Testing the Addition of a New Anti-cancer Drug, Venetoclax, to Usual Chemotherapy for High Grade B-cell Lymphomas
Testing the Addition of a New Anti-cancer Drug, Venetoclax, to Usual Chemotherapy for High Grade B-cell Lymphomas
This phase II/III trial tests whether it is possible to decrease the chance of high-grade
 B-cell lymphomas returning or getting worse by adding a new drug, venetoclax to the usual
 combination of drugs used for treatment. Venetoclax may stop the growth of cancer cells by
 blocking a protein called Bcl-2. Drugs used in usual chemotherapy, such as rituximab,
 cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide, work in different ways
 to stop the growth of cancer cells, either by killing the cells, by stopping them from
 dividing, or by stopping them from spreading. Giving venetoclax together with usual
 chemotherapy may work better than usual chemotherapy alone in treating patients with
 high-grade B-cell lymphomas, and may increase the chance of cancer going into remission and
 not returning.
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. (Key Secondary
 Objective) 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
 correlate with PFS, EFS, and OS.

 VII. To determine whether local subtyping results for DHL and DEL are consistent with central
 analysis.

 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.

 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.

 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.

 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.

 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.
Inclusion Criteria:

 -  Pathologic diagnosis of diffuse large B-cell lymphoma (DLBCL) or high grade B-cell
 lymphoma (HGBCL). Eligible subtypes include DLBCL not otherwise specified (NOS),
 Epstein Barr Virus positive (EBV+) DLBCL, and DLBCL/HGBCL transformed from an
 underlying indolent B-cell lymphoma. Patients with T-cell/histiocyte rich large B-cell
 lymphoma and primary mediastinal B-cell lymphoma are not eligible

 -  Double hit lymphoma (DHL) or double expressing lymphoma (DEL)

 -  DHL is defined as high grade B-cell lymphoma with one of the below:

 -  Translocations of MYC and BCL2

 -  Translocations of MYC and BCL2 and BCL6 (triple hit lymphoma)

 -  Translocations of MYC and BCL6 without BCL2 translocation BUT with
 immunohistochemistry (IHC) expression of BCL2 (>=50%)

 -  DEL is defined as DLBCL or high grade B-cell lymphoma not otherwise specified
 (NOS) with protein expression by IHC of both MYC (>= 40%) and BCL2 (>= 50%) in
 the absence of dual translocations of both MYC and BCL2). (Double Expressing
 Lymphoma, DEL). Local determination of fluorescence in situ hybridization (FISH)
 and IHC will be performed per standardized guidelines and will be acceptable for
 study entry, but local IHC and FISH results for MYC must be available in order to
 determine eligibility if enrolling as DEL based on local results

 -  The diagnosis of DLBCL/HGBCL and assessment of DEL/DHL will be performed per
 standardized guidelines at local institutions and patients will be enrolled based on
 local determination. Given the heterogeneity in diagnostic work-up and interpretation,
 all local determinations will be followed by central confirmation in real time.
 Diagnostic slides and stains (or recuts/blocks) from all cases will be submitted to a
 central reference laboratory (Cleveland Clinic Laboratories). Immunostains will be
 reviewed or repeated (if unavailable or technically unsatisfactory) to confirm double
 expressing (DE) status. All DE cases will also be investigated for double hit (DH)
 status, if not already performed. To exclude DHL status, FISH for translocations of
 MYC (break apart and IGH/MYC dual fusion probes) must be performed (either by
 referring site or at the central laboratory), along with BCL2 (break apart probes) and
 BCL6 (break apart probes). Any missing information from the referring site will be
 supplemented by the central lab on required submitted unstained slides or blocks.
 Cases submitted as DHL will be accepted as such upon review of submitted laboratory
 reports. Cases submitted as DHL must demonstrate the presence of a MYC translocation
 as well as a translocation of BCL2, BCL6, or both. Cases submitted as a DEL must
 demonstrate appropriate IHC protein expression of MYC and BCL2, and be negative for a
 MYC translocation by FISH.

 -  No prior treatment for DLBCL/HGBCL is allowed with the exception of corticosteroids
 administered for palliation, or a single cycle of either rituximab, cyclophosphamide,
 doxorubicin, vincristine, and prednisone (R-CHOP) or dose adjusted etoposide,
 prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R)
 administered prior to enrollment. Corticosteroids or local radiation therapy are also
 allowed. Patients may have received intrathecal chemotherapy for CNS prophylaxis prior
 to registration. This single pre-registration cycle is being allowed to facilitate
 enrolling patients who required immediate initiation of therapy for rapidly
 progressing disease, or for patients where FISH or IHC results returned after
 initiation of chemotherapy rendered them protocol eligible. Patients with DLBCL or
 HGBCL transformed from an underlying indolent lymphoma cannot have received prior
 chemotherapy, but prior anti-CD20 monoclonal antibody therapy or radiation therapy for
 an indolent B-cell lymphoma is allowed.

 -  Not pregnant and not nursing, because this study involves an investigational agent
 whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn
 are unknown.

 Therefore, for women of childbearing potential only, a negative pregnancy test done =< 14
 days prior to registration is required.

 -  Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2.

 -  Absolute neutrophil count (ANC) >= 1,000/mm^3.

 -  Unless attributable to lymphoma.

 -  Platelet count >= 100,000/mm^3.

 -  Unless attributable to lymphoma.

 -  Creatinine =< 1.5 mg/dL OR calculated (calc.) creatinine clearance >= 50 mL/min.

 -  Unless attributable to lymphoma.

 -  Total bilirubin =< 2.0 mg/dL.

 -  Unless attributable to lymphoma.

 -  Unless attributable to Gilbert's disease.

 -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 times
 institution upper limit of normal (ULN).

 -  Unless attributable to lymphoma.

 -  Archival tissue must be available for submission in all patients for histopathology
 review, though participation in correlative substudies is optional.

 -  No active ischemic heart disease or congestive heart failure, and left ventricular
 ejection fraction (LVEF) >= 45%.

 -  No known active human immunodeficiency virus (HIV) disease. Human immunodeficiency
 virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable
 viral load within 6 months are eligible for this trial.

 -  No known lymphomatous involvement of the central nervous system (CNS). A lumbar
 puncture or neuroimaging prior to study enrollment is not required in the absence of
 neurological signs or symptoms concerning for CNS involvement.

 -  No active hepatitis B or hepatitis C infection. Patients with prior hepatitis B virus
 (HBV) exposure (positive HBV core antibody and/or surface antigen) are eligible if
 they have no detectable viral load, and are taking appropriate prophylactic antiviral
 therapy to prevent reactivation. Patients with history of hepatitis C virus (HCV) are
 eligible if they have been treated for HCV and have an undetectable HCV viral load.

 -  Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this
 study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days
 prior to initiation of venetoclax.

 -  Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients
 must discontinue the drug 14 days prior to the start of venetoclax.