Study of Venetoclax Plus DA-EPOCH-R for the Treatment of Aggressive B-Cell Lymphomas

NCT03036904 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: 1607017413
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 6

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.

Conditions

Diffuse Large B-Cell Lymphoma; High Grade B-Cell Lymphoma

Keywords

venetoclax; dose-adjusted EPOCH-R; aggressive B-Cell lymphoma; Lymphoma; Non-Hodgkin lymphoma; Diffuse large B-cell lymphoma; Double hit lymphoma

Outcome Measures

Primary Outcomes (2)

• Determination of the maximal tolerated dose (MTD)

  Determination of the maximal tolerated dose (MTD)

  Approximately 24 months

• Determination of dose limiting toxicity (DLT)

  Determination of dose limiting toxicity (DLT)

  Approximately 24 months

Secondary Outcomes (6)

• Define incidence and severity of adverse events, defined according to CTCAE v 4.0.

  Approximately 24 months

• Overall response rate

  Approximately 24 months

• Complete response rate

  Approximately 24 months

• Event-free survival

  Approximately 24 months

• Progression Free Survival

  Approximately 24 months

Study Arms (1)

Venetoclax plus DA-EPOCH-R

EXPERIMENTAL

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; Drug: Rituximab; Drug: Etoposide; Drug: Vincristine Sulfate; Drug: Cyclophosphamide; Drug: Prednisone; Drug: Doxorubicin Hydrochloride

Interventions

Venetoclax DRUG

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.

Also known as: Venclexta

Venetoclax plus DA-EPOCH-R

Rituximab DRUG

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.

Also known as: Rituxan, IDEC-C2B8, chimeric anti-CD20 monoclonal antibody

Venetoclax plus DA-EPOCH-R

Etoposide DRUG

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.

Also known as: VP-16, VePesid, etopophos, toposar

Venetoclax plus DA-EPOCH-R

Vincristine Sulfate DRUG

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.

Also known as: LCR, VCR

Venetoclax plus DA-EPOCH-R

Cyclophosphamide DRUG

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.

Also known as: cytoxan

Venetoclax plus DA-EPOCH-R

Prednisone DRUG

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.

Also known as: Deltasone, Orasone, Paracort, Cortan

Venetoclax plus DA-EPOCH-R

Doxorubicin Hydrochloride DRUG

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.

Also known as: Hydroxydaunomycin Hydrochloride, Hydroxydoxorubicin Hydrochloride

Venetoclax plus DA-EPOCH-R

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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:

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead
• Genentech, Inc.: collaborator
• Massachusetts General Hospital: collaborator
• M.D. Anderson Cancer Center: collaborator

Study Sites (6)

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 02284, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Weill Cornell Medicine

New York, New York, 10065, United States

Location

Ohio State University Medical Center

Columbus, Ohio, 43210, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• 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.

  PMID: 34634256 DERIVED

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse; Lymphoma; Lymphoma, Non-Hodgkin

Interventions

venetoclax; Rituximab; Etoposide; etoposide phosphate; Vincristine; Cyclophosphamide; Prednisone; Doxorubicin

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Aminoglycosides

Study Officials

• John P. Leonard, M.D.

  Weill Medical College of Cornell University

  STUDY CHAIR

• Jeremy S. Abramson, M.D.

  Massachusetts General Hospital

  STUDY CHAIR

• Sarah Rutherford, M.D.

  Weill Medical College of Cornell University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 27, 2017
• First Posted: January 30, 2017
• Study Start: February 6, 2017
• Primary Completion: November 11, 2021
• Study Completion: November 11, 2021
• Last Updated: August 24, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (6)