Clinical Trials /

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

NCT03984448

Description:

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.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Double-Hit Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of a New Anti-cancer Drug, Venetoclax, to Usual Chemotherapy for High Grade B-cell Lymphomas
  • Official Title: Randomized Phase II/III Study of Venetoclax (ABT199) Plus Chemoimmunotherapy for MYC/BCL2 Double-Hit and Double Expressing Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-03711
  • SECONDARY ID: NCI-2019-03711
  • SECONDARY ID: A051701
  • SECONDARY ID: A051701
  • SECONDARY ID: U10CA180821
  • NCT ID: NCT03984448

Conditions

  • BCL2 Gene Translocation
  • C-Myc Translocation
  • Diffuse Large B-Cell Lymphoma
  • Double-Expressor Lymphoma
  • High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements
  • High Grade B-Cell Lymphoma, Not Otherwise Specified
  • Neoplastic Cells With Double Expression of MYC and BCL2 Proteins Present

Interventions

DrugSynonymsArms
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719ARM A (R-CHOP, DA-EPOCH-R)
DoxorubicinAdriablastin, Hydroxydaunomycin, Hydroxyl Daunorubicin, HydroxyldaunorubicinARM A (R-CHOP, DA-EPOCH-R)
Doxorubicin Hydrochloride5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin HCl, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, RubexARM A (R-CHOP, DA-EPOCH-R)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16ARM A (R-CHOP, DA-EPOCH-R)
Prednisone.delta.1-Cortisone, 1, 2-Dehydrocortisone, Adasone, Cortancyl, Dacortin, DeCortin, Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome, Deltacortene, Deltacortisone, Deltadehydrocortisone, Deltasone, Deltison, Deltra, Econosone, Lisacort, Meprosona-F, Metacortandracin, Meticorten, Ofisolona, Orasone, Panafcort, Panasol-S, Paracort, Perrigo Prednisone, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, Prednisone Intensol, Prednisonum, Prednitone, Promifen, Rayos, Servisone, SK-PrednisoneARM A (R-CHOP, DA-EPOCH-R)
RituximabABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, rituximab biosimilar TQB2303, rituximab-abbs, RTXM83, TruximaARM A (R-CHOP, DA-EPOCH-R)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, VenclyxtoARM B (R-CHOP, DA-EPOCH-R, venetoclax)
VincristineLEUROCRISTINE, VCR, VincrystineARM A (R-CHOP, DA-EPOCH-R)
Vincristine SulfateKyocristine, Leurocristine sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateARM A (R-CHOP, DA-EPOCH-R)

Purpose

This phase II/III trial tests how well a new anti-cancer drug, venetoclax, works when given with usual chemotherapy in treating patients with high-grade B-cell lymphomas. 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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
ARM A (R-CHOP, DA-EPOCH-R)Active ComparatorDEL: Patients with DEL receive R-CHOP chemotherapy regimen consisting of rituximab IV on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV on day 1, vincristine sulfate IV on day 1, and prednisone PO QD on days 1-5. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. DHL: Patients with DHL receive 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 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.
  • Cyclophosphamide
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Etoposide
  • Prednisone
  • Rituximab
  • Vincristine
  • Vincristine Sulfate
ARM B (R-CHOP, DA-EPOCH-R, venetoclax)ExperimentalDEL: 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. 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.
  • Cyclophosphamide
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Etoposide
  • Prednisone
  • Rituximab
  • Venetoclax
  • Vincristine
  • Vincristine Sulfate

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS) (phase II)
Time Frame:From randomization date until the earlier of disease progression, or death from any cause, assessed up to 10 years
Safety Issue:
Description:Will be compared between the experimental and control arms using a stratified log-rank test. If one of the stratum has 0 events or there are numerical issues due to the sparseness of the date within stratum, an unstratified log-rank test will be used. The Kaplan-Meier method will be used to estimate PFS distributions. One-year PFS estimates, medians, and corresponding hazard ratios will be provided with 95% confidence intervals for each of the double hit lymphoma (DHL) and double expressing lymphoma (DEL) cohorts.

Secondary Outcome Measures

Measure:Overall survival (OS) (phase III)
Time Frame:From randomization date until death from any cause, assessed up to 10 years
Safety Issue:
Description:Using a modified intent-to-treat approach, all eligible patients who are centrally confirmed as having a DHL/DEL subtype will be considered evaluable and included in the analysis of the key secondary endpoint in the arm to which they were randomized and under the centrally designated subtype. OS will be compared between the experimental and control arms using a stratified log-rank test. Two-year OS estimates, medians, and corresponding hazard ratios will be provided with 95% confidence intervals overall.
Measure:Event-free survival
Time Frame:From randomization date until the earlier of non-protocol lymphoma therapy, disease progression, or death from any cause, assessed up to 10 years
Safety Issue:
Description:Will be compared between the experimental and control arms using a log-rank test. Estimated using Kaplan-Meier method by arm and lymphoma subtype.
Measure:Response rate
Time Frame:Up to 10 years post treatment
Safety Issue:
Description:Response will be evaluated using the Lugano criteria for lymphoma response. Best achieved response rate with the intervention will be determined, defined as the number of patients who attain a complete or partial response using positron emission tomography (PET)/computed tomography (CT) out of the total number of evaluable patients who are randomized. Response rates will be compared between arms using a chi-square test once all patients on the study have been evaluated for response. Response rates will be estimated by arm and lymphoma subtype with 95% confidence intervals. Logistic regression will be used in a multivariable analysis to identify baseline variables associated with response.
Measure:Inconsistency of local and central results for DEL or DHL status
Time Frame:Up to 10 years posttreatment
Safety Issue:
Description:Estimated by the number of patients with a local determination of DHL but not central determination of DHL (i.e., positive for DEL or negative for both DHL and DEL) or local determination of DEL but not central determination of DEL (i.e., positive for DHL or negative for both DHL and DEL) divided by the total number of registered patients with adequate material/tissue for central review.

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

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