Tazemetostat and Venetoclax in Relapsed/Refractory Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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The goal of this clinical trial is to learn about how a combination of tazemetostat and venetoclax in people with relapsed/refractory Non-Hodgkin Lymphoma (R/R NHL). The main questions that this trial aims to answer are what is the best dose of venetoclax to give with tazemetostat to people with R/R NHL; what types of side effects do people with R/R NHL get when taking venetoclax with tazemetostat; and what effects does this combination have on R/R NHL. Participants will need to take pills by mouth every day and regularly come to the clinic for blood work and imagining to monitor side effects and cancer progression. Participants may receive study drugs for up to 24 months.

Detailed Description
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This a phase 1, single arm, non-randomized trial of tazemetostat in combination with venetoclax in participants with two types of relapsed/refractory non-Hodgkin lymphoma. The purpose of this study is to evaluate the safety of the combination of tazemetostat and venetoclax in patients with relapsed/refractory (R/R) Follicular Lymphoma (FL) and Diffuse Large B-cell Lymphoma (DLBCL). This trial will be conducted in two parts. Part one will be a single-arm, open-label sequential dose escalation (3+3) of venetoclax in combination with a fixed dose of tazemetostat (800mg BID) to determine the maximum tolerated dose (MTD) of venetoclax. In part two, two expansion cohorts (R/R DLBCL and R/R FL) will be enrolled to further characterize the safety and tolerability of the combination, and to estimate the preliminary efficacy. Up to 18 participants will be enrolled in part 1 and 20 participants will be enrolled in part 2.

Official Title
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Phase I Trial of Tazemetostat in Combination With Venetoclax in Patients With Relapsed/Refractory Non-Hodgkin Lymphoma

Conditions
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Lymphoma, Non-Hodgkin, Diffuse Large B Cell Lymphoma, Follicular Lymphoma

Intervention / Treatment
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* Drug: Venetoclax
* Drug: Tazemetostat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed, biopsy-proven diagnosis of FL or DLBCL. Subjects must have been treated with at least one prior line of therapy for lymphoma with evidence of disease progression. Subjects are eligible if they have progressed after ASCT OR if they are ineligible for ASCT Exclusion Criteria: Significant cardiovascular impairment, such as history of congestive heart failure, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months of the first dose of study drug Known hypersensitivity to any of the study drugs History of other cancer (some exceptions apply) Known CNS (brain or spinal cord) involvement at diagnosis Richter's transformation from CLL Evidence of uncontrolled systemic infection (viral, bacterial, or fungal) Major surgery within 3 weeks prior to the start of study treatment Venous thrombosis or pulmonary embolism within the last 3 months before starting study Uncontrolled infection with human immunodeficiency virus (HIV) or human T-cell leukemia virus 1 Pregnant or lactating (people capable of becoming pregnant or getting someone else pregnant must be willing to use highly effective birth control) Malabsorption syndrome or other condition that precludes enteral route of administration Inability to swallow tablets Known allergy to both xanthine oxidase inhibitors and rasburicase Clinically significant history of liver disease, including but not limited to viral or other hepatitis, current alcohol abuse, or cirrhosis Active hepatitis C (defined as a positive HCV viral load) Chronic use of moderate or strong CYP3A4 modulators (inhibitor or inducer); chronic use of a P-gp inhibitor, or a P-gp substrate with a narrow therapeutic index; or use of certain other prohibited medications Prior exposure to either tazemetostat or venetoclax Prior history of T-LBL/T-ALL Previous solid organ transplant Requires the use of warfarin (because of potential drug-drug interactions that may potentially increase the exposure of warfarin) Vaccination with live vaccines within 28 days prior to treatment Consumed grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of study drug

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tazemetostat and Venetoclax<br>All participants will receive a combination of oral 800 mg tazemetostat BID and oral venetoclax. Since this is a phase 1 trial, the dose of venetoclax will be determined by the investigators per a sequential dose escalation (3+3). Participants will be provided study drug in the form of pills to take at home. Study participants will need to regularly come to the clinic for blood work, imaging, and to monitor and side effects. Participants may receive study drug until their cancer progresses or for up to 24 months. | Drug: Venetoclax<br>* Participants will receive oral venetoclax taken once per day. The dose will be between 200 and 800 mg daily, with the exact dose determined by the protocol.<br>* Other names: Venclexta;Drug: Tazemetostat<br>* Tazemetostat 800mg taken orally, twice daily.<br>* Other names: Tazverik;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum-tolerated dose (MTD) determination (Part 1) | In part 1 of this study, participants will be assigned a dose of venetoclax following a (3+3) dose escalation design and monitored for dose-limiting toxicities (DLTs) during the first treatment cycle. Based on observed DLTs observed in each dose level cohort, the maximum-tolerated dose will be determined. The # of patients experiencing a DLT among the evaluable patients for each dose level in part 1 will be tabulated. | Day 0 to 28 | 
| Number of participants who experience dose-limiting toxicities (DLTs) | In part 1 of this study, participants will be assigned a dose of venetoclax following a (3+3) dose escalation design and monitored for dose-limiting toxicities (DLTs) during the first treatment cycle. Dose limiting toxicity (DLT) will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0). | Day 0 to 28 | 
| Number of participants who experience adverse events (AEs), from baseline to 30 days after the last dose of study drug, as assessed by CTCAE v5.0 | The safety analysis population will consist of all enrolled patients who receive at least one dose of study drug. AEs and SAEs will be tabulated by type, grade, and attribution for all patients overall and by treatment group. For each patient, and within each type of toxicity, the patient will be counted only once at the highest grade of that toxicity. Participants will be evaluated for AEs/SAEs from the time they sign the informed consent form until 30 days after their last dose of study drug. | Baseline through 25 months | 
| Number of adverse events (AEs) by severity from baseline to 30 days, after the last dose of study drug as assessed, by CTCAE v5.0 | The safety analysis population will consist of all enrolled patients who receive at least one dose of study drug. AEs and SAEs will be tabulated by type, grade, and attribution for all patients overall and by treatment group. For each patient, and within each type of toxicity, the patient will be counted only once at the highest grade of that toxicity. Participants will be evaluated for AEs/SAEs from the time they sign the informed consent form until 30 days after their last dose of study drug. | Baseline through 25 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants who Achieve Complete Response (CR) | CR will be assessed for all evaluable patients in parts 1+2 according to Lugano response criteria. | Day 0 through 24 months | 
| Number of Participants who Achieve Partial Response (PR) | PR will be assessed for all evaluable patients in parts 1+2 according to Lugano response criteria. | Day 0 through 24 months | 
| Overall Response Rate (ORR) | The ORR response rate is the proportion of patients with a best overall response of either complete response (CR) or partial response (PR) among all evaluable patients. ORR, CR, and PR will be assessed for all evaluable patients in parts 1+2 according to Lugano response criteria. The best overall response is the best response recorded from the start of treatment until progressive disease. | Day 0 through 24 months | 
| Duration of Response (DoR) | The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or PD is objectively documented (taking as reference for PD the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented. Duration of stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started. | From date of treatment initiation until the date of first documented progression or date of death from any cause, whichever came first, as assessed at 5 years | 
| Progression-Free Survival | PFS is defined as the duration of time from start of treatment to time of documentation of progression or death from any cause. | From date of treatment initiation until the date of first documented progression or date of death from any cause, whichever came first, as assessed at 5 years | 
| Overall Survival (OS) | OS is defined as the duration of time from start of treatment to death from any cause. | From date of treatment initiation until the date of death from any cause, as assessed at 5 years |