Clinical Trials /

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

NCT03609593

Description:

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.

Related Conditions:
  • Chronic Lymphocytic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Bendamustine/Rituximab Followed by Venetoclax and Rituximab for Treatment of Chronic Lymphocytic Leukemia
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: AAAR6357
  • NCT ID: NCT03609593

Conditions

  • Chronic Lymphocytic Leukemia

Interventions

DrugSynonymsArms
BendamustineTreandaBR followed by venetoclax and rituximab
VenetoclaxABT-199, VenclextaBR followed by venetoclax and rituximab
RituximabRituxanBR followed by venetoclax and rituximab

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
BR followed by venetoclax and rituximabExperimentalSubjects 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.
  • Bendamustine
  • Venetoclax
  • Rituximab

Eligibility Criteria

        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
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR) after the completion of all therapy
Time Frame:15 months
Safety Issue:
Description:Proportion of patients with reduction in tumor burden of a predefined amount

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Nicole Lamanna

Trial Keywords

  • Chronic Lymphocytic Leukemia (CLL)
  • Leukemia
  • Bendamustine
  • Rituximab
  • Venetoclax

Last Updated

November 13, 2019