Trial record 1 of 1 for:
a051701
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 |
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Recruitment Status :
Recruiting
First Posted : June 13, 2019
Last Update Posted : December 5, 2019
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Sponsor:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI)
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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 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 | Drug: Cyclophosphamide Drug: Doxorubicin Drug: Doxorubicin Hydrochloride Drug: Etoposide Drug: Prednisone Biological: Rituximab Drug: Venetoclax Drug: Vincristine Drug: Vincristine Sulfate | Phase 2 Phase 3 |
Show Detailed Description
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 351 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
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: ARM A (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
Other Names:
Drug: Doxorubicin Given IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Drug: Prednisone Given PO
Other Names:
Biological: Rituximab Given IV
Other Names:
Drug: Vincristine Given IV
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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Experimental: ARM B (R-CHOP, DA-EPOCH-R, venetoclax)
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. 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. |
Drug: Doxorubicin
Given IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Drug: Prednisone Given PO
Other Names:
Biological: Rituximab Given IV
Other Names:
Drug: Venetoclax Given PO
Other Names:
Drug: Vincristine Given IV
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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Primary Outcome Measures :
- 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.
- 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 :
- 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.
- 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.
- 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.
- 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.
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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).
- 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.
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Absolute neutrophil count (ANC) >= 1,000/mm^3.
- Unless attributable to lymphoma.
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Platelet count >= 100,000/mm^3.
- Unless attributable to lymphoma.
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Creatinine =< 1.5 mg/dL OR calculated (calc.) creatinine clearance >= 50 mL/min.
- Unless attributable to lymphoma.
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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.
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
Show 386 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Jeremy S Abramson | Alliance for Clinical Trials in Oncology |
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT03984448 History of Changes |
| 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: | December 5, 2019 |
| Last Verified: | October 2019 |
| 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 |
| 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 Cortisone Cyclophosphamide Rituximab Doxorubicin |
Liposomal doxorubicin Etoposide Etoposide phosphate Vincristine Venetoclax Antineoplastic Agents, Immunological Antibodies Immunoglobulins Antibodies, Monoclonal Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents |