A Phase II Study of Venetoclax in Combination With Dose-adjusted EPOCH-R or R-CHOP for Patients With Richter's Syndrome

NCT03054896 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 16-596
• Study Type: interventional
• Target: 69
• Locations: 1 country
• Sites: 3

Brief Summary

This research study is evaluating the combination of a study drug, venetoclax, and a standard chemotherapy regimen, R-EPOCH or R-CHOP, as a possible treatment for Richter's Syndrome. The drugs involved in this study are:

• Venetoclax
• R-EPOCH:
• Rituximab
• Etoposide
• Prednisone
• Vincristine Sulfate (Oncovin)
• Cyclophosphamide
• Doxorubicin Hydrochloride (Hydroxydaunomycin)
• R-CHOP:
• Rituximab
• Cyclophosphamide Vincristine
• Doxorubicin Hydrochloride (Hydroxydaunomycin)
• Sulfate (Oncovin)
• Prednisone

Conditions

Richter Syndrome

Keywords

Richter Syndrome

Outcome Measures

Primary Outcomes (1)

• Rate of Complete Response by 2008 IW-CLL Response Criteria

  Complete Response Rate

  2 years

Secondary Outcomes (4)

• Partial Response Rate by 2008 IW-CLL Response Criteria

  2 years

• Progression Free Survival

  2 years

• Overall Survival Rate

  2 years

• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  2 years

Study Arms (2)

VR-EPOCH

EXPERIMENTAL

* Standard chemotherapy regimen, DA-EPOCH-R, with a novel oral Bcl-2 inhibitor, venetoclax will be administered to patients * Chemotherapy cycles will be administered approximately every 3 weeks * Initial venetoclax dose ramp-up will be done in a condensed fashion over approximately 5 days, followed by continuous daily dosing

Drug: Venetoclax; Other: DA-EPOCH-R

VR-CHOP

EXPERIMENTAL

* Standard chemotherapy regimen, R-CHOP, with a novel oral Bcl-2 inhibitor, venetoclax will be administered to patients * Chemotherapy cycles will be administered approximately every 3 weeks * Initial venetoclax dose ramp-up will be done in a condensed fashion over approximately 5 days, followed by continuous daily dosing

Drug: Venetoclax; Other: R-CHOP

Interventions

Venetoclax DRUG

Venetoclax is an Antineoplastic Agent; BCL-2 Inhibitor

Also known as: Venclexta

VR-CHOP; VR-EPOCH

DA-EPOCH-R OTHER

Intensive chemotherapy regiment

VR-EPOCH

R-CHOP OTHER

Intensive chemotherapy regiment

VR-CHOP

Eligibility Criteria

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

You may qualify if:

• Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma as per IW-CLL 2008 criteria (Hallek et al, 2008) with biopsy proven transformation to diffuse large B cell lymphoma (DLBCL), consistent with Richter's Syndrome.
• Age greater than or equal to 18 years. Because CLL and Richter's Syndrome are extremely rare in persons \<18 years of age, children are excluded from this study.
• ECOG performance status \<2 (see Appendix A)
• Patients must meet the following hematologic criteria at screening, unless they have significant bone marrow involvement of their malignancy confirmed on biopsy:
• Absolute neutrophil count ≥1000 cells/mm3 (0.5 x 109/L). Growth factor allowed to achieve
• Platelet count ≥40,000 cells/mm3 (40 x 109/L) independent of transfusion within 7 days of screening
• Subject must have adequate coagulation, renal, and hepatic function, per laboratory reference range at Screening as follows:
• Creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min using 24-hour urine collection for creatinine clearance
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × ULN;
• Bilirubin ≤ 1.5 × ULN;
• Subjects with Gilbert's Syndrome or resolving autoimmune hemolytic anemia may have a bilirubin up to 3.0 × ULN and are still eligible
• The effects of venetoclax on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Contraception must continue for an additional 30 days post last dose of venetoclax for women, and an additional 90 days post last dose in men. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately and venetoclax must be discontinued immediately.
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception and agreement to refrain from donating eggs, as defined below:
• Women must remain abstinent or use contraceptive methods with a failure rate of \<1% per year during the treatment period and for at least 30 days after the last dose of venetoclax and 12 months after the last dose of chemotherapy, whichever is later. Women must refrain from donating eggs during this same period.
• A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations. Examples of contraceptive methods with a failure rate of \<1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

You may not qualify if:

• Patients with the Hodgkin variant transformation of CLL will be excluded
• History of severe allergic or anaphylactic reactions to monoclonal antibody therapy or to the chemotherapy drugs used in this study (see Appendix D), unless the antibody can be given through a desensitization program in consultation with an allergist
• Subject has received any of the following within 14 days or 5 drug half-lives (whichever is shortest) prior to the first dose of chemotherapy, or has not recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(s) of the previous therapy:
• Any anti-cancer therapy including chemotherapy, biologic agents for anti-neoplastic treatment (e.g. monoclonal antibodies) or radiotherapy, investigational therapy, including targeted small molecule agents. Patients who are currently receiving treatment with ibrutinib or acalabrutinib may continue this agent until the day prior to starting venetoclax, to reduce the risk of tumor flare on treatment cessation.
• Received previous treatment with R-CHOP, R-EPOCH, or R-hyper-CVAD
• History of other malignancies, except:
• Malignancy treated with curative intent and with no known active disease present before the first dose of study drug and felt to be at low risk for recurrence by treating physician.
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
• Adequately treated carcinoma in situ without evidence of disease
• Low-risk prostate cancer on active surveillance
• Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc.) within 28 days of the first dose of study drug.
• Corticosteroids are allowed, but must be dosed at prednisone 20 mg (or equivalent) or lower prior to the start of chemotherapy.
• Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
• Known bleeding disorders (eg, von Willebrand's disease) or hemophilia.
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Genentech, Inc.: collaborator

Study Sites (3)

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Davids MS, Rogers KA, Tyekucheva S, Wang Z, Pazienza S, Renner SK, Montegaard J, Ihuoma U, Lehmberg TZ, Parry EM, Wu CJ, Jacobson CA, Fisher DC, Thompson PA, Brown JR. Venetoclax plus dose-adjusted R-EPOCH for Richter syndrome. Blood. 2022 Feb 3;139(5):686-689. doi: 10.1182/blood.2021011386.

  PMID: 34788401 DERIVED

MeSH Terms

Interventions

venetoclax; R-CHOP protocol

Study Officials

• Matthew S. Davids, MD, MMSc

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 10, 2017
• First Posted: February 16, 2017
• Study Start: March 8, 2017
• Primary Completion: December 1, 2024
• Study Completion (Estimated): December 1, 2027
• Last Updated: August 14, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)