Refractory Non-Hodgkin Lymphoma Clinical Trial
Official title:
Phase 1/Expansion Study of Tazemetostat Plus Belinostat for the Treatment of Relapsed or Refractory Lymphoma
Verified date | April 2024 |
Source | National Cancer Institute (NCI) |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
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) |
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 |
Lead Sponsor | Collaborator |
---|---|
National Cancer Institute (NCI) |
United States,
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 |
Status | Clinical Trial | Phase | |
---|---|---|---|
Recruiting |
NCT05420493 -
Clinical Study of Chimeric Antigen Receptor T Lymphocytes (CAR-T) in the Treatment of Relapsed/Refractory Non-Hodgkin Lymphoma
|
Phase 1 | |
Completed |
NCT00005803 -
Autologous Stem Cell Transplant Followed by Donor Stem Cell Transplant in Treating Patients With Relapsed or Refractory Lymphoma
|
Phase 1/Phase 2 | |
Active, not recruiting |
NCT03233204 -
Olaparib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Defects in DNA Damage Repair Genes (A Pediatric MATCH Treatment Trial)
|
Phase 2 | |
Recruiting |
NCT04545762 -
Anti-CD19 Chimeric Antigen Receptor T Cells for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma
|
Phase 1 | |
Active, not recruiting |
NCT03583424 -
Venetoclax, Carmustine, Etoposide, Cytarabine, and Melphalan Before Stem Cell Transplant in Treating Participants With Relapsed or Refractory Non-Hodgkin Lymphoma
|
Phase 1/Phase 2 | |
Recruiting |
NCT04923789 -
A Study of ASCT Bridging CART Cell Therapy in Relapsed/Refractory B-cell Lymphoma
|
||
Active, not recruiting |
NCT04150913 -
A Phase 2 Trial of Anakinra for the Prevention of CAR-T Cell Mediated Neurotoxicity
|
Phase 2 | |
Active, not recruiting |
NCT03213691 -
Selumetinib Sulfate in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Activating MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)
|
Phase 2 | |
Recruiting |
NCT06026319 -
CD79b-19 CAR T Cells in Non-Hodgkin Lymphoma
|
Phase 1 | |
Recruiting |
NCT06119685 -
IDP-023 as a Single Agent and in Combination With Antibody Therapies in Patients With Advanced Hematologic Cancers
|
Phase 1/Phase 2 | |
Recruiting |
NCT05892718 -
A Safety and Efficacy Study of HCB101, Fc-fusion Protein Targeting SIRPα-CD47 Pathway, in Solid or Hematological Tumors
|
Phase 1 | |
Active, not recruiting |
NCT04284774 -
Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial
|
Phase 2 | |
Recruiting |
NCT04851119 -
Tegavivint for the Treatment of Recurrent or Refractory Solid Tumors, Including Lymphomas and Desmoid Tumors
|
Phase 1/Phase 2 | |
Active, not recruiting |
NCT03220035 -
Vemurafenib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With BRAF V600 Mutations (A Pediatric MATCH Treatment Trial)
|
Phase 2 | |
Terminated |
NCT02420795 -
Akt/ERK Inhibitor ONC201 in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma
|
Phase 1/Phase 2 | |
Active, not recruiting |
NCT03778619 -
MG4101 Plus Rituximab Including Lymphodepletion in Patient With r/r NHL B-cell Origin
|
Phase 1/Phase 2 | |
Active, not recruiting |
NCT03213678 -
Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)
|
Phase 2 | |
Active, not recruiting |
NCT02568553 -
Lenalidomide and Blinatumomab for the Treatment of Relapsed Non-Hodgkin Lymphoma
|
Phase 1 | |
Active, not recruiting |
NCT03698994 -
Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)
|
Phase 2 | |
Active, not recruiting |
NCT03213665 -
Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)
|
Phase 2 |