetic targeting (Phase I: Dose expansion).~SECONDARY OBJECTIVES:~I. To observe and record anti-tumor activity. II. To evaluate the pharmacokinetic profile for tazemetostat and belinostat when given as a combination.~III. Define the overall response rate (ORR), progression free survival (PFS), and duration of response (DOR) in patients with relapsed or refractory EZH2 mutated and EZH2 wild-type aggressive germinal-center derived B-cell lymphoma (transformed disease, GC-DLBCL defined by Hans criteria).~IV. To describe the maximum number of cycles received, the number of dose reductions and delays at the MTD.~EXPLORATORY OBJECTIVES:~I. Determine a biomarker for response by assessing the basal mutation and gene expression status of key epigenetic regulators and correlating this signature with the response to the combination.~II. Determine the change in gene expression in tumor tissue following exposure the combined epigenetic therapy.~III. Determine the effect of combination epigenetic therapy on modulation of acetylation and methylation of histone K27.~IV. Determine the effect of combination epigenetic therapy on modulation of the immune response.~OUTLINE: This is a phase I dose-escalation study of tazemetostat and belinostat followed by a dose-expansion study.~Patients receive tazemetostat orally (PO) twice daily (BID) on days 2-21 of cycle 1 and days 1-21 of subsequent cycles, and belinostat intravenously (IV) over 30 minutes on days 1-5 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.~Patients may undergo a tumor biopsy during screening and on study (dose-expansion only). Patients undergo blood sample collection while on study and positron emission tomography/computed tomography(PET/CT) scan throughout the study. Patients may also undergo computed tomography (CT) scan alone throughout the study.~After completion of study treatment, patients are followed up at 4 weeks, then every 3 months for a year or until they begin a new treatment for their disease.
This phase I trial tests the safety, side effects, and best dose of combination therapy with tazemetostat and belinostat in treating patients with lymphomas that have returned (relapsed) or resisted treatment (refractory). Tazemetostat is in a class of medications called EZH2 inhibitors. The EZH2 gene provides instructions for making a type of enzyme called histone methyltransferase which is involved in gene expression and cell division. Blocking EZH2 may help keep cancer cells from growing. Belinostat is in a class of medications called histone deacetylase inhibitors. Histone deacetylases are enzymes needed for cell division. Belinostat may kill cancer cells by blocking histone deacetylase. It may also prevent the growth of new blood vessels that tumors need to grow and may help make cancer cells easier to kill with other anticancer drugs. There is some evidence in animals and in living human cells that combination therapy with tazemetostat and belinostat can shrink or stabilize cancer, but it is not known whether this will happen in people. This trial may help doctors learn more about treatment of patients with relapsed or refractory lymphoma.