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Bendamustine/Rituximab Followed by Venetoclax and Rituximab for Treatment of Chronic Lymphocytic Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03609593
Recruitment Status : Recruiting
First Posted : August 1, 2018
Last Update Posted : November 15, 2019
Information provided by (Responsible Party):
Nicole Lamanna, Columbia University

Brief Summary:
The purpose of this study is to determine the efficacy of bendamustine and rituximab (BR) followed by venetoclax for 12 months. The total time on therapy is 15 months. Bendamustine and rituximab is a commonly used treatment for CLL. Venetoclax is an oral drug that blocks a protein called BCL-2 which is present on CLL cells. It is approved for patients with relapsed (the cancer has come back) or refractory (the cancer did not respond) CLL who harbor a deletion in the short arm of chromosome 17 [del(17p)]. When this drug is used by itself, many patients needed to be admitted to the hospital to monitor for a complication known as tumor lysis syndrome. This is an oncologic emergency that is caused by massive destruction of tumor cells with the release of large amounts of electrolytes and other molecules into the blood that can lead to renal failure and potentially death.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Drug: Bendamustine Drug: Venetoclax Drug: Rituximab Phase 2

Detailed Description:
This is a single-center phase II study using bendamustine-rituximab (BR) followed by venetoclax and rituximab for the upfront treatment of chronic lymphocytic leukemia (CLL). The activity, safety, and survival data have been presented previously for BR alone in patients with previously untreated disease and venetoclax alone in relapsed/refractory patients and those with high-risk disease. After pretreatment evaluation, patients will receive three cycles of BR followed by venetoclax via a five-week dose escalation to 400 mg daily. Once patients reach 400 mg of venetoclax daily, patients will receive six cycles (months) of rituximab as consolidation. Total time of venetoclax therapy will be 12 months and total time on therapy (BR plus venetoclax plus rituximab) will be 15 months. Responses and endpoints will be assessed after 3, 6, 9 (laboratory only), 12, 18, 24, 30, and 36 cycles. Minimal residual disease (MRD) testing will be done after 3, 6, 9, 12, 18, and 24 cycles via an 8-color flow cytometry panel. Bone marrow testing for MRD can be performed if the peripheral blood is MRD negative (or was MRD negative at the last test). Anti-infective prophylaxis against H. zoster and P. jiroveci will be mandated. Tumor lysis syndrome (TLS) prophylaxis with allopurinol and/or an alternative will be mandated.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Single-arm, Multi-center Phase II Trial of Bendamustine/Rituximab Induction Followed by Venetoclax and Rituximab Consolidation for the Frontline Treatment of Chronic Lymphocytic Leukemia (CLL)
Actual Study Start Date : November 12, 2018
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2025

Arm Intervention/treatment
Experimental: BR followed by venetoclax and rituximab
Subjects will be on Bendamustine 50-90 mg/m2 on days 1-2 for three cycles with each cycle being 28 days, and Rituximab 375 mg/m2 on day 1 or days 1-2 for three cycles with each cycle being 28 days. Venetoclax will then be started in a step-wise fashion per the package insert.
Drug: Bendamustine
Subjects will receive Bendamustine 50-90 mg/m2 on days 1-2 for three cycles with each cycle being 28 days.
Other Name: Treanda

Drug: Venetoclax

Venetoclax: 12 cycles

Venetoclax will then be started after 3 cycles of BR. Dosing for venetoclax will be in a step wise fashion as follows:

  • Cycle 4 days 1-7 (Week 1): 20 mg once daily
  • Cycle 4 days 8-14 (Week 2): 50 mg once daily
  • Cycle 4 days 15-21 (Week 3): 100 mg once daily
  • Cycle 4 days 22-28 (Week 4): 200 mg once daily
  • Cycle 4 day 29 and thereafter (Week 5 and on): 400 mg once daily; continue until disease progression, unacceptable toxicity, or 12 cycles duration.
Other Names:
  • ABT-199
  • Venclexta

Drug: Rituximab
For cycles 1 through 3, subjects will receive BR on days 1 and 2. For cycles 5-10, subjects will receive rituximab monotherapy at 375 mg/m2 (cycle 5) or rituximab at 500 mg/m2 (cycles 6-10) on day 1 (or days 1 and 2 if split-dose).
Other Name: Rituxan

Primary Outcome Measures :
  1. Overall response rate (ORR) after the completion of all therapy [ Time Frame: 15 months ]
    Proportion of patients with reduction in tumor burden of a predefined amount

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Age ≥ 18 years of age.
  • Diagnosed with CLL
  • 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.
  • Histologic and immunophenotypic analysis should demonstrate small to moderate size lymphocytes with flow cytometry demonstrating a certain population of lymphocytes.
  • No prior therapy for their disease. Topical or inhaled corticosteroids are permitted for other medical conditions, ie asthma or dermatologic reasons.
  • Eastern Oncology Cooperative Group (ECOG) performance score of ≤ 2.
  • Subjects with autoimmune hemolytic anemia or autoimmune thrombocytopenia will be eligible for treatment on this protocol regardless of disease stage upon discussion with the principal investigator.
  • An absolute neutrophil count > 1.0 109/L; hemoglobin > 8 g/dL; or a platelet count > 50 x 109/L (unless due to bone marrow failure).
  • Adequate hepatic function
  • activated partial thromboplastin time (aPTT) and prothrombin time (PT) not to exceed 1.5x the upper limit of reference ranges.
  • Ability to understand and the willingness to sign a written informed consent document.
  • 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 β-human chorionic gonadotropin (βhCG) pregnancy test must be performed within 1 week before randomization (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]).
    • 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.

Exclusion Criteria:

  • Subjects who have been previously treated for CLL or small lymphocytic lymphoma (SLL), except with corticosteroids for symptom relief.
  • 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:

    1. Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
    2. 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 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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03609593

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Contact: Lisa Olmos, RN 212-342-5162
Contact: Hanna Weissbrot (212) 304-5558

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United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Sponsors and Collaborators
Nicole Lamanna
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Principal Investigator: Nicole Lamanna, MD Columbia University
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Responsible Party: Nicole Lamanna, Associate Clinical Professor of Medicine, Columbia University Identifier: NCT03609593    
Other Study ID Numbers: AAAR6357
First Posted: August 1, 2018    Key Record Dates
Last Update Posted: November 15, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Nicole Lamanna, Columbia University:
Chronic Lymphocytic Leukemia (CLL)
Additional relevant MeSH terms:
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Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Bendamustine Hydrochloride
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action