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Phase II Study of Bendamustine and Rituximab Plus Venetoclax in Untreated Mantle Cell Lymphoma Over 60 Years of Age (PrE0405)

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: NCT03834688
Recruitment Status : Recruiting
First Posted : February 8, 2019
Last Update Posted : June 25, 2021
Genentech, Inc.
Information provided by (Responsible Party):

Tracking Information
First Submitted Date  ICMJE February 6, 2019
First Posted Date  ICMJE February 8, 2019
Last Update Posted Date June 25, 2021
Actual Study Start Date  ICMJE January 13, 2020
Estimated Primary Completion Date March 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 6, 2019)
Complete Response (CR) rate at end of induction [ Time Frame: 30 months ]
CR assessed in accordance with Lymphoma Response Criteria (Cheson Criteria)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 6, 2019)
  • Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [ Time Frame: 60 months ]
    Number of participants with abnormal laboratory values and/or adverse events with particular attention to TLS related to treatment
  • Overall Response Rate (ORR) [ Time Frame: 60 months ]
    ORR assessed in accordance with Lymphoma Response Criteria (Cheson Criteria)
  • Progression-Free Survival (PFS) [ Time Frame: 60 months ]
    PFS assessed in accordance with Lymphoma Response Criteria (Cheson Criteria)
  • Overall Survival (OS) [ Time Frame: 60 months ]
    OS assessed in accordance with Lymphoma Response Criteria (Cheson Criteria)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Phase II Study of Bendamustine and Rituximab Plus Venetoclax in Untreated Mantle Cell Lymphoma Over 60 Years of Age
Official Title  ICMJE Phase II Study of Bendamustine and Rituximab Plus Venetoclax in Untreated Mantle Cell Lymphoma Over 60 Years of Age
Brief Summary

Eligible untreated patients will receive single arm venetoclax, bendamustine and rituximab as induction therapy. After 6 cycles, maintenance rituximab may be administered per physician discretion.

Venetoclax is an oral Bcl-2 family protein inhibitor. It targets the B-cell lymphoma 2 (BCL-2) protein, which supports cancer cell growth and is overexpressed in many patients with mantle cell lymphoma. Venetoclax may make the cancer cells sensitive to chemotherapy. This may help to slow down the growth of cancer or may cause cancer cells to die.

The purpose of this study is to see if venetoclax in combination with bendamustine and rituximab chemotherapy is effective in treating people who have mantle cell lymphoma and to examine the side effects, good and bad, associated with this combination.

Detailed Description

Mantle cell lymphoma (MCL) is a subtype of Non-Hodgkin Lymphoma (NHL) which is considered incurable with conventional therapy. With an incidence of approximately 70,000 cases diagnosed in the United States (US) per year, the disease is rare.

This is an open-label phase II study of venetoclax in combination with bendamustine and rituximab. Patients will receive induction therapy with venetoclax, bendamustine and rituximab for six cycles (1 cycle = 28 days). There will be an interim analysis after 19 patients are enrolled to evaluate for tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells which can lead to electrolyte and kidney problems.

Tumor assessments will be performed after Cycle 3-4 and at end of induction therapy.

Mandatory pre-treatment tumor tissue sample (i.e., obtained in the course of standard biopsy or surgery) will be required for research (if sufficient tissue is available).

Mandatory bone marrow aspirate (obtained in the course of standard biopsy) and peripheral blood sample will be collected at the end of treatment for Minimal Residual Disease (MRD). MRD measures the disease remaining after treatment. Optional peripheral blood samples will also be collected for future research.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
Open-Label, Single-Arm Study, Cycle 1 Dose Escalation
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Mantle Cell Lymphoma
Intervention  ICMJE
  • Drug: Venetoclax

    Cycle 1: Venetoclax by mouth daily. The dose will gradually increase during Cycle 1. (Day 1-7: 20 mg; Day 8-14: 50 mg; Day 15-21: 100 mg; Day 22-28: 200 mg.)

    Cycles 2-6: Venetoclax 400 mg by mouth daily on Days 1-10 (1 cycle = 28 days).

    Other Names:
    • GDC-0199
    • ABT-199
    • RO5537382
  • Drug: Bendamustine
    Cycle 1-6: Bendamustine 90 mg/m² intravenous (IV) on Days 1 and 2 of each cycle. Bendamustine may be started at 70 mg/m² in patients over the age of 75 years with comorbid conditions or patients over the age of 80 years without comorbid conditions.
    Other Name: Bendamustine hydrochloride
  • Drug: Rituximab
    Cycle 1-6: Rituximab 375 mg/m² IV on Day 1 of each cycle. After 2 consecutive cycles of Rituximab IV are well tolerated, Rituximab may be given subcutaneously.
    Other Names:
    • Chimeric anti-CD20 monoclonal antibody
    • Rituxan
Study Arms  ICMJE Experimental: Induction
Venetoclax, bendamustine and rituximab as induction therapy for 6 cycles of 28 days.
  • Drug: Venetoclax
  • Drug: Bendamustine
  • Drug: Rituximab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 6, 2019)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2025
Estimated Primary Completion Date March 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must have histologically confirmed (biopsy-proven) diagnosis of mantle cell lymphoma (MCL), with documented cyclin D1 (BCL1) expression by immunohistochemical stains and/or t(11;14) by cytogenetics or FISH.
  • Patients must have measurable or evaluable disease as defined as a lymph node measuring >1.5 cm in any dimension or splenomegaly with spleen >15 cm in craniocaudal dimension.
  • Age ≥ 60 years.
  • No intention to undergo consolidation with high dose chemotherapy and autologous stem cell rescue (Autologous Stem Cell Transplant) in first remission.
  • ECOG performance status of 0-2.
  • Ability to understand and willingness to sign Institutional Review Board (IRB)-approved informed consent.
  • Willing to provide mandatory tissue samples (if sufficient tissue available), bone marrow and blood samples for research purposes.
  • Adequate organ function as measured by the following criteria, obtained ≤ 2 weeks prior to registration:

    • Absolute Neutrophil Count (ANC) ≥ 1000/mm³
    • Hemoglobin ≥ 8 g/dL
    • Platelets ˃75,000/mm³
    • Creatinine clearance ≥ 40 mL/min, calculated with the use of 24-hour creatinine clearance or by Cockcroft-Gault formula
    • Total Bilirubin ≤ 1.5x Upper Limit of Normal (ULN) or ≤ 3x ULN for patients with documented Gilbert's syndrome
    • Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ≤ 2.5x ULN
  • All females of childbearing potential (not surgically sterilized and between menarche and 1 year post menopause) must have a blood test to rule out pregnancy within 2 weeks prior to registration.
  • Women must not be pregnant or breastfeeding. Females of childbearing potential who are sexually active with a non-sterilized male partner and sexually active men must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) prior to study entry, for the duration of study participation, and for 12 months after last dose of therapy. Method of contraception must be documented.
  • Patients should not have prior chemotherapy, radiotherapy or immunotherapy for lymphoma.
  • Patients must have no recent (<1 year) history of malignancy except for the following:

    • adequately treated non-melanoma skin cancer
    • adequately treated Stage I melanoma of the skin
    • in situ cervical cancer
    • low grade prostate adenocarcinoma (Gleason grade ≤ 6) managed with observation and stable for 6 months.
  • Patients should not have known evidence of central nervous system (CNS) lymphoma.
  • Patients must not have received a prior allogeneic stem cell transplant or solid organ transplant (except for cornea) for any indication.
  • Patients must have no active, uncontrolled infections.
  • Patients must not have active hepatitis B or be chronic carriers of hepatitis B. This is defined as patients with hepatitis B surface antigen (HBsAg) positive. Patients with prior exposure to hepatitis B (hepatitis B core antibody (anti-HBc) positive AND HBsAg negative) are allowed with a protective level hepatitis B surface antibody AND a negative hepatitis B viral load by polymerase-chain reaction (PCR).
  • Patients must not have active hepatitis C (HCV) as defined by a hepatitis C viral load detectable by PCR. Patients with a negative HCV antibody are assumed to have a negative HCV viral load. Patients with a positive HCV antibody must have a negative hepatitis C viral load by PCR. Prior treatment for an active HCV infection will be allowed as long as the hepatitis C viral load by PCR is negative.
  • Patients must not have known active Human Immunodeficiency Virus (HIV). Testing not required in absence of clinical suspicion.
  • Patients must not have evidence of significant, uncontrolled concomitant diseases, including psychiatric diseases, that could affect compliance with the protocol or interpretation of results or that could increase risk to the patient.
  • Patients must not have conditions that preclude oral administration or absorption of medications through the GI tract, including but not limited to the inability to swallow pills or malabsorption syndromes.
  • Patients must not have known allergies to both xanthine oxidase inhibitors and rasburicase.
  • Patients must not require the use of warfarin. Blood thinners of other classes are permitted.
  • Patient may not receive the following agents within 7 days prior to the first dose of venetoclax:

    • Strong and moderate CYP3A inhibitors
    • Strong and moderate CYP3A inducers
    • Strong and moderate P-gp inhibitors
  • Patients must not have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of venetoclax.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 60 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Carolyn Andrews, RN 267-207-4070
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03834688
Other Study ID Numbers  ICMJE PrE0405
ML40551 ( Other Identifier: Genentech )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Data is proprietary
Responsible Party PrECOG, LLC.
Study Sponsor  ICMJE PrECOG, LLC.
Collaborators  ICMJE Genentech, Inc.
Investigators  ICMJE
Study Chair: Craig Portell, MD University of Virginia
PRS Account PrECOG, LLC.
Verification Date June 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP