Bendamustine, Rituximab, and Venetoclax in Treating Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia
- Subjects must have a diagnosis of chronic lymphocytic leukemia (CLL) according to the IWCLL National Cancer Institute (NCI) Working Group (WG) criteria or small lymphocytic lymphoma (SLL) according to the World Health Organization criteria.
- To be considered CLL the subject must have an absolute lymphocytosis in the blood of at least 5,000 lymphocytes per microliter, or bone marrow lymphocytosis greater than or equal to 30% of all nucleated cells.
- Subject must have histologic and immunophenotypic analysis that should demonstrate small to moderate size lymphocytes with flow cytometry demonstrating a predominant population of lymphocytes that share both B-cell antigens (CD19, CD20 [typically dim expression] or CD23) as well as CD5 in the absence of other pan-T-cell markers and clonality as evidenced by kappa or lambda light chain expression (typically dim immunoglobulin expression) or other genetic method (e.g. immunoglobulin heavy chain variable [IGHV] analysis). It is recognized that an occasional subject with CLL may have a slightly aberrant immunophenotype. All such cases need to be reviewed with the principal investigator prior to being registered for the study.
- Subjects must have had no prior therapy for their disease. Topical or inhaled corticosteroids are permitted for other medical conditions, i.e. asthma or dermatologic reasons.
- Eastern Oncology Cooperative Group (ECOG) performance score of =< 2.
- An absolute neutrophil count >= 1.0 10^9/L (unless due to documented bone failure).
- Hemoglobin >= 8 g/dL (unless due to documented bone failure).
- Platelet count > 50 x 10^9/L (unless due to bone marrow failure).
- Note: Subjects with inadequate values due to autoimmune hemolytic anemia or autoimmune thrombocytopenia will be eligible for treatment on this protocol regardless of disease stage upon discussion with the principal investigator.
- Aspartate transaminase (AST) and alanine transaminase (ALT) =< 3.0 X upper limit of normal (ULN).
- Bilirubin =< 1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin).
- For patients not receiving therapeutic anticoagulation: Prothrombin time (PT) or activated partial thromboplastin time (aPTT) =< 1.5 x ULN; for patients on therapeutic anticoagulation or underlying known cause, approval from principal investigator may be given for values above 1.5 x ULN or PT and/or aPTT.
- Subject must have the ability to understand and the willingness to sign a written informed consent document.
- Additionally, based on animal data, venetoclax may compromise fertility in males. For this reason, women of child-bearing potential and men must agree to use adequate contraception (see below) for at least 90 days prior to study entry and for the duration of study participation. For women of childbearing potential (WCBP): a negative serum beta-human chorionic gonadotropin (betahCG) pregnancy test must be performed during screening. (WCBP defined as a sexually mature woman who has not undergone surgical sterilization or who has not been naturally post-menopausal for at least 24 consecutive months [women =< 55 years] or 12 consecutive months [women > 55 years]).
- Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men must also refrain from donating sperm for a period of 90 days after the last dose of study drug.
- Male and female subjects who are not surgically sterile or postmenopausal must be willing to use medically acceptable methods of birth control from the first dose of study drug to 30 days after the last dose of study drug. Sexually active men, and women using oral contraceptive pills, should also use barrier contraception.
- Acceptable forms on contraception include the following: * Total abstinence from sexual intercourse as the preferred life style of the subject; periodic abstinence is not acceptable. * Surgically sterile partner(s); acceptable sterility surgeries are: vasectomy, bilateral tubal ligation, bilateral oophorectomy or hysterectomy. * Intrauterine device (IUD). * Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal jellies or cream AND a condom). * Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months prior to study drug administration.
- Subjects who have been previously treated for CLL or small lymphocytic leukemia (SLL), except with corticosteroids for symptom relief.
- Subjects who have received treatment with any of the following within 7 days prior to the first dose of study drug: * Steroid therapy for anti-neoplastic intent. * Moderate or strong cytochrome P450 3A (CYP3A) inhibitors. * Moderate or strong CYP3A inducers.
- Subject has known allergy to both xanthine oxidase inhibitors and/or rasburicase.
- Subject has a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease that in the opinion of the investigator would adversely affect his/her participating in this study.
- Subject has evidence of other clinically significant uncontrolled condition(s) including, but not limited to: * Uncontrolled and/or active systemic infection (viral, bacterial or fungal). * Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface [HBs] antigen negative-, anti-HBs antibody positive and anti-hepatitis B core [HBc] antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate.
- Subject is known to be positive for human immunodeficiency virus (HIV). (HIV testing is not required.)
- New York Heart Association (NYHA) class II-IV heart failure or arrhythmia requiring treatment.
- Pregnant or lactating women. Women and men of childbearing age should use effective contraception.
- Subject has a history of active malignancies other than CLL within the past 2 years prior to study entry with the exception of: adequately treated in situ carcinoma of the cervix uteri, adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin, or previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
- Subjects may receive intravenous immunoglobulin (IVIG) for hypogammaglobulinemia while on protocol. Subjects may receive erythropoietin, filgrastim, pegfilgrastim, or sargramostim while on protocol.
- Subject has malabsorption syndrome or other condition that precludes enteral route of administration.
- Subjects with known Richter’s syndrome or a history of Richter’s syndrome.
- Subjects who are actively being treated for a non-hematologic autoimmune disease, or are on other immunomodulatory agents (e.g. cyclosporine, tacrolimus, etc.) will be excluded.
- Subjects who have received an allogeneic stem cell transplant.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to BCL-2 inhibitors, bendamustine, or anti-CD20 monoclonal antibodies.
- Administration or consumption of any of the following within 3 days prior to the first dose of study drug: * Grapefruit or grapefruit products. * Seville oranges (including marmalade containing Seville oranges). * Star fruit.
I. Overall response rate (ORR) after the completion of all therapy, as defined by the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) guidelines update in 2008.
I. Proportion of patients who attain a complete response (CR), proportion of patients who attain a complete remission with incomplete marrow recovery (CRi), the proportion of patients with a partial response (PR).
II. Time to first response (starting from cycle 1 of bendamustine hydrochloride-rituximab [BR]), time to next treatment (TTNT; the number of days from the first cycle of BR to the next treatment program).
III. Duration of response (the number of days from first response to recurrence or progression of disease).
IV. Progression-free survival (PFS) (the number of days from cycle 1 of BR to progression of disease.
V. Proportion of patients who attain minimal residual disease (MRD)-negativity, and time to MRD-negativity.
Patients receive bendamustine hydrochloride intravenously (IV) on days 1-2 of cycles 1-3 and rituximab IV on day 1 or days 1-2 of cycles 1-3 and 5-10. Beginning cycle 4, patients also receive venetoclax orally (PO) once daily (QD). Treatment repeats every 28 days for up to 15 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 3 years.
Trial Phase Phase II
Trial Type Treatment
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
- Primary ID AAAR6357
- Secondary IDs NCI-2018-02230
- Clinicaltrials.gov ID NCT03609593