Randomized Phase II/III Study of Venetoclax (ABT199) Plus Chemoimmunotherapy for MYC/BCL2 Double-Hit and Double Expressing Lymphomas (A051701)

Testing the Addition of a New Anti-cancer Drug, Venetoclax, to Usual Chemotherapy for High Grade B-cell Lymphomas

Overview

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.

Key Inclusion Criteria

For a patient to be eligible for participation in this study, all of the following criteria must apply.

  • 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.

Learn More

To learn more, visit ClinicalTrials.Gov

Study Type

Phase 2/3

Sponsor(s)

National Cancer Institute (NCI)