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Venetoclax, Rituximab, and Combination Chemotherapy in Treating Patients with Richter Syndrome

Trial Status: Active

This phase II trial studies how well venetoclax, rituximab, and combination chemotherapy works in treating patients with Richter syndrome. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell growth. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride, 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, rituximab, and combination chemotherapy may work better in treating patients with Richter syndrome.

Inclusion Criteria

  • Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma as per International Workshop on Chronic Lymphocytic Leukemia (IW-CLL) 2008 criteria with biopsy proven transformation to diffuse large B cell lymphoma (DLBCL), consistent with Richter’s Syndrome
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Absolute neutrophil count >= 1000 cells/mm^3 (1.0 x 10^9/L), unless they have significant bone marrow involvement of their malignancy confirmed on biopsy (completed within 2 weeks prior to start of protocol therapy); growth factor allowed to achieve
  • Platelet count >= 40,000 cells/mm^3 (40 x 10^9/L) independent of transfusion within 7 days of screening, unless they have significant bone marrow involvement of their malignancy confirmed on biopsy
  • Creatinine =< 1.5 x ULN or creatinine clearance >= 50 mL/min using 24-hour urine collection for creatinine clearance (completed within 2 weeks prior to start of protocol therapy)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN (completed within 2 weeks prior to start of protocol therapy)
  • Bilirubin =< 1.5 x ULN (completed within 2 weeks prior to start of protocol therapy)
  • Subjects with Gilbert's syndrome or resolving autoimmune hemolytic anemia may have a bilirubin up to 3.0 x 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., Mullerian 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 ** For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm, as defined below: *** With a female partner of childbearing potential who is not pregnant, men who are not surgically sterile must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 90 days after the last dose of venetoclax or 12 months after completion of chemotherapy, whichever is later; men must refrain from donating sperm during this same period. With a pregnant female partner, men must remain abstinent or use a condom during the treatment period and for at least 90 days after the last dose of venetoclax or 12 months after the last dose of chemotherapy, whichever is later, to avoid exposing the embryo
  • Patients who have undergone prior allogeneic transplantation are eligible provided they do not have significant active graft versus host disease and that their transplant day 0 is > 6 months from their first dose of chemotherapy
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

  • 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, 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 rituximab and hyperfractionated cyclophosphamide-vincristine-adriamycin-dexamethasone (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 (e.g., 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 (e.g., von Willebrand’s disease) or hemophilia
  • History of stroke or intracranial hemorrhage within 6 months prior to enrollment
  • History of human immunodeficiency virus (HIV) or human T-cell leukemia virus 1 (HTLV-1), or active hepatitis C virus (HCV) or hepatitis B virus (HBV); patients who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment; i.e. HBV deoxyribonucleic acid (DNA) must be undetectable, provided that they are willing to undergo monthly DNA testing; those who are PCR positive will be excluded; patients who are positive for HCV antibody are eligible only if PCR is negative for HCV ribonucleic acid (RNA)
  • Any uncontrolled active systemic infection
  • Major surgery within 4 weeks of first dose of study drug
  • Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 2 or higher congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization
  • Unable to swallow tablets or malabsorption syndrome, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction at time of screening
  • Breastfeeding or pregnant; serum pregnancy test will be conducted
  • Male subject who is considering fathering a child or donating sperm during the study or for approximately 90 days after the last dose of study drugs
  • Unwilling or unable to participate in all required study evaluations and procedures; unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations)
  • Patients receiving any other study agents
  • Patients with known central nervous system (CNS) involvement
  • Baseline Fridericia's correction formula (QTcF) or corrected QT (QTc) > 480 ms.; NOTE: This criterion does not apply to patients with a left bundle branch block
  • Patients who require warfarin or other vitamin K antagonists for anticoagulation (other anticoagulants are allowed)
  • Concurrent administration of medications or foods that are strong inhibitors or inducers of CYP3A
  • Patients with ongoing use of prophylactic antibiotics are eligible as long as there is no evidence of active infection and the antibiotic is not a prohibited medication
  • Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), and herpes zoster (varicella zoster virus [VZV]) at start of treatment
  • Significant co-morbid condition or disease which in the judgment of the principal investigator would place the patient at undue risk or interfere with the study

Massachusetts

Boston
Brigham and Women's Hospital
Status: ACTIVE
Contact: Matthew Steven Davids
Phone: 617-632-6331
Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Matthew Steven Davids
Phone: 617-632-6331

Ohio

Columbus
Ohio State University Comprehensive Cancer Center
Status: ACTIVE
Contact: Kerry Anne Rogers
Phone: 614-366-9338

Texas

Houston
M D Anderson Cancer Center
Status: ACTIVE
Contact: Philip A Thompson
Phone: 713-792-7430

PRIMARY OBJECTIVE:

I. To assess the rate of complete response (CR) of venetoclax plus dose-adjusted rituximab, etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride (EPOCH-R) (cohort 1) or rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine (Oncovin) and prednisone (R-CHOP) (cohort 2) for patients with Richter’s syndrome of chronic lymphocytic leukemia (CLL).

SECONDARY OBJECTIVES:

I. Safety and toxicity profile of this regimen In particular, our goal is to demonstrate improved tolerability or venetoclax (V)R-CHOP relative to R-EPOCH + venetoclax.

II. Rate of partial response (PR).

III. Rate of complete response (CR) after 3 cycles versus (vs.) 6 cycles of chemotherapy.

IV. Rate at which patients in PR after combination therapy convert to CR on venetoclax maintenance.

V. Progression free survival.

VI. Overall survival.

VII. Association of response with CLL prognostic factors including fluorescence in situ hybridization (FISH) cytogenetics, IGHV mutation status.

VIII. Association of response to whether the Richter’s syndrome (RS) is clonally-related to the antecedent CLL.

IX. Percentage of patients who are allogeneic transplant candidates who are able to receive a transplant.

X. Rate of undetectable CLL minimal residual disease (MRD) in the bone marrow after 3 and 6 months of combination therapy.

XI. To assess the correlation between bone marrow MRD and progression free survival (PFS) and overall survival (OS).

EXPLORATORY OBJECTIVES:

I. To assess whether complete response is associated with the level of mitochondrial priming for apoptosis in Richter’s cells.

II. To evaluate for the presence or absence of subclonal driver mutations in the Richter’s cells, both pre-treatment and at time of progression, and assess for association of these mutations with complete response.

III. To assess whether the presence of minimal residual Richter’s cells in the peripheral blood as determined by the adaptive ClonoSEQ assay is predictive of progression free and overall survival.

IV. To assess for alterations in phenotypic and genotypic markers in samples at time of progression compared to baseline.

V. To assess whether circulating tumor DNA (ctDNA) can be used to evaluate the whole tumor genomic landscape (“liquid biopsy”) and as a biomarker for response during therapy.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I (CLOSED TO ACCRUAL): Patients receive rituximab intravenously (IV) on day 1, doxorubicin hydrochloride IV over 96 hours on days 1-4, etoposide IV over 96 hours on days 1-4, vincristine sulfate IV over 96 hours on days 1-4, prednisone orally (PO) twice daily (BID) on days 1-5, and cyclophosphamide IV on day 5. Patients also receive venetoclax PO once daily (QD) on days 22-26 of cycle 1, and on days 1-10 of cycles 2-6. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients who do not achieve a sufficient remission or do not have a transplant donor available receive venetoclax PO QD. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve CR may discontinue treatment with the option to resume at time of disease relapse.

ARM II: Patients receive rituximab IV on day 1, doxorubicin hydrochloride IV over 15 minutes on day 1, vincristine sulfate IV over 15 minutes on day 1, cyclophosphamide IV over 1 hour on day 1, and prednisone PO on day 1-5. Patients also receive venetoclax PO on days 22-26 of cycle 1, and on days 1-10 of cycles 2-6. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients who do not achieve a sufficient remission or do not have a transplant donor available receive venetoclax PO QD. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve CR may discontinue treatment with the option to resume at time of disease relapse.

After completion of study treatment, patients are followed up every 3 months for 2 years, and every 6 months for 3 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Matthew Steven Davids

  • Primary ID 16-596
  • Secondary IDs NCI-2017-00489
  • Clinicaltrials.gov ID NCT03054896