Trial Title:
Testing the Safety of the Anti-cancer Drugs Tazemetostat and Belinostat in Patients With Lymphomas That Have Resisted Treatment
NCT ID:
NCT05627245
Condition:
Recurrent B-Cell Non-Hodgkin Lymphoma
Recurrent Diffuse Large B-Cell Lymphoma Germinal Center B-Cell Type
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 Diffuse Large B-Cell Lymphoma Germinal Center B-Cell Type
Refractory Non-Hodgkin Lymphoma
Refractory Primary Cutaneous T-Cell Non-Hodgkin Lymphoma
Refractory T-Cell Non-Hodgkin Lymphoma
Refractory Transformed Non-Hodgkin Lymphoma
Conditions: Official terms:
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Lymphoma, T-Cell
Lymphoma, T-Cell, Cutaneous
Recurrence
Belinostat
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Belinostat
Description:
Given IV
Arm group label:
Treatment (tazemetostat, belinostat)
Other name:
Beleodaq
Other name:
PXD 101
Other name:
PXD-101
Other name:
PXD101
Intervention type:
Procedure
Intervention name:
Biopsy
Description:
Undergo biopsy
Arm group label:
Treatment (tazemetostat, belinostat)
Other name:
BIOPSY_TYPE
Other name:
Bx
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Treatment (tazemetostat, belinostat)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT scan
Arm group label:
Treatment (tazemetostat, belinostat)
Other name:
CAT
Other name:
CAT Scan
Other name:
Computed Axial Tomography
Other name:
Computerized Axial Tomography
Other name:
Computerized axial tomography (procedure)
Other name:
Computerized Tomography
Other name:
Computerized Tomography (CT) scan
Other name:
CT
Other name:
CT Scan
Other name:
tomography
Intervention type:
Other
Intervention name:
Pharmacokinetic Study
Description:
Pharmacokinetic study
Arm group label:
Treatment (tazemetostat, belinostat)
Other name:
PHARMACOKINETIC
Other name:
PK Study
Intervention type:
Procedure
Intervention name:
Positron Emission Tomography and Computed Tomography Scan
Description:
Undergo PET-CT
Arm group label:
Treatment (tazemetostat, belinostat)
Other name:
PET-CT Scan
Other name:
PET/CT SCAN
Other name:
Positron Emission Tomography/Computed Tomography
Intervention type:
Drug
Intervention name:
Tazemetostat
Description:
Given PO
Arm group label:
Treatment (tazemetostat, belinostat)
Other name:
E 7438
Other name:
E-7438
Other name:
E7438
Other name:
EPZ 6438
Other name:
EPZ-6438
Other name:
EPZ6438
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.
Detailed 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.
Criteria for eligibility:
Criteria:
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)
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
University of California Davis Comprehensive Cancer Center
Address:
City:
Sacramento
Zip:
95817
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
916-734-3089
Investigator:
Last name:
Joseph M. Tuscano
Email:
Principal Investigator
Facility:
Name:
Yale University
Address:
City:
New Haven
Zip:
06520
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
203-785-5702
Email:
canceranswers@yale.edu
Investigator:
Last name:
Tarsheen Sethi
Email:
Principal Investigator
Facility:
Name:
University of Kansas Clinical Research Center
Address:
City:
Fairway
Zip:
66205
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
913-588-3671
Email:
KUCC_Navigation@kumc.edu
Investigator:
Last name:
Aung M. Tun
Email:
Principal Investigator
Facility:
Name:
University of Kansas Cancer Center
Address:
City:
Kansas City
Zip:
66160
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
913-588-3671
Email:
KUCC_Navigation@kumc.edu
Investigator:
Last name:
Aung M. Tun
Email:
Principal Investigator
Facility:
Name:
University of Kansas Hospital-Westwood Cancer Center
Address:
City:
Westwood
Zip:
66205
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
913-588-3671
Email:
KUCC_Navigation@kumc.edu
Investigator:
Last name:
Aung M. Tun
Email:
Principal Investigator
Facility:
Name:
Rutgers Cancer Institute of New Jersey
Address:
City:
New Brunswick
Zip:
08903
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
732-235-7356
Investigator:
Last name:
Yun Kyoung Tiger
Email:
Principal Investigator
Facility:
Name:
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
Address:
City:
New York
Zip:
10032
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
212-342-5162
Email:
cancerclinicaltrials@cumc.columbia.edu
Investigator:
Last name:
Jennifer E. Amengual
Email:
Principal Investigator
Facility:
Name:
University of Oklahoma Health Sciences Center
Address:
City:
Oklahoma City
Zip:
73104
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
405-271-8777
Email:
ou-clinical-trials@ouhsc.edu
Investigator:
Last name:
Sami Ibrahimi
Email:
Principal Investigator
Facility:
Name:
Huntsman Cancer Institute/University of Utah
Address:
City:
Salt Lake City
Zip:
84112
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
888-424-2100
Email:
cancerinfo@hci.utah.edu
Investigator:
Last name:
Lindsey Fitzgerald
Email:
Principal Investigator
Facility:
Name:
Virginia Commonwealth University/Massey Cancer Center
Address:
City:
Richmond
Zip:
23298
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Email:
CTOclinops@vcu.edu
Investigator:
Last name:
Victor Y. Yazbeck
Email:
Principal Investigator
Start date:
March 1, 2023
Completion date:
March 1, 2025
Lead sponsor:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
National Cancer Institute (NCI)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05627245
