A Phase 1b Study of Tazemetostat in Combination With Zanubrutinib and Anti-CD20 Monoclonal Antibody in Relapsed or Refractory Indolent B-cell Non-Hodgkin Lymphomas (TARZAN Trial)
A Phase 1b Study of Tazemetostat in Combination With Zanubrutinib and Anti-CD20 Monoclonal Antibody in Relapsed or Refractory Indolent B-cell Non-Hodgkin Lymphomas (TARZAN Trial)
The purpose of this clinical trial is to learn if the study drug Tazemetostat combined with Zanubrutinib and anti-CD20 monoclonal antibody is safe and effective in treating patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma.
Inclusion Criteria:
Subject aged ≥ 18 years.
Eligible histologies include MCL, MZL (including splenic, nodal, and extranodal sub-types), and WM who received at least one line of prior systemic therapy and FL who received at least two prior lines of systemic therapy
Measurable disease: at least one lesion >1.5 cm in longest diameter or 1 extranodal lesion >1 cm in the longest diameter.
--Note: For MZL, isolated splenomegaly and involvement of any biopsy proven extranodal site is considered measurable for this study. For MCL, clonal lymphocyte measured by flow cytometry is considered measurable. For WM, serum IgM level >0.5 g/dL is considered measurable.
Patients must have an indication for treatment.
For R/R FL: active disease requiring treatment
For R/R MCL: active disease requiring treatment
For R/R MZL: active disease requiring treatment
For R/R WM: Meeting at least 1 criterion for treatment according to consensus panel criteria from the Seventh International Workshop on Waldenstrom's Macroglobulinemia68
ECOG Performance Status ≤ 2.
Adequate organ function as defined as:
Hematologic:
Hepatic:
Renal:
Estimated creatinine clearance ≥ 30 mL/min by Cockcroft-Gault formula:
Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio (INR) not greater than 1.5 x ULN.
Life expectancy of >3 months, in the opinion of the investigator
For female subjects: Negative pregnancy test or evidence of post-menopausal status. The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
Women < 50 years of age:
Women ≥ 50 years of age:
Female subjects of childbearing potential and male subjects with a sexual partner of childbearing potential must agree to use a highly effective method of contraception and lactation requirements as described in Section 5.3.1 and 5.3.2.
Subjects must agree to not breastfeed while on treatment or within 1 week of the last dose of tazemetostat or 2 weeks of zanubrutinib.
Ability to swallow oral tablets
Patients or their legal representatives must be able to read, understand, and provide informed consent to participate in the trial.
Willing and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.
Time between prior anticancer therapy and first dose of tazemetostat as below:
Cytotoxic chemotherapy - At least 21 days
Non-cytotoxic chemotherapy (e.g., small molecule inhibitor) - At least 14 days
Monoclonal antibody(ies) - At least 28 days
Radiotherapy
High-dose therapy with autologous hematopoietic cell infusion - At least 60 days
CART cell therapy - At least 60 days
Moderate CYP3A inhibitors - At least 3 elimination half-lives
Moderate CYP3A inducers - At least 14 days
Strong CYP3A inducers or inhibitors - At least 14 days ----Note: Must be able to obtain zanubrutinib and anti-CD20 mAb commercially
Exclusion Criteria:
Prior exposure to tazemetostat or other inhibitor(s) of EZH2
Any prior history of myeloid malignancies including MDS/AML or MPN
Any prior history of T-LBL, T-ALL, or B-ALL
Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drugs
Major surgery within 4 weeks prior to enrollment
Known history of bleeding diathesis or active bleeding
Known history of stroke or intracranial hemorrhage within 6 months of enrollment
Significant cardiovascular disease defined as:
Significant liver disease (>Child Pugh Class A)
Patients with CNS involvement
Prolongation of the QT interval corrected for heart rate (QTcF) > 480 msec. QTcF is calculated using Fridericia's Formula (QTcF): QTcF = QT/(RR0.33).
Patients who have tested positive for Human Immunodeficiency Virus (HIV)
Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on criteria below:
Known Cytomegalovirus (CMV) infection.
Evidence of other clinically significant uncontrolled condition(s) including but not limited to, uncontrolled systemic bacterial, viral, fungal, or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the investigator and medical monitor may pose a risk for patient participation. Screening for chronic conditions is not required.
Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts.
Active second malignancy unless in remission and with life expectancy > 2 years.
Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist.
Receipt of live virus vaccines within 28 days prior to the initiation of study treatment or need for live-virus vaccines at any time during study treatment
Have a known hypersensitivity to any of the excipients of tazemetostat.
Subjects taking medications that are known strong CYP3A4 inducers or inhibitors and cannot come off the medication.
Subjects taking medications that are known moderate CYP3A inducers and cannot come off the medication.