Testing the Safety of the Anti-cancer Drugs Tazemetostat and Belinostat in Patients With Lymphomas That Have Resisted Treatment
Phase 1/Expansion Study of Tazemetostat Plus Belinostat for the Treatment of Relapsed or Refractory Lymphoma
4 other identifiers
interventional
48
1 country
11
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_1
Started Mar 2023
Typical duration for phase_1
11 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
November 23, 2022
CompletedFirst Posted
Study publicly available on registry
November 25, 2022
CompletedStudy Start
First participant enrolled
March 1, 2023
CompletedPrimary Completion
Last participant's last visit for primary outcome
September 1, 2026
ExpectedStudy Completion
Last participant's last visit for all outcomes
September 1, 2026
April 22, 2026
April 1, 2026
3.5 years
November 23, 2022
April 21, 2026
Conditions
Outcome Measures
Primary Outcomes (1)
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.
Up to end of cycle 1 (Cycles = 21 days)
Secondary Outcomes (10)
Disease response
Following cycle 2 and 6, and every 3-6 cycles, assessed up to 1 year after completion of study treatment
Overall response rate
Up to 1 year after completion of study treatment
Progression-free survival
From time to enrollment to progression or death, assessed up to 1 year after completion of study treatment
Overall survival
From time to enrollment to death, assessed up to 1 year after completion of study treatment
Duration of response
From first response to relapse or death, assessed up to 1 year after completion of study treatment
- +5 more secondary outcomes
Other Outcomes (4)
Modulation in immune function
During cycle 1 (Cycles = 21 days)
Histone acetylation and methylation
Up to 2 years
Gene signature biomarker for response
Up to 2 years
- +1 more other outcomes
Study Arms (1)
Treatment (tazemetostat, belinostat)
EXPERIMENTALPatients receive tazemetostat PO BID on days 2-21 of cycle 1 and days 1-21 of subsequent cycles, and belinostat 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 CT or PET/CT scan throughout the study.
Interventions
Undergo blood sample collection
Undergo CT scan
Pharmacokinetic study
Given PO
Given IV
Undergo biopsy
Undergo PET-CT
Eligibility Criteria
You may qualify if:
- 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 follicular, transformed lymphoma or germinal center B-cell diffuse large B-cell Lymphoma (GCB-DLBCL) as defined by Hans criteria, as well as T-cell lymphomas. For patients with B-cell lymphomas, 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 \>= 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: absolute neutrophil count (ANC) \>= 0.75 Ă— 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 =\< 1.5 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
- +10 more criteria
You may not qualify if:
- 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)
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (11)
University of California Davis Comprehensive Cancer Center
Sacramento, California, 95817, United States
Yale University
New Haven, Connecticut, 06520, United States
University of Kansas Clinical Research Center
Fairway, Kansas, 66205, United States
University of Kansas Cancer Center
Kansas City, Kansas, 66160, United States
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas, 66205, United States
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, 08903, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York, New York, 10032, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210, United States
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104, United States
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, 84112, United States
VCU Massey Comprehensive Cancer Center
Richmond, Virginia, 23298, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Jennifer E Amengual
Yale University Cancer Center LAO
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NA
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
November 23, 2022
First Posted
November 25, 2022
Study Start
March 1, 2023
Primary Completion (Estimated)
September 1, 2026
Study Completion (Estimated)
September 1, 2026
Last Updated
April 22, 2026
Record last verified: 2026-04
Data Sharing
- IPD Sharing
- Will share
NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page