PRIMARY OBJECTIVE:
I. To compare the progression-free survival (PFS) of rituximab (R)-chemotherapy plus
venetoclax versus R-chemotherapy alone in MYC/BCL2 double-hit and double expressing
lymphomas.
SECONDARY OBJECTIVES:
I. To compare the overall survival (OS) of R-chemotherapy plus venetoclax versus
R-chemotherapy alone in MYC/BCL2 double-hit and double expressing lymphomas.
II. To compare the event-free survival (EFS) of R-chemotherapy plus venetoclax versus
R-chemotherapy alone in MYC/BCL2 double-hit and double expressing lymphomas.
III. To assess the toxicity profile of the experimental regimens in MYC/BCL2 double-hit and
double expressing lymphomas using Common Terminology Criteria for Adverse Events (CTCAE) and
patient reported outcomes (PRO)-CTCAE.
IV. To compare response rates of R-chemotherapy plus venetoclax versus R-chemotherapy alone
in MYC/BCL2 double-hit and double expressing lymphomas.
V. To estimate differences in response rates, EFS, PFS, and OS of R-chemotherapy plus
venetoclax versus R-chemotherapy alone within each of the disease subtypes (double hit
lymphoma [DHL] and double expressing lymphoma [DEL]).
VI. To determine whether cell of origin and intensity of the MYC and BCL2 protein expression
on diagnostic tumor biopsy correlate with PFS, EFS, and OS.
VII. To determine whether local subtyping results for DHL and DEL are consistent with central
analysis (phase II only).
OUTLINE: Patients are randomized to Arm 1 or Arm 2.
ARM 1 (DEL): Patients with DEL receive R-CHOP chemotherapy regimen consisting of rituximab
intravenously (IV) on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV on
day 1, vincristine sulfate IV on day 1, and prednisone orally (PO) once daily (QD) on days
1-5. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or
unacceptable toxicity. Patients undergo position emission tomography (PET) scan, computed
tomography (CT) scan and blood sample collection and may undergo bone marrow biopsy and
lumbar puncture throughout the study.
ARM 1 (DHL): Patients with DHL receive dose-adjusted (DA)-EPOCH-R chemotherapy regimen
consisting of rituximab IV on day 1, doxorubicin hydrochloride IV on days 1-4, etoposide IV
on days 1-4, vincristine sulfate IV on days 1-4, prednisone PO twice daily (BID) on days 1-5,
and cyclophosphamide IV on day 5. Treatment repeats every 21 days for 6 cycles in the absence
of disease progression or unacceptable toxicity. Patients undergo PET scan, CT scan and blood
sample collection and may undergo bone marrow biopsy and lumbar puncture throughout the
study.
ARM 2 (DEL): Patients with DEL receive R-CHOP chemotherapy regimen as in Arm 1. Patients also
receive venetoclax PO QD on days 4-8 of cycle 1 and days 1-5 for cycles 2-6. Treatment
repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable
toxicity. Patients undergo PET scan, CT scan and blood sample collection and may undergo bone
marrow biopsy and lumbar puncture throughout the study.
ARM 2 (DHL): Patients with DHL receive DA-EPOCH-R chemotherapy regimen as in Arm 1. Patients
also receive venetoclax PO QD on days 4-8 of cycle 1 and days 1-5 for cycles 2-6. Treatment
repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable
toxicity. Patients undergo PET scan, CT scan and blood sample collection and may undergo bone
marrow biopsy and lumbar puncture throughout the study.
After completion of study treatment, patients are followed up every 12 weeks for 2 years,
then every 24 weeks for up to 5 years, and then every 6 months for up to 10 years from
registration.