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NCT03984448

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

Last Updated: 2025-12-30

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

ACTIVE_NOT_RECRUITING

Clinical Phase

PHASE2/PHASE3

Total Enrollment

363 participants

Study Classification

INTERVENTIONAL

Study Start Date

2019-10-22

Study Completion Date

2028-04-01

Brief Summary

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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.

Detailed Description

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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.

Conditions

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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 Transformed Indolent B-Cell Non-Hodgkin Lymphoma to Diffuse Large B-Cell Lymphoma

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Intervention Type DRUG

Other Intervention Names

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Biological Sample Collection Biospecimen Collected Specimen Collection Biopsy of Bone Marrow Biopsy, Bone Marrow CAT CAT Scan Computed Axial Tomography Computerized Axial Tomography Computerized axial tomography (procedure) Computerized Tomography Computerized Tomography (CT) scan CT CT Scan Diagnostic CAT Scan Diagnostic CAT Scan Service Type tomography (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Asta B 518 B 518 B-518 B518 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 WR-138719 WR138719 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 FI106 hydroxydaunorubicin Rubex Demethyl Epipodophyllotoxin Ethylidine Glucoside EPEG Lastet Toposar Vepesid VP 16 VP 16-213 VP 16213 VP-16 VP-16-213 VP-16213 VP16 VP16213 LP Spinal Tap Medical Imaging, Positron Emission Tomography PET PET Scan Positron emission tomography (procedure) Positron Emission Tomography Scan Positron-Emission Tomography PT .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 ABP 798 ABP-798 ABP798 BI 695500 BI-695500 BI695500 Blitzima C2B8 Monoclonal Antibody Chimeric Anti-CD20 Antibody CT P10 CT-P10 CTP10 GP 2013 GP-2013 GP2013 IDEC 102 IDEC-102 IDEC-C2B8 IDEC-C2B8 Monoclonal Antibody IDEC102 Ikgdar Mabtas MabThera Monoclonal Antibody IDEC-C2B8 PF 05280586 PF-05280586 PF05280586 Riabni Ritemvia Rituxan Rituximab ABBS Rituximab ARRX Rituximab Biosimilar ABP 798 Rituximab Biosimilar BI 695500 Rituximab Biosimilar CT-P10 Rituximab Biosimilar GB241 Rituximab Biosimilar GP2013 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-blit Rituximab-pvvr Rituximab-rite Rituximab-rixa Rituximab-rixi Rixathon Riximyo RTXM 83 RTXM-83 RTXM83 Ruxience Truxima ABT 199 ABT-0199 ABT-199 ABT199 GDC 0199 GDC-0199 GDC0199 RG7601 Venclexta Venclyxto Kyocristine Leurocristine Sulfate Leurocristine, sulfate Oncovin Vincasar Vincosid Vincrex Vincristine, sulfate

Eligibility Criteria

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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.

Minimum Eligible Age

18 Years

Maximum Eligible Age

80 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Jeremy S Abramson

Role: PRINCIPAL_INVESTIGATOR

Alliance for Clinical Trials in Oncology

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Rutherford SC, Abramson JS, Bartlett NL, Barta SK, Khan N, Joyce R, Maddocks K, Ali-Shaw T, Senese S, Yuan Y, Westin J, Leonard JP. Venetoclax with dose-adjusted EPOCH-R as initial therapy for patients with aggressive B-cell lymphoma: a single-arm, multicentre, phase 1 study. Lancet Haematol. 2021 Nov;8(11):e818-e827. doi: 10.1016/S2352-3026(21)00273-8. Epub 2021 Oct 8.

Reference Type DERIVED

PMID: 34634256 (View on PubMed)

Provided Documents

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Document Type: Informed Consent Form

View Document

Other Identifiers

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NCI-2019-03711

Identifier Type: REGISTRY

Identifier Source: secondary_id

A051701

Identifier Type: OTHER

Identifier Source: secondary_id

A051701

Identifier Type: OTHER

Identifier Source: secondary_id

U10CA180821

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2019-03711

Identifier Type: -

Identifier Source: org_study_id

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

Study Results

Basic Information

Brief Summary

Detailed Description

Conditions

Study Design

Study Groups

Arm 1 (R-CHOP, DA-EPOCH-R)

Biospecimen Collection

Bone Marrow Biopsy

Computed Tomography

Cyclophosphamide

Doxorubicin Hydrochloride

Etoposide

Positron Emission Tomography

Prednisone

Rituximab

Vincristine Sulfate

Arm 2 (R-CHOP, DA-EPOCH-R, venetoclax)

Biospecimen Collection

Bone Marrow Biopsy

Computed Tomography

Cyclophosphamide

Etoposide

Lumbar Puncture

Positron Emission Tomography

Prednisone

Rituximab

Venetoclax

Vincristine Sulfate

Interventions

Biospecimen Collection

Bone Marrow Biopsy

Computed Tomography

Cyclophosphamide

Doxorubicin Hydrochloride

Etoposide

Lumbar Puncture

Positron Emission Tomography

Prednisone

Rituximab

Venetoclax

Vincristine Sulfate

Other Intervention Names

Eligibility Criteria

Inclusion Criteria

Sponsors

National Cancer Institute (NCI)

Responsible Party

Principal Investigators

Jeremy S Abramson

Locations

Mercy Hospital Joplin

Mercy Clinic-Rolla-Cancer and Hematology

Phelps Health Delbert Day Cancer Institute

Heartland Regional Medical Center

Sainte Genevieve County Memorial Hospital

Mercy Hospital Springfield

CoxHealth South Hospital

University of Alabama at Birmingham Cancer Center

Anchorage Associates in Radiation Medicine

Anchorage Radiation Therapy Center

Alaska Breast Care and Surgery LLC

Alaska Oncology and Hematology LLC

Alaska Women's Cancer Care

Anchorage Oncology Centre

Katmai Oncology Group

Providence Alaska Medical Center

Fairbanks Memorial Hospital

Cancer Center at Saint Joseph's

Mercy Hospital Fort Smith

CHI Saint Vincent Cancer Center Hot Springs

Mission Hope Medical Oncology - Arroyo Grande

Providence Saint Joseph Medical Center/Disney Family Cancer Center

Community Cancer Institute

University Oncology Associates

Loma Linda University Medical Center

Fremont - Rideout Cancer Center

University of California Davis Comprehensive Cancer Center