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

Status: Active

Description

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 some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as rituximab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor 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.

Eligibility Criteria

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
  • Activated partial thromboplastin time (aPTT) and prothrombin time (PT) not to exceed 1.5 x upper limit of normal (ULN) (completed within 2 weeks prior to start of protocol therapy)
  • 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; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • 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
  • Prior therapy with R-EPOCH
  • 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 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; those who are PCR positive will be excluded
  • 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 capsules 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

Locations & Contacts

Massachusetts

Boston
Brigham and Women's Hospital
Status: Active
Contact: Matthew Steven Davids
Phone: 617-632-6331
Email: Matthew_Davids@dfci.harvard.edu
Dana-Farber Cancer Institute
Status: Active
Contact: Matthew Steven Davids
Phone: 617-632-6331
Email: Matthew_Davids@dfci.harvard.edu

Ohio

Columbus
Ohio State University Comprehensive Cancer Center
Status: Active
Contact: Kerry Anne Rogers
Phone: 614-366-9338
Email: Kerry.Rogers@osumc.edu

Texas

Houston
M D Anderson Cancer Center
Status: Active
Contact: Philip A Thompson
Phone: 713-792-7430
Email: PAThompson2@mdanderson.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

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) for patients with Richter’s syndrome of chronic lymphocytic leukemia (CLL).

SECONDARY OBJECTIVES:

I. Rate of partial response (PR).

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

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

IV. Progression free survival.

V. Overall survival.

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

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

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

IX. Safety and toxicity profile of this regimen.

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.

OUTLINE:

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 on days 22-26 of course 1, and on days 1-10 of courses 2-6. Courses repeat every 21 days for 6 courses 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 on day 1. Courses 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 & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Matthew Steven Davids

Trial IDs

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