Purpose

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.

Conditions

Eligibility

Eligible Ages
Between 18 Years and 80 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Criteria


Inclusion Criteria:

- Pathologic diagnosis of diffuse large B-cell lymphoma (DLBCL) or high grade B-cell
lymphoma not otherwise specified (HGBCL not otherwise specified [NOS]). Eligible
subtypes include DLBCL NOS, Epstein Barr Virus positive (EBV+) DLBCL, HGBCL NOS 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 and/or BCL6). (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 submitted for central review in order to determine eligibility if enrolling as
DEL based on local results during phase II. Central pathology review is no longer
required as of Update #03.

- 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. 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 translocations of MYC along with translocations of BCL2 and/or BCL6 by
FISH. Patients with MYC translocations and no translocations of either BCL2 or BCL6
are eligible for the DEL cohort

- Patients must have FDG-avid disease on PET/CT

- 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.

- Age 18 - 80 years

- 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.

Study Design

Phase
Phase 2/Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Active Comparator
Arm 1 (R-CHOP, DA-EPOCH-R)
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. Patients undergo PET scan, CT scan and blood sample collection and may undergo bone marrow biopsy and lumbar puncture throughout the study. 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. Patients undergo PET scan, CT scan and blood sample collection and may undergo bone marrow biopsy and lumbar puncture throughout the study
  • Procedure: Biospecimen Collection
    Undergo blood sample collection
    Other names:
    • Biological Sample Collection
    • Biospecimen Collected
    • Specimen Collection
  • Procedure: Bone Marrow Biopsy
    Undergo bone marrow biopsy
    Other names:
    • Biopsy of Bone Marrow
    • Biopsy, Bone Marrow
  • Procedure: Computed Tomography
    Undergo CT scan
    Other names:
    • CAT
    • CAT Scan
    • Computed Axial Tomography
    • Computerized Axial Tomography
    • Computerized axial tomography (procedure)
    • Computerized Tomography
    • Computerized Tomography (CT) scan
    • CT
    • CT Scan
    • tomography
  • Drug: Cyclophosphamide
    Given IV
    Other names:
    • (-)-Cyclophosphamide
    • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
    • Asta B 518
    • B-518
    • 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
    • WR-138719
  • Drug: Doxorubicin Hydrochloride
    Given IV
    Other names:
    • 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
  • Drug: Etoposide
    Given IV
    Other names:
    • Demethyl Epipodophyllotoxin Ethylidine Glucoside
    • EPEG
    • Lastet
    • Toposar
    • Vepesid
    • VP 16
    • VP 16-213
    • VP 16213
    • VP-16
    • VP-16-213
    • VP16
  • Procedure: Positron Emission Tomography
    Undergo PET scan
    Other names:
    • Medical Imaging, Positron Emission Tomography
    • PET
    • PET Scan
    • Positron emission tomography (procedure)
    • Positron Emission Tomography Scan
    • Positron-Emission Tomography
    • proton magnetic resonance spectroscopic imaging
    • PT
  • Drug: Prednisone
    Given PO
    Other names:
    • .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
  • Biological: Rituximab
    Given IV
    Other names:
    • ABP 798
    • BI 695500
    • C2B8 Monoclonal Antibody
    • Chimeric Anti-CD20 Antibody
    • CT-P10
    • IDEC-102
    • IDEC-C2B8
    • IDEC-C2B8 Monoclonal Antibody
    • Ikgdar
    • Mabtas
    • MabThera
    • Monoclonal Antibody IDEC-C2B8
    • PF-05280586
    • Riabni
    • Rituxan
    • Rituximab ABBS
    • Rituximab ARRX
    • 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 PVVR
    • Rituximab-abbs
    • Rituximab-arrx
    • Rituximab-pvvr
    • RTXM83
    • Ruxience
    • Truxima
  • Drug: Vincristine Sulfate
    Given IV
    Other names:
    • Kyocristine
    • Leurocristine Sulfate
    • Leurocristine, sulfate
    • Oncovin
    • Vincasar
    • Vincosid
    • Vincrex
    • Vincristine, sulfate
Experimental
Arm 2 (R-CHOP, DA-EPOCH-R, venetoclax)
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. Patients undergo PET scan, CT scan and blood sample collection and may undergo bone marrow biopsy and lumbar puncture throughout the study. 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. Patients undergo PET scan, CT scan and blood sample collection and may undergo bone marrow biopsy and lumbar puncture throughout the study.
  • Procedure: Biospecimen Collection
    Undergo blood sample collection
    Other names:
    • Biological Sample Collection
    • Biospecimen Collected
    • Specimen Collection
  • Procedure: Bone Marrow Biopsy
    Undergo bone marrow biopsy
    Other names:
    • Biopsy of Bone Marrow
    • Biopsy, Bone Marrow
  • Procedure: Computed Tomography
    Undergo CT scan
    Other names:
    • CAT
    • CAT Scan
    • Computed Axial Tomography
    • Computerized Axial Tomography
    • Computerized axial tomography (procedure)
    • Computerized Tomography
    • Computerized Tomography (CT) scan
    • CT
    • CT Scan
    • tomography
  • Drug: Cyclophosphamide
    Given IV
    Other names:
    • (-)-Cyclophosphamide
    • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
    • Asta B 518
    • B-518
    • 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
    • WR-138719
  • Drug: Etoposide
    Given IV
    Other names:
    • Demethyl Epipodophyllotoxin Ethylidine Glucoside
    • EPEG
    • Lastet
    • Toposar
    • Vepesid
    • VP 16
    • VP 16-213
    • VP 16213
    • VP-16
    • VP-16-213
    • VP16
  • Procedure: Lumbar Puncture
    Undergo lumbar puncture
    Other names:
    • LP
    • Spinal Tap
  • Procedure: Positron Emission Tomography
    Undergo PET scan
    Other names:
    • Medical Imaging, Positron Emission Tomography
    • PET
    • PET Scan
    • Positron emission tomography (procedure)
    • Positron Emission Tomography Scan
    • Positron-Emission Tomography
    • proton magnetic resonance spectroscopic imaging
    • PT
  • Drug: Prednisone
    Given PO
    Other names:
    • .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
  • Biological: Rituximab
    Given IV
    Other names:
    • ABP 798
    • BI 695500
    • C2B8 Monoclonal Antibody
    • Chimeric Anti-CD20 Antibody
    • CT-P10
    • IDEC-102
    • IDEC-C2B8
    • IDEC-C2B8 Monoclonal Antibody
    • Ikgdar
    • Mabtas
    • MabThera
    • Monoclonal Antibody IDEC-C2B8
    • PF-05280586
    • Riabni
    • Rituxan
    • Rituximab ABBS
    • Rituximab ARRX
    • 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 PVVR
    • Rituximab-abbs
    • Rituximab-arrx
    • Rituximab-pvvr
    • RTXM83
    • Ruxience
    • Truxima
  • Drug: Venetoclax
    Given PO
    Other names:
    • ABT-0199
    • ABT-199
    • ABT199
    • GDC-0199
    • RG7601
    • Venclexta
    • Venclyxto
  • Drug: Vincristine Sulfate
    Given IV
    Other names:
    • Kyocristine
    • Leurocristine Sulfate
    • Leurocristine, sulfate
    • Oncovin
    • Vincasar
    • Vincosid
    • Vincrex
    • Vincristine, sulfate

More Details

Status
Active, not recruiting
Sponsor
National Cancer Institute (NCI)

Study Contact

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. 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 on diagnostic tumor biopsy correlate with PFS, EFS, and OS. VII. To determine whether local subtyping results for DHL and DEL are consistent with central analysis (phase II only). 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. Patients undergo position emission tomography (PET) scan, computed tomography (CT) scan and blood sample collection and may undergo bone marrow biopsy and lumbar puncture throughout the study. 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. Patients undergo PET scan, CT scan and blood sample collection and may undergo bone marrow biopsy and lumbar puncture throughout the study. 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. Patients undergo PET scan, CT scan and blood sample collection and may undergo bone marrow biopsy and lumbar puncture throughout the study. 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. Patients undergo PET scan, CT scan and blood sample collection and may undergo bone marrow biopsy and lumbar puncture throughout the study. 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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.