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Study of Venetoclax Plus DA-EPOCH-R for the Treatment of Aggressive B-Cell Lymphomas (V+DA-EPOCH-R)

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ClinicalTrials.gov Identifier: NCT03036904
Recruitment Status : Active, not recruiting
First Posted : January 30, 2017
Last Update Posted : September 30, 2019
Sponsor:
Collaborators:
Genentech, Inc.
Massachusetts General Hospital
M.D. Anderson Cancer Center
Information provided by (Responsible Party):
Weill Medical College of Cornell University

Brief Summary:
This is a phase I, open label, single-arm, multi-center, dose-finding study of venetoclax in combination with DA-EPOCH-R in patients with aggressive B-Cell Lymphomas.

Condition or disease Intervention/treatment Phase
Diffuse Large B-Cell Lymphoma High Grade B-Cell Lymphoma Drug: Venetoclax Drug: Rituximab Drug: Etoposide Drug: Vincristine Sulfate Drug: Cyclophosphamide Drug: Prednisone Drug: Doxorubicin Hydrochloride Phase 1

Detailed Description:

This clinical trial is for men and women with aggressive B-Cell Lymphomas which includes:

  • Diffuse large B-cell lymphoma (DLBCL),
  • B-cell lymphoma unclassifiable with intermediate features between DLBCL and Burkitt Lymphoma (BL),
  • High grade B-cell lymphoma (HGBCL),
  • Transformed indolent NHL (TiNHL). The aggressive B-cell lymphomas enrolling on this study have been recognized to have a poor prognosis with the use of conventional chemoimmunotherapy. DA-EPOCH-R is an alternative highly effective chemoimmunotherapy platform for these lymphomas and may serve as an optimal chemotherapy backbone for the incorporation of novel agents such as venetoclax.

The Bcl-2 protein plays a significant role in the regulation of cell death in malignant cells. Overexpression of Bcl-2 family proteins is associated with chemo-resistance of a broad variety of cancers, and BCL2 abnormalities are common in aggressive B-cell Lymphomas. Venetoclax is a highly selective Bcl-2 family protein inhibitor that binds to Bcl-2 family proteins to potentially overcome resistance and enhance responses to therapy. This study has been designed to evaluate the safety and preliminary efficacy of venetoclax in combination with DA-EPOCH-R.

Subjects will receive venetoclax in conjunction with six 21-day cycles of DA-EPOCH-R. Dosing for DA-EPOCH-R will follow established protocols. Venetoclax will be administered on days 3 through 12 during cycle 1 and days 1 through 10 of each subsequent cycle. Following completion of therapy, subjects will be followed every three months for up to two years. Subjects removed from study due to toxicity will be followed until resolution or stabilization of the toxicity.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 34 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Venetoclax Plus DA-EPOCH-R for the Treatment of Aggressive B-Cell Lymphomas
Actual Study Start Date : February 6, 2017
Actual Primary Completion Date : July 8, 2019
Estimated Study Completion Date : August 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma
Drug Information available for: Venetoclax

Arm Intervention/treatment
Experimental: Venetoclax plus DA-EPOCH-R
Venetoclax will be given in conjunction with 6 cycles of DA-EPOCH-R (doxorubicin hydrochloride, etoposide, vincristine sulfate, cyclophosphamide, prednisone, rituximab). The dosing schedule and regimen for DA-EPOCH-R will follow established protocols. Venetoclax will be administered days 1-10 of each 21-day cycle, with the exception of cycle 1, during which venetoclax dose will commence on day 3 and continue through day 12, so as to clarify attribution of any observed TLS and/or infusion reactions, and minimize tumor lysis syndrome (TLS) risk.
Drug: Venetoclax
Venetoclax will be administered orally on days 3-12 in cycle 1, and days 1-10 with all subsequent cycles except dose level -1. If dose level -1 is required, venetoclax will be administered on days 3-7 in cycle 1 and 1-5 with subsequent cycles.
Other Name: Venclexta

Drug: Rituximab
Rituximab will be administered as an IV infusion at 375 mg/m2 on day 1 of each cycle of DA-EPOCH-R, immediately prior to the start of chemotherapy. Oral pre-medication 650 mg of acetaminophen and 50-100 mg diphenhydramine hydrochloride will be administered 30 to 60 minutes prior to starting each infusion of rituximab. The first rituximab infusion should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr. If this rate of escalation is well tolerated the second and subsequent infusions can begin at a rate of 100 mg/hr and increase in 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. CAUTION: DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.
Other Names:
  • Rituxan
  • IDEC-C2B8
  • chimeric anti-CD20 monoclonal antibody

Drug: Etoposide
Etoposide will be obtained from commercial supply, and will be given for a total of 6 cycles for all patients. The drug will be given by IV route.
Other Names:
  • VP-16
  • VePesid
  • etopophos
  • toposar

Drug: Vincristine Sulfate
Vincristine Sulfate will be obtained from commercial supply, and will be given for a total of 6 cycles for all patients. The drug will be given by IV route.
Other Names:
  • LCR
  • VCR

Drug: Cyclophosphamide
Cyclophosphamide will be obtained from commercial supply, and will be given for a total of 6 cycles for all patients. The drug will be given by IV route.
Other Name: cytoxan

Drug: Prednisone
Prednisone will be obtained from commercial supply, and will be given for a total of 6 cycles for all patients. Prednisone will be given orally.
Other Names:
  • Deltasone
  • Orasone
  • Paracort
  • Cortan

Drug: Doxorubicin Hydrochloride
Doxorubicin Hydrochloride will be obtained from commercial supply, and will be given for a total of 6 cycles for all patients. The drug will be given by IV route.
Other Names:
  • Hydroxydaunomycin Hydrochloride
  • Hydroxydoxorubicin Hydrochloride




Primary Outcome Measures :
  1. Determination of the maximal tolerated dose (MTD) [ Time Frame: Approximately 24 months ]
    Determination of the maximal tolerated dose (MTD)

  2. Determination of dose limiting toxicity (DLT) [ Time Frame: Approximately 24 months ]
    Determination of dose limiting toxicity (DLT)


Secondary Outcome Measures :
  1. Define incidence and severity of adverse events, defined according to CTCAE v 4.0. [ Time Frame: Approximately 24 months ]
    Define incidence and severity of adverse events, defined according to CTCAE v 4.0.

  2. Overall response rate [ Time Frame: Approximately 24 months ]
    Overall response rate

  3. Complete response rate [ Time Frame: Approximately 24 months ]
    Complete response rate

  4. Event-free survival [ Time Frame: Approximately 24 months ]
    Event-free survival

  5. Progression Free Survival [ Time Frame: Approximately 24 months ]
    Progression Free Survival

  6. Overall survival [ Time Frame: Approximately 24 months ]
    Overall survival



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Adults age 18-80 years
  • Histologically confirmed, biopsy-proven diagnosis of DLBCL, BCLu, HGBCL, or TiNHL.

Richter's transformation from Chronic Lymphocytic Leukemia (CLL) is not eligible.

  • Subjects with DLBCL, BCLu, HGBCL NOS, or HGBCL with translocations of MYC and BCL2 and/or BCL6, must have had no prior chemotherapy for lymphoma. Steroids for palliation prior to enrollment are allowed.
  • Subjects with TiNHL are eligible if they have received no prior cytotoxic chemotherapy for lymphoma. Steroids, rituximab, and external beam radiation therapy as prior therapy for indolent lymphoma is allowed.
  • Ann Arbor stage II-IV disease (Stage I primary mediastinal B-cell lymphoma will also be eligible)
  • Ability to provide signed Informed Consent Form
  • Ability and willingness to comply with the requirements of the study protocol
  • Measureable disease (defined as at least 1.5 cm in diameter).
  • Adequate organ and bone marrow function:
  • Absolute neutrophil count (ANC) at least 1,000/mm3
  • Platelet count at least 100,000/mm3.
  • Total bilirubin at most1.5 x the upper limit of the normal range (ULN), except Gilbert's disease
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at most 3 x ULN.
  • Calculated creatinine clearance at least 30 mL/min.

Exclusion criteria:

  • Known hypersensitivity to any of the study drugs
  • History of other malignancy that could affect compliance with the protocol or interpretation of results
  • Patients with a history of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix are generally eligible. Patients with a malignancy that has been treated, but not with curative intent, will also be excluded, unless the malignancy has been in remission without treatment for at least 2 years prior to enrollment.
  • Known CNS involvement at diagnosis
  • Richter's transformation from CLL
  • Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal)
  • Major surgery within 3 weeks prior to the start of study treatment
  • Infection with human immunodeficiency virus (HIV)
  • Women who are pregnant or lactating
  • Female patients who are not surgically sterile or postmenopausal (for at least 1 year) must practice at least one of the following methods of birth control throughout the duration of study participation and for at least 3 months after study treatment:
  • Total abstinence from sexual intercourse
  • A vasectomized partner
  • Hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) that started at least 3 months prior to study drug administration
  • Double-barrier method (condom plus diaphragm or cervical cup with spermicidal contraceptive sponge, jellies, or cream)
  • Non-vasectomized male patients must comply with at least one of the following methods of birth control throughout the duration of study participation and for at least 3 months after study treatment:
  • A partner who is surgically sterile or postmenopausal (for at least 1 year) or who is taking hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) for at least 3 months prior to study drug administration
  • Total abstinence from sexual intercourse
  • Double-barrier method (condom plus diaphragm or cervical cup with spermicidal, contraceptive sponge, jellies, or cream)
  • Malabsorption syndrome or other condition that precludes enteral route of administration
  • Known allergy to both xanthine oxidase inhibitors and rasburicase
  • Subjects with positive HBV core antibody or surface antigen are eligible as long as they have an undetectable HBV DNA PCR, and receive concurrent antiviral therapy with entecavir, tenofovir, or lamivudine, and continued for a minimum of 6 months after completion of therapy.
  • Active hepatitis C (defined as a positive HCV viral load)
  • Chronic use of moderate or strong CYP3A4 modulators (inhibitor or inducer) or any other prohibited medications. A washout period of 7 days is required prior to venetoclax dosing if a prohibited medication is discontinued.
  • Chronic use of a P-gp inhibitor, or a P-gp substrate with a narrow therapeutic index. A washout period of 7 days is required prior to venetoclax dosing if a prohibited medication is discontinued.

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): NCT03036904


Locations
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United States, Massachusetts
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, United States, 02284
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New York
Weill Cornell Medicine
New York, New York, United States, 10065
United States, Ohio
Ohio State University Medical Center
Columbus, Ohio, United States, 43210
United States, Pennsylvania
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States, 19111
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Weill Medical College of Cornell University
Genentech, Inc.
Massachusetts General Hospital
M.D. Anderson Cancer Center
Investigators
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Study Chair: John P. Leonard, M.D. Weill Cornell Medicine
Study Chair: Jeremy S. Abramson, M.D. Massachusetts General Hospital
Principal Investigator: Sarah Rutherford, M.D. Weill Cornell Medicine

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Responsible Party: Weill Medical College of Cornell University
ClinicalTrials.gov Identifier: NCT03036904     History of Changes
Other Study ID Numbers: 1607017413
First Posted: January 30, 2017    Key Record Dates
Last Update Posted: September 30, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Weill Medical College of Cornell University:
venetoclax
dose-adjusted EPOCH-R
aggressive B-Cell lymphoma
Lymphoma
Non-Hodgkin lymphoma
Diffuse large B-cell lymphoma
Double hit lymphoma
Additional relevant MeSH terms:
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Venetoclax
Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Aggression
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Behavioral Symptoms
Prednisone
Cyclophosphamide
Rituximab
Doxorubicin
Liposomal doxorubicin
Etoposide
Etoposide phosphate
Vincristine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists