Clinical Trial: NCT03984448 - My Cancer Genome

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
Double-Hit Lymphoma
High Grade B-Cell Lymphoma, Not Otherwise Specified
Triple-Hit Lymphoma

Recruiting Status:

Suspended

Phase:

Phase 2/Phase 3

URL:

https://clinicaltrials.gov/show/NCT03984448

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

Diffuse Large B-Cell Lymphoma
Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
Double-Expressor Lymphoma
EBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
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

Drug	Synonyms	Arms
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, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719	Arm 1 (R-CHOP, DA-EPOCH-R)
Doxorubicin Hydrochloride	5,12-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, Rubex	Arm 1 (R-CHOP, DA-EPOCH-R)
Etoposide	Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16	Arm 1 (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-Prednisone	Arm 1 (R-CHOP, DA-EPOCH-R)
Rituximab	ABP 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 ABBS, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar JHL1101, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, Rituximab Biosimilar SIBP-02, rituximab biosimilar TQB2303, rituximab-abbs, RTXM83, Truxima	Arm 1 (R-CHOP, DA-EPOCH-R)
Venetoclax	ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto	Arm 2 (R-CHOP, DA-EPOCH-R, venetoclax)
Vincristine Sulfate	Kyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfate	Arm 1 (R-CHOP, DA-EPOCH-R)

Purpose

Detailed Description

      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.

Trial Arms

Name	Type	Description	Interventions
Arm 1 (R-CHOP, DA-EPOCH-R)	Active Comparator	DEL: 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 Hydrochloride Etoposide Prednisone Rituximab Vincristine Sulfate
Arm 2 (R-CHOP, DA-EPOCH-R, venetoclax)	Experimental	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. 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.	Cyclophosphamide Etoposide Prednisone Rituximab Venetoclax Vincristine Sulfate

Eligibility Criteria

        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.

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 strata has 0 events or there are numerical issues due to the sparseness of the date within strata, 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 1 week after end of cycle 6
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:	Until last patient is registered, up to month 57
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:	Suspended
Lead Sponsor:	National Cancer Institute (NCI)

Last Updated

August 27, 2021

Clinical Trials /

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