Tazemetostat and Venetoclax in Relapsed/Refractory Non-Hodgkin Lymphoma

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

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.

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. 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) we will conduct a phase I trial in two parts. In part one, we will perform a single-arm, open-label sequential dose escalation (3+3) of venetoclax in combination with tazemetostat, given at its recommended phase II dose (RP2D) of 800mg BID, to determine the maximum tolerated dose (MTD) of venetoclax. In part two, we will enroll two expansion cohorts (R/R DLBCL and R/R FL) 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.

Inclusion Criteria:

Patients must meet the following criteria for study entry:

1. Adults aged ≥18

2. Require therapy as determined by the treating physician

3. Patients must have adequate organ and bone marrow function:

   • Absolute neutrophil count (ANC) ≥ 1 x 109/L without growth factor support (filgrastim or pegfilgrastim) for at least 14 days
   • Platelet count ≥75 x 109/L, evaluated at least 7 days after last platelet transfusion
   • Hemoglobin ≥9.0g/dL, independent of transfusion
   • Total bilirubin < 1.5 x's the upper limit of the normal range (ULN), except Gilbert's disease
   • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 x's ULN.
   • Calculated creatinine clearance according to the Cockcroft-Gault equation. ≥ 40 mL/min

4. ECOG PS 0-2

5. Ability and willingness to provide signed Informed Consent Form

6. Ability and willingness to comply with the requirements of the study protocol

7. Measurable disease (defined as ≥ 1.5cm in diameter) In addition, patients must meet the following conditions for enrollment based on whether they have DLBCL or FL.

R/R DLBCL Cohort:

1. Histologically confirmed, biopsy-proven diagnosis of DLBCL (as determined by WHO standard classification criteria).

   Please note: Transformed DLBCL patients are eligible, with the exception of Richter's transformation.

2. Subjects must have received at least two prior lines of therapy for lymphoma with evidence of disease progression.

3. Subjects are eligible if they have progressed after ASCT OR if they are ineligible for ASCT, as determined by their treating physician.

R/R FL Cohort:

1. Histologically confirmed, biopsy-proven diagnosis of FL
2. Subjects are eligible if they have progressed after two or more lines of therapy for lymphoma or have no satisfactory treatment alternatives

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from study entry:

1. Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months of the first dose of study drug; or cardiac ventricular arrhythmia.

2. Known hypersensitivity to any of the study drugs

3. History of other malignancy that could affect compliance with the protocol or interpretation of results

   a. Patients with a history of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix are generally eligible. Patients with a malignancy that has been treated, but not with curative intent, will also be excluded, unless the malignancy has been in remission without treatment for 2 years prior to enrollment.

4. Known CNS involvement at diagnosis (CNS evaluation not required in the absence of clinical suspicion)

5. Richter's transformation from CLL

6. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal).

7. Major surgery within 3 weeks prior to the start of study treatment

8. Venous thrombosis or pulmonary embolism within the last 3 months before starting study; whereas subjects greater than 3 months since deep vein thrombosis/pulmonary embolism are eligible but are recommended to receive prophylaxis.

9. Uncontrolled infection with human immunodeficiency virus (HIV) or human T-cell leukemia virus 1

10. Pregnant or lactating

11. Patients capable of becoming pregnant or getting someone else pregnant must be willing to use highly effective birth control as described in Section 4.4

12. Malabsorption syndrome or other condition that precludes enteral route of administration Patients who meet any of the following criteria will be excluded from study entry:

13. Inability to swallow tablets

14. Known allergy to both xanthine oxidase inhibitors and rasburicase

15. Clinically significant history of liver disease, including but not limited to viral or other hepatitis, current alcohol abuse, or cirrhosis Note: Subjects with positive HBV core antibody or surface antigen are eligible as long as they have an undetectable HBV DNA PCR and are willing to undergo monthly DNA testing, and receive concurrent antiviral therapy with entecavir, tenofovir, or lamivudine, and continued for a minimum of 6 months after completion of therapy.

16. Active hepatitis C (defined as a positive HCV viral load)

17. Chronic use of moderate or strong CYP3A4 modulators (inhibitor or inducer) or any other prohibited medications. A washout period of 5 half-lives or 14 days, whichever is longer, is required prior to venetoclax or tazemetostat dosing if a prohibited medication is discontinued.

18. Chronic use of a P-gp inhibitor, or a P-gp substrate with a narrow therapeutic index (see Section 7.8). A washout period of 5 half-lives or 14 days, whichever is longer is required prior to venetoclax or tazemetostat dosing if a prohibited medication is discontinued.

19. Prior exposure to either tazemetostat or venetoclax

20. Has a prior history of T-LBL/T-ALL

21. Subjects who have undergone a solid organ transplant

22. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the subject's participation in this study OR interfere with their ability to receive study treatment or complete the study.

23. Requires the use of warfarin (because of potential drug-drug interactions that may potentially increase the exposure of warfarin)

24. Vaccination with live vaccines within 28 days prior to treatment

25. 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