Clinical Trials /

Bendamustine, Obinutuzumab, and Venetoclax in Patients With Untreated Mantle Cell Lymphoma

NCT03872180

Description:

This phase II trial studies how well bendamustine, obinutuzumab, and venetoclax work in treating patients with mantle cell lymphoma. Drugs used in chemotherapy, such as bendamustine and venetoclax, 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. Immunotherapy with monoclonal antibodies, such as obinutuzumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving bendamustine, obinutuzumab, and venetoclax may work better in treating patients with mantle cell lymphoma.

Related Conditions:
  • Mantle Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Bendamustine, Obinutuzumab, and Venetoclax in Patients With Untreated Mantle Cell Lymphoma
  • Official Title: A Phase II Evaluation of Bendamustine, Obinutuzumab and Venetoclax in Patients With Untreated Mantle Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: IRB00102827
  • SECONDARY ID: NCI-2018-00995
  • SECONDARY ID: Winship4363-18
  • SECONDARY ID: ML40204
  • NCT ID: NCT03872180

Conditions

  • CCND1 Positive
  • Mantle Cell Lymphoma
  • t(11;14) Positive

Interventions

DrugSynonymsArms
BendamustineSDX-105Venetoclax, bendamustine, obinutuzumab
ObinutuzumabGA-101, Gazyva, RO5072759Venetoclax, bendamustine, obinutuzumab
VenetoclaxABT-199, GDC-0199, RG7601, Venclexta, RO5537382Venetoclax, bendamustine, obinutuzumab

Purpose

This phase II trial studies how well bendamustine, obinutuzumab, and venetoclax work in treating patients with mantle cell lymphoma. Drugs used in chemotherapy, such as bendamustine and venetoclax, 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. Immunotherapy with monoclonal antibodies, such as obinutuzumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving bendamustine, obinutuzumab, and venetoclax may work better in treating patients with mantle cell lymphoma.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To evaluate the efficacy of the combination of bendamustine, obinutuzumab and venetoclax
      in patients with untreated mantle cell lymphoma.

      SECONDARY OBJECTIVES:

      I. To evaluate the safety and dose intensity of the combination of bendamustine, obinutuzumab
      and venetoclax in untreated mantle cell lymphoma.

      II. To explore methods of determining molecular remission for patients with untreated mantle
      cell lymphoma (MCL).

      III. To evaluate long-term outcomes including progression-free and overall survival for
      patients with untreated MCL who receive the combination.

      OUTLINE:

      Patients receive venetoclax orally (PO) on days 1-28 of course 1 and days 1-10 of subsequent
      courses, bendamustine intravenously (IV) on days 1 and 2, and obinutuzumab IV on days 1, 8,
      and 15 of course 1 and day 1 of subsequent courses. Treatment repeats every 28 days for up to
      6 courses in the absence of disease progression or unaccepted toxicity.

      After completion of study treatment, patients are followed up at 45-60 days.
    

Trial Arms

NameTypeDescriptionInterventions
Venetoclax, bendamustine, obinutuzumabExperimentalPatients receive venetoclax PO on days 1-28 of course 1 and days 1-10 of subsequent courses, bendamustine IV on days 1 and 2, and obinutuzumab IV on days 1, 8, and 15 of course 1 and day 1 of subsequent courses. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unaccepted toxicity.
  • Bendamustine
  • Obinutuzumab
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Signed informed consent form

          -  Ability and willingness to comply with the requirements of the study protocol

          -  Histologic diagnosis of mantle cell lymphoma. This diagnosis must be confirmed at the
             treating center and patients must have this diagnosis confirmed by at least one of the
             following criteria:

               -  Fluorescent in situ hybridization (FISH) or conventional cytogenetics positive
                  for t(11;14)

               -  Cyclin D1 positive by immunohistochemistry

               -  Documentation by a hematopathologist at the treating institution that there is
                  pathologic evidence of mantle cell lymphoma if neither criteria above are met

          -  No previous therapy for diagnosis of lymphoma (note that in patients deemed to be
             high-risk for tumor lysis syndrome or for rapid clinical deterioration due to
             symptomatic disease by the investigator, a short course of steroids designed to
             decrease tumor burden is permitted)

          -  Eastern Cooperative Oncology Group performance status of 0, 1, or 2

          -  Hemoglobin ≥ 9 g/dL

          -  Absolute neutrophil count ≥ 1.5 x 10⁹/L

          -  Platelet count ≥ 75 x 10⁹/L

          -  Serum creatinine ≤ 2.0 mg/dL or creatinine clearance ≥ 40 mL/min

          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 x upper limit
             of normal (ULN)

          -  Total bilirubin < 1.5 x ULN (or ≤ 3 x ULN for patients with documented Gilbert
             syndrome)

               -  NOTE: Patients with renal or hepatic impairment that is disease-related (ie,
                  hydronephrosis, hepatic involvement) in the opinion of the investigator but who
                  meet all other eligibility criteria may be considered for enrollment in
                  consultation with the investigational new drug (IND) sponsor, Dr. Jonathon Cohen.
                  Documentation of prior adequate renal/hepatic function and clear association with
                  the disease will be required

          -  For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use a contraceptive method with a failure rate of < 1%
             per year during the treatment period and for at least 30 days after the last dose of
             venetoclax or 18 months after the last dose of obinutuzumab, whichever is longer

               -  A woman is considered to be of childbearing potential if she is postmenarcheal,
                  has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with
                  no identified cause other than menopause), and has not undergone surgical
                  sterilization (removal of ovaries and/or uterus)

               -  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

               -  The reliability of sexual abstinence should be evaluated in relation to the
                  duration of the clinical trial and the preferred and usual lifestyle of the
                  patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
                  postovulation methods) and withdrawal are not acceptable methods of contraception

          -  For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
             contraceptive measures, and agreement to refrain from donating sperm, as defined
             below:

               -  With female partners of childbearing potential, men 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 6
                  months after the last dose of obinutuzumab. Men must refrain from donating sperm
                  during this same period

               -  With pregnant female partners, men must remain abstinent or use a condom during
                  the treatment period and for at least 6 months after the last dose of
                  obinutuzumab to avoid exposing the embryo

               -  The reliability of sexual abstinence should be evaluated in relation to the
                  duration of the clinical trial and the preferred and usual lifestyle of the
                  patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
                  postovulation methods) and withdrawal are not acceptable methods of contraception

        Exclusion Criteria:

          -  History of other malignancy that could affect compliance with the protocol or
             interpretation of results

               -  Patients with a history of curatively treated basal or squamous cell carcinoma or
                  Stage 1 melanoma of the skin or in situ carcinoma of the cervix are eligible.

               -  Individuals in documented remission without treatment for ≥ 2 years prior to
                  enrollment may be included at the discretion of the investigator. Patients with
                  more recently treated low risk prostate cancer, thyroid cancer, or ductal
                  carcinoma in situ (DCIS) who are felt to be at low risk for progression and who
                  are not currently taking any chemotherapy, hormonal therapy or other anti-cancer
                  therapy are eligible. Patients who have been treated and been in remission for <
                  2 years must be cleared with the study chair prior to initiating study therapy

          -  Evidence of significant, uncontrolled concomitant diseases that could affect
             compliance with the protocol or interpretation of results or that could increase risk
             to the patient, including renal disease that would preclude chemotherapy
             administration

          -  Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
             (excluding fungal infections of nail beds) at study enrollment

          -  Requires the use of warfarin (because of potential drug-drug interactions that may
             potentially increase the exposure of warfarin)

          -  Received strong or moderate CYP3A inhibitors or inducers within 7 days of initiating
             venetoclax. Consumed grapefruit, grapefruit products, Seville oranges (including
             marmalade containing Seville oranges), or star fruit within 3 days prior to first dose
             of venetoclax

          -  Clinically significant history of liver disease, including viral or other hepatitis,
             current alcohol abuse, or cirrhosis

          -  Presence of positive test results for hepatitis B virus (HBV), hepatitis B surface
             antigen (HBsAg), or hepatitis C (HCV) antibody

               -  Patients who are positive for HCV antibody must be negative for HCV by polymerase
                  chain reaction (PCR) to be eligible for study participation

               -  Patients with occult or prior HBV infection (defined as positive total hepatitis
                  B core antibody [HBcAb] and negative HBsAg) may be included if HBV
                  deoxyribonucleic acid (DNA) is undetectable. These patients must be willing to
                  undergo monthly DNA testing and to remain on hepatitis B prophylaxis during
                  therapy

          -  Patients with human immunodeficiency virus (HIV) are eligible if they have a CD4 count
             > 400 and an undetectable viral load. They must be under the care of an infectious
             disease physician and have no history of an acquired immune deficiency syndrome
             (AIDS)-defining illness (except lymphoma)

          -  Receipt of live-virus vaccines within 28 days prior to the initiation of study
             treatment or need for live-virus vaccines at any time during study treatment

          -  Pregnant or lactating, or intending to become pregnant during the study

               -  Women of childbearing potential must have a negative serum pregnancy test result
                  within 21 days prior to initiation of study drug

          -  Recent major surgery (within 6 weeks prior to the start of cycle 1, day 1) other than
             for diagnosis or line placement

          -  Malabsorption syndrome or other condition that precludes enteral route of
             administration

          -  Known allergy to both xanthine oxidase inhibitors (ie, allopurinol) and rasburicase
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of complete response at completion of induction therapy with this combination
Time Frame:Up to 2.5 years from study start
Safety Issue:
Description:Response will be assessed by PET/CT imaging according to the Lugano Classification for response assessment in lymphoma, developed at the 2014 International Conference on Malignant Lymphoma.

Secondary Outcome Measures

Measure:Rate of minimal residual disease (MRD) negative complete response by ClonoSEQ mantle cell lymphoma (MCL) assay
Time Frame:Up to 7 years from study start
Safety Issue:
Description:MRD will be assessed by peripheral blood using the ClonoSEQ assay available from Adaptive Biotechnologies.
Measure:Overall response rate
Time Frame:Up to 7 years from study start
Safety Issue:
Description:Will be summarized descriptively.
Measure:Time to tumor progression
Time Frame:Up to 7 years from study start
Safety Issue:
Description:Will be summarized descriptively.
Measure:Progression free survival (PFS)
Time Frame:Up to 7 years from study start
Safety Issue:
Description:Will be described using the Kaplan-Meier methodology. Some patients may undergo consolidative autologous stem cell transplant without evidence of disease progression. This will not be counted against PFS.
Measure:Overall survival
Time Frame:Up to 7 years from study start
Safety Issue:
Description:Will be described using the Kaplan-Meier methodology.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Emory University

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