Clinical trial NCT03036904: Study of Venetoclax Plus DA-EPOCH-R for the Treatment of Aggressive B-Cell Lymphomas
Official title: Phase I Study of Venetoclax Plus DA-EPOCH-R for the Treatment of Aggressive B-Cell Lymphomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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
Lead sponsor: Weill Medical College of Cornell University
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
name: Massachusetts General Hospital
name: M.D. Anderson Cancer Center
First posted: 2017-01-30
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Determination of the maximal tolerated dose (MTD)
timeFrame: Approximately 24 months
measure: Determination of dose limiting toxicity (DLT)
timeFrame: Approximately 24 months
Secondary outcomes:
measure: Define incidence and severity of adverse events, defined according to CTCAE v 4.0.
timeFrame: Approximately 24 months
measure: Overall response rate
timeFrame: Approximately 24 months
measure: Complete response rate
timeFrame: Approximately 24 months
measure: Event-free survival
timeFrame: Approximately 24 months
measure: Progression Free Survival
timeFrame: Approximately 24 months
measure: Overall survival
timeFrame: Approximately 24 months
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: Weill Medical College of Cornell University
name: John P. Leonard, M.D.
role: STUDY_CHAIR
affiliation: Massachusetts General Hospital
name: Jeremy S. Abramson, M.D.
role: STUDY_CHAIR
affiliation: Weill Medical College of Cornell University
name: Sarah Rutherford, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.