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.

Inclusion Criteria

• Pathologic diagnosis of diffuse large B-cell lymphoma (DLBCL) or high grade B-cell lymphoma (HGBCL).
• High grade B-cell lymphoma with translocations of MYC and BCL2 (double hit lymphoma, DHL), or DLBCL or high grade B-cell lymphoma not otherwise specified (NOS) with protein expression by immunohistochemistry (IHC) of both MYC (>= 40%) and BCL2 (>= 50%) in the absence of dual translocations (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.
• 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 DH status, FISH for translocations of BCL2 (break apart probes), BCL6 (break apart probes), and MYC (break apart and IGH/MYC dual fusion probes) must be performed (either by referring site or at the central laboratory). Any missing information from the referring site will be supplemented by the central lab on required submitted unstained slides or blocks. Cases submitted as DH will be accepted as such upon review of submitted laboratory report.
• 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. 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.
• 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.
• 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 active human immunodeficiency virus (HIV) disease. Patients with history of HIV are eligible if they 1) have an undetectable viral load within the prior 6 months, or 2) have a detectable viral load with a CD4 count >= 200.
• 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 protocol therapy.
• Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment.

PRIMARY OBJECTIVES:

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 A or Arm B.

ARM A (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 A (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 B (DEL): Patients with DEL receive R-CHOP chemotherapy regimen as in Arm A. 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 B (DHL): Patients with DHL receive DA-EPOCH-R chemotherapy regimen as in Arm A. 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.

Lead Organization
Alliance for Clinical Trials in Oncology

Principal Investigator
Jeremy S. Abramson