A Phase 2 Study of Epcoritamab Plus Tazemetostat for Treatment of Relapsed/Refractory Follicular Lymphoma
A Phase 2 Study of Epcoritamab Plus Tazemetostat for Treatment of Relapsed/Refractory Follicular Lymphoma
This phase II trial tests the safety, side effects and effectiveness of epcoritamab and tazemetostat in treating patients with grade I-IIIa follicular lymphoma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Epcoritamab is a bispecific monoclonal antibody that binds to two different antigens on the surface of cancer cells that may help the body's immune system attack the cancer and may interfere with the ability of the cancer cells to grow and spread. Tazemetostat, a EZH2 inhibitor, may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving epcoritamab and tazemetostat may be safe, tolerable and/or effective in treating patients with relapsed or refractory grade I-IIIa follicular lymphoma.
PRIMARY OBJECTIVES:
I. To assess the safety/tolerability of epcoritamab in combination with tazemetostat in patients with relapsed/refractory follicular lymphoma (FL). (Safety lead-In) II. To evaluate the anti-tumor activity of epcoritamab in combination with tazemetostat in patients with relapsed/refractory FL by complete response rate. (Phase II)
SECONDARY OBJECTIVES:
I. To estimate overall response rate (ORR) duration of response (DOR) of the combination of epcoritamab and tazemetostat.
II. To estimate progression-free survival, and overall survival of the combination of epcoritamab and tazemetostat.
III. To assess the toxicities of the combination of epcoritamab and tazemetostat.
EXPLORATORY OBJECTIVES:
I. To characterize the T-cell population balance in patients treated with epcoritamab and tazemetostat in different compartments (peripheral blood, tumor).
II. To explore correlation between response and presence of EZH2 mutations. III. To evaluate minimal residual disease (MRD) dynamics during treatment and explore the correlation of MRD kinetics with response.
OUTLINE:
Patients receive tazemetostat orally (PO) twice daily (BID) on days 1-28 of each cycle. Patients also receive epcoritamab subcutaneously (SC) on days 1, 8, 15, and 22 of cycles 2-4 then on day 1 of remaining cycles. Cycles repeat every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood samples on study and undergo bone marrow biopsy and computed tomography (CT) or positron emission tomography (PET)/CT throughout the study.
After completion of study treatment, patients are followed up at 30 and 60 days then for up to 2 years.
Inclusion Criteria:
Documented informed consent of the participant and/or legally authorized representative
Agreement to allow the use of archival tissue from diagnostic tumor biopsies
Age: ≥ 18 years
Eastern Cooperative Oncology Group (ECOG) ≤ 2
Histologically confirmed follicular lymphoma, grades 1-3A
Relapsed/ refractory disease after at least one line of prior lymphoma therapy
Radiologically measurable lymphadenopathy (≥ 1.5 cm) or ≥ 1 measurable extranodal lesion (long axis > 1.0 cm) on CT scan or magnetic resonance imaging (MRI)
Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prior anti-cancer therapy
WITHOUT BONE MARROW INVOLVEMENT: Absolute neutrophil count (ANC) ≥ 1,000/mm^3 (NOTE: Growth factor use is allowed to reach ANC)
WITH BONE MARROW INVOLVEMENT: ANC ≥ 500/mm^3 (NOTE: Growth factor use is allowed to reach ANC)
WITHOUT BONE MARROW INVOLVEMENT: Platelets ≥ 50,000/mm^3 (NOTE: Platelet transfusions are within 14 days of platelet assessment if thrombocytopenia is secondary to disease involvement)
WITH BONE MARROW INVOLVEMENT: Platelets ≥ 25,000/mm^3 (NOTE: Platelet transfusions are within 14 days of platelet assessment if thrombocytopenia is secondary to disease involvement)
Total bilirubin ≤ 2 x upper limit of normal (ULN) (unless has Gilbert's disease or secondary to disease)
Aspartate aminotransferase (AST) ≤ 2.5 x ULN
Alanine aminotransferase (ALT) ≤ 2.5 x ULN
Creatinine clearance of ≥ 45 mL/min per 24 hour urine test or the Cockcroft-Gault formula
If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin (PT) ≤ 1.5 x ULN; If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants
If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN; If on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants
Fridericia's formula-corrected QT interval (QTcF) ≤ 480 ms (Note: To be performed within 28 days prior to day 1 of protocol therapy)
If seropositive for HIV, hepatitis C virus (HCV) or hepatitis B virus (HBV), nucleic acid quantitation must be performed. Viral load must be undetectable. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
Meets other institutional and federal requirements for infectious disease titer requirements (Note Infectious disease testing to be performed within 28 days prior to day 1 of protocol therapy)
Women of childbearing potential (WOCBP): negative serum pregnancy test
Agreement by females of childbearing potential must agree to either abstain from heterosexual intercourse or to use two effective methods of birth control simultaneously (effective methods described below). The time period for effective contraceptive requirements begins ≥ 28 days prior to initiating tazemetostat and for the course of the study treatment period through at least 6 months after the last dose of tazemetostat, 4 months after the last dose of epcoritamab, or 4 months after the last dose of tocilizumab (if applicable), whichever is longer. Childbearing potential is defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only). Two effective methods includes one highly effective method and one barrier method.
Highly effective methods:
Barrier methods:
Agreement by males to either practice complete abstinence or agree to use a latex or synthetic condom, even with a successful vasectomy (medically confirmed azoospermia), during sexual contact with a female of childbearing potential from first dose of study drug, during study treatment (including during dose interruptions), and for 3 months after study drug discontinuation. NOTE: Male subjects must not donate semen or sperm from first dose of tazemetostat, during study treatment (including during dose interruptions), and for 3 months after discontinuation of tazemetostat
Exclusion Criteria:
Concurrent enrollment in another therapeutic investigational study
Prior bispecific antibodies or tazemetostat
Autologous stem cell transplant within 30 days prior to day 1 of protocol therapy
Allogeneic stem cell transplant if complicated by active graft versus host disease (GVHD) or if on immunosuppressive agents
Chemotherapy, radiation therapy, biological therapy, immunotherapy within 21 days or five half-lives (whichever is shorter for non-radiation therapy) prior to day 1 of protocol therapy
Immunosuppressive agents other than prednisolone 20 mg daily or equivalent
Major surgery within 4 weeks of first dose of study drug
Vaccination with live vaccines within 4 weeks of the first dose of study drug
Strong and moderate CYP3A4 inducers/ inhibitors within 14 days prior to day 1 of protocol therapy
Current evidence of central nervous system involvement by the lymphoma
Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia, or NYHA (New York Heart Association) heart failure class III-IV, or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months of screening
History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
History of active human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV)
Known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
If a patient has signs/symptoms suggestive of SARS-CoV-2 infection or have had recent known exposure to someone with SARS-CoV-2 infection, the patient must have a negative molecular (e.g., PCR) test, or 2 negative antigen test results at least 24 hours apart, to rule out SARS-CoV-2 infection
Subjects who do not meet SARS-CoV-2 infection eligibility criteria must be screen failed and may only rescreen after they meet the following SARS-CoV-2 infection viral clearance criteria:
Clinically significant uncontrolled illness
Uncontrolled active systemic infection
Any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or myeloproliferative neoplasm (MPN) or any prior history of T lymphoblastic leukemia (T-LBL)/T acute lymphoblastic leukemia (T-ALL) or B acute lymphoblastic leukemia (B-ALL)
Other active malignancy. 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. Exceptions are:
Inability to take oral medication or have malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea, vomiting) that might impair the bioavailability of tazemetostat
Females only: Pregnant or breastfeeding
Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)