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Trial record 1 of 1 for:    A051701
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Testing the Addition of a New Anti-cancer Drug, Venetoclax, to Usual Chemotherapy for High Grade B-cell Lymphomas

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ClinicalTrials.gov Identifier: NCT03984448
Recruitment Status : Suspended (End of Initial Phase of Multi-phase protocol)
First Posted : June 13, 2019
Last Update Posted : June 16, 2022
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Drug: Cyclophosphamide Drug: Doxorubicin Hydrochloride Drug: Etoposide Drug: Prednisone Biological: Rituximab Drug: Venetoclax Drug: Vincristine Sulfate Phase 2 Phase 3

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Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 374 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized Phase II/III Study of Venetoclax (ABT199) Plus Chemoimmunotherapy for MYC/BCL2 Double-Hit and Double Expressing Lymphomas
Actual Study Start Date : August 7, 2019
Estimated Primary Completion Date : April 1, 2028
Estimated Study Completion Date : April 1, 2028

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma
Drug Information available for: Venetoclax

Arms and Interventions
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Arm Intervention/treatment
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.

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.

 Drug: Cyclophosphamide
Given IV

Drug: Doxorubicin Hydrochloride
Given IV

Drug: Etoposide
Given IV

Drug: Prednisone
Given PO

Biological: Rituximab
Given IV

Drug: Vincristine Sulfate
Given IV
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.

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.

 Drug: Cyclophosphamide
Given IV

Drug: Etoposide
Given IV

Drug: Prednisone
Given PO

Biological: Rituximab
Given IV

Drug: Venetoclax
Given PO

Drug: Vincristine Sulfate
Given IV


Outcome Measures
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Primary Outcome Measures :
  1. 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 ]
    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.

  2. PFS (phase III) [ Time Frame: At 24 months ]
    Will be compared between the experimental and control arms using a Mantel-Haenszel test without a continuity correction. In the event that there is censoring prior to 24 months, a test based on the complementary log-log transformation of Kaplan-Meier estimates will compare PFS at 24 months between experimental and control arms. Two-year PFS estimates, medians, and corresponding hazard ratios will be provided with 95% confidence intervals overall.


Secondary Outcome Measures :
  1. Overall survival (OS) (phase III) [ Time Frame: From randomization date until death from any cause, assessed up to 10 years ]
    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.

  2. 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 ]
    Will be compared between the experimental and control arms using a log-rank test. Estimated using Kaplan-Meier method by arm and lymphoma subtype.

  3. Response rate [ Time Frame: Up to 1 week after end of cycle 6 ]

    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.


  4. Inconsistency of local and central results for DEL or DHL status [ Time Frame: Until last patient is registered, up to month 57 ]
    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.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03984448


Locations
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Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Jeremy S Abramson Alliance for Clinical Trials in Oncology
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03984448    
Other Study ID Numbers: NCI-2019-03711
NCI-2019-03711 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
A051701 ( Other Identifier: Alliance for Clinical Trials in Oncology )
A051701 ( Other Identifier: CTEP )
U10CA180821 ( U.S. NIH Grant/Contract )
First Posted: June 13, 2019    Key Record Dates
Last Update Posted: June 16, 2022
Last Verified: February 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Prednisone
Cyclophosphamide
Rituximab
Doxorubicin
Liposomal doxorubicin
 Etoposide
Vincristine
Venetoclax
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors