Testing the Safety of the Anti-cancer Drugs Tazemetostat and Belinostat in Patients With Lymphomas That Have Resisted Treatment

Refractory Non-Hodgkin Lymphoma Clinical Trial

Official title:

Phase 1/Expansion Study of Tazemetostat Plus Belinostat for the Treatment of Relapsed or Refractory Lymphoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05627245
• Other study ID #: NCI-2022-05327
• Secondary ID: NCI-2022-0532710
• Status: Recruiting
• Phase: Phase 1
• Start date: March 1, 2023
• Est. completion date: March 1, 2025

Study information

• Verified date: April 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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 30-180 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 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 64
• Est. completion date: March 1, 2025
• Est. primary completion date: March 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• DOSE ESCALATION PHASE: Patients with relapsed or refractory non-Hodgkin lymphoma including both B-cell non-Hodgkin lymphoma (NHL) and T-cell NHL. Refractory cutaneous T-cell lymphoma (CTCL) will be allowed if greater or equal to stage 1B and have previously failed two systemic therapies

• DOSE EXPANSION PHASE: Patients with relapsed or refractory transformed lymphoma or germinal center B-cell diffuse large B-cell Lymphoma (GCB-DLBCL) as defined by Hans criteria. Equal numbers of patients will be enrolled onto one of 2 arms: (1) mutated EZH2 or (2) wild-type EZH2. EZH2 mutations will be identified by polymerase chain reaction (PCR)

• Patients must not be eligible for, or have refused, stem cell transplantation or chimeric antigen receptor T-cell (CAR T-cell) therapy

• Patients who have undergone 1-5 prior treatments of any type (progression after transplant/cellular therapy allowed) are eligible

• Patients must have measurable disease according to the Lugano classification

• Age >= 18 years. Because no dosing or adverse event data are currently available on the use of tazemetostat in combination with belinostat in patients < 18 years of age, children are excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Absolute neutrophil count (ANC) >= 1,000/mcL

• If there is documented lymphomatous involvement of the bone marrow as assessed by bone marrow biopsy within 90 days prior to registration, participants should have: ANC >= 0.75 × 10^9/L

• Platelets >= 75,000/mcL

• If there is documented lymphomatous involvement of the bone marrow as assessed by bone marrow biopsy within 90 days prior to registration, participants should have: platelets >= 50 x 10^9/L

• Total bilirubin =< .5 institutional upper limit of normal (ULN); unless due to Gilbert's disease, hemolysis, or lymphomatous involvement of liver in which case total bilirubin should be =< 5 x institutional ULN

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN; unless due to Gilbert's disease, hemolysis, or lymphomatous involvement of liver, in which case AST(SGOT)/ALT(SGPT) should be =< 5 x institutional ULN

• Glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression

• 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 for this trial. Patients whose lymphoma has transformed from a less aggressive histology remain eligible

• Patients should be New York Heart Association Functional Classification of class II or better

• Patients must have a QT interval corrected by Fridericia's formula (QTcF) =< 450 msec

• Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption, such as malabsorption syndrome or major resection of the stomach or bowels

• The effects of tazemetostat and belinostat on the developing human fetus are unknown. For this reason, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for 6 months after the last dose of the study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of tazemetostat and belinostat administration

• Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity who have a legally-authorized representative (LAR) and/or family member available will also be eligible

• Patients that have received prior chemotherapy or radiotherapy must have completed their last treatment at least 2 weeks before entering the study. Rituximab given between EZH2 analysis and initiation of study drugs will be allowed

Exclusion Criteria:

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia

• Patients who are receiving any other investigational agents

• Patients with active central nervous system (CNS) metastases, including lymphomatous meningitis, as the study drugs are not known to effectively treat CNS disease

• History of allergic reactions attributed to belinostat or tazemetostat, or to compounds of similar chemical or biologic composition to these agents

• Patients receiving any medications or substances that are strong or moderate inhibitors or inducers of CYP3A4 within 14 days prior to study treatment are ineligible. Patients receiving strong UGT1A1 inhibitors are ineligible due to expected increased exposure to belinostat and potential for increased toxicity. Because the list of these agents is constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product

• Patients with known UGT1A1 genetic polymorphisms, such as UGT1A1*28, are excluded as they can have reduced UGTA1A activity and may be at risk for increased belinostat exposure

• Patients with uncontrolled intercurrent illness

• Pregnant women are excluded from this study because belinostat, as an HDAC inhibitor, and tazemetostat, as an EZH2 inhibitor, both have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with belinostat and tazemetostat, breastfeeding should be discontinued if the mother is treated with belinostat and tazemetostat. Women of childbearing potential must have negative urine or serum pregnancy test to be eligible for this study

• Systemic steroids that have not been stabilized to the equivalent of =< 10 mg/day prednisone prior to the start of the study drugs and throughout the study. Patients are allowed to receive dexamethasone as premedication during belinostat infusion

• Has thrombocytopenia, neutropenia, or anemia of grade >= 3 (per Common Terminology Criteria for Adverse Events [CTCAE] 5.0 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS)

• Has abnormalities known to be associated with MDS (e.g. 5q deletion [del 5q], chromosome 7 abnormality [chr 7 abn]) and multiple primary neoplasms (MPN) (e.g. JAK2 V617F) observed in cytogenetic testing and deoxyribonucleic acid (DNA) sequencing

• Has a prior history of T lymphoblastic lymphoma/T acute lymphoblastic leukemia (T-LBL/T-ALL)

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse
• Lymphoma, Non-Hodgkin
• Lymphoma, T-Cell
• Lymphoma, T-Cell, Cutaneous
• Recurrence
• Recurrent B-Cell Non-Hodgkin Lymphoma
• Recurrent Non-Hodgkin Lymphoma
• Recurrent Primary Cutaneous T-Cell Non-Hodgkin Lymphoma
• Recurrent T-Cell Non-Hodgkin Lymphoma
• Recurrent Transformed Non-Hodgkin Lymphoma
• Refractory B-Cell Non-Hodgkin Lymphoma
• Refractory Non-Hodgkin Lymphoma
• Refractory Primary Cutaneous T-Cell Non-Hodgkin Lymphoma
• Refractory T-Cell Non-Hodgkin Lymphoma
• Refractory Transformed Non-Hodgkin Lymphoma

Intervention

Drug:
• Belinostat
Given IV

Procedure:
• Biopsy
Undergo biopsy
• Biospecimen Collection
Undergo blood sample collection
• Computed Tomography
Undergo CT scan

Other:
• Pharmacokinetic Study
Pharmacokinetic study

Procedure:
• Positron Emission Tomography and Computed Tomography Scan
Undergo PET-CT

Drug:
• Tazemetostat
Given PO

Locations

Country	Name	City	State
United States	University of Kansas Clinical Research Center	Fairway	Kansas
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Yale University	New Haven	Connecticut
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Modulation in immune function	Will be presented in descriptive terms.	During cycle 1
Other	Histone acetylation and methylation	Will be assessed separately for the wild type (WT) and the mutant (MUT) groups and will be compared using a two-sample Wilcoxon rank-sum test.	Up to 2 years
Other	Gene signature biomarker for response	Will be evaluated next generation sequencing (NGS) and presented in descriptive terms. Gene signature biomarker data analysis will be completed using Lasso-based elastic net method.	Up to 2 years
Other	Modulation of histone acetylation and methylation	Will be presented in descriptive terms.	Up to 2 years
Primary	Maximum tolerated dose (MTD) (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 (DLT) in the first cycle.	Up to end of cycle 1 (Cycles = 21 days)
Secondary	Disease response	Will be assessed by positron emission tomography/computed tomography (PET/CT) scan following cycle 2 and 6, and then every 3-6 cycles. Response will be defined by the Lugano Classification.	Following cycle 2 and 6, and every 3-6 cycles, assessed up to 1 year after completion of study treatment
Secondary	Overall response rate (ORR)	Defined as complete response + partial response. Will be estimated and the exact 95% confidence interval will be constructed based on binomial distribution.	Up to 1 year after completion of study treatment
Secondary	Progression-free survival (PFS)	Will be estimated by the Kaplan-Meier method and compared by the log-rank test.	From time to enrollment to progression or death, assessed up to 1 year after completion of study treatment
Secondary	Overall survival (OS)	Will be estimated by the Kaplan-Meier method and compared by the log-rank test.	From time to enrollment to death, assessed up to 1 year after completion of study treatment
Secondary	Duration of response (DOR)	Will be estimated by the Kaplan-Meier method.	From first response to relapse or death, assessed up to 1 year after completion of study treatment
Secondary	Total number of cycles	The mean and range will be calculated.	Up to 2 years
Secondary	Number of dose delays	The mean and range will be calculated.	Up to 2 years
Secondary	Number of dose reductions	The mean and range will be calculated.	Up to 2 years
Secondary	Pharmacokinetic profile for tazemetostat and belinostat	Plasma concentrations of both tazemetostat and belinostat using area under the "concentration time" curve (AUC), maximum concentration (Cmax), time to maximum concentration Tmax, and half-life (T1/2) will be calculated for the two study drugs.	Cycle 1, day 1 (C1D1) (belinostat only) and C2D1
Secondary	Incidence of adverse events	National Cancer Institute (NCI) toxicity Grade 3 and Grade 4 laboratory abnormalities will be listed. Summary statistics will be provided for all laboratory values.	Up to 4 weeks after completion of study treatment