This phase I trial tests the safety, side effects, and best dose of combination therapy with tazemetostat and belinostat in treating patients with lymphoma that has come back after a period of improvement (relapsed) or that does not respond to 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.
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 B-cell lymphoma (follicular lymphoma, transformed disease, diffuse large B-cell lymphoma germinal center B-cell type \[GC-DLBCL\] defined by Hans criteria), and T-cell lymphomas. (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 germinal-center derived B-cell lymphoma (follicular lymphoma, transformed disease, GC-DLBCL defined by Hans criteria), as well as T-cell lymphomas. 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 30-180 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 computed tomography (CT) or positron emission tomography (PET)/CT scan 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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
48
Given IV
Undergo biopsy
Undergo blood sample collection
Undergo CT scan
Pharmacokinetic study
Undergo PET-CT
Given PO
University of California Davis Comprehensive Cancer Center
Sacramento, California, United States
RECRUITINGYale University
New Haven, Connecticut, United States
RECRUITINGUniversity of Kansas Clinical Research Center
Fairway, Kansas, United States
RECRUITINGUniversity of Kansas Cancer Center
Kansas City, Kansas, United States
RECRUITINGUniversity of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas, United States
RECRUITINGRutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, United States
RECRUITINGNYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York, New York, United States
RECRUITINGOhio State University Comprehensive Cancer Center
Columbus, Ohio, United States
RECRUITINGUniversity of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States
RECRUITINGHuntsman Cancer Institute/University of Utah
Salt Lake City, Utah, United States
RECRUITING...and 1 more locations
Maximum tolerated dose (Dose escalation)
Defined as the highest dose level at which \< 33% of the dose cohort (0 of 3 or 1 of 6) experience a dose-limiting toxicity in the first cycle.
Time frame: Up to end of cycle 1 (Cycles = 21 days)
Disease response
Will be assessed by positron emission tomography/computed tomography scan following cycle 2 and 6, and then every 3-6 cycles. Response will be defined by the Lugano Classification.
Time frame: Following cycle 2 and 6, and every 3-6 cycles, assessed up to 1 year after completion of study treatment
Overall response rate
Defined as complete response + partial response. Will be estimated and the exact 95% confidence interval will be constructed based on binomial distribution.
Time frame: Up to 1 year after completion of study treatment
Progression-free survival
Will be estimated by the Kaplan-Meier method and compared by the log-rank test.
Time frame: From time to enrollment to progression or death, assessed up to 1 year after completion of study treatment
Overall survival
Will be estimated by the Kaplan-Meier method and compared by the log-rank test.
Time frame: From time to enrollment to death, assessed up to 1 year after completion of study treatment
Duration of response
Will be estimated by the Kaplan-Meier method.
Time frame: From first response to relapse or death, assessed up to 1 year after completion of study treatment
Total number of cycles
The mean and range will be calculated.
Time frame: Up to 2 years
Number of dose delays
The mean and range will be calculated.
Time frame: Up to 2 years
Number of dose reductions
The mean and range will be calculated.
Time frame: Up to 2 years
Pharmacokinetic profile for tazemetostat and belinostat
Plasma concentrations of both tazemetostat and belinostat using area under the "concentration time" curve, maximum concentration, time to maximum concentration, and half-life will be calculated for the two study drugs.
Time frame: Cycle 1, day 1 (C1D1) (belinostat only) and C2D1
Incidence of adverse events
National Cancer Institute toxicity Grade 3 and Grade 4 laboratory abnormalities will be listed. Summary statistics will be provided for all laboratory values.
Time frame: Up to 4 weeks after completion of study treatment
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