Don't get left behind! The modernized is coming. Check it out now.
Say goodbye to!
The new site is coming soon - go to the modernized
Working… Menu

Phase II Venetoclax, Obinutuzumab and Bendamustine in High Tumor Burden Follicular Lymphoma as Front Line Therapy (PrE0403)

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. Read our disclaimer for details. Identifier: NCT03113422
Recruitment Status : Completed
First Posted : April 13, 2017
Results First Posted : July 18, 2022
Last Update Posted : March 28, 2023
Genentech, Inc.
Information provided by (Responsible Party):

Brief Summary:

Patients with high tumor burden, low grade follicular lymphoma that has never been treated, will receive venetoclax in combination with obinutuzumab and bendamustine.

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 follicular lymphoma. Venetoclax may help to slow down the growth of cancer or may cause cancer cells to die.

The purpose of this study is to see whether adding venetoclax to obinutuzumab and bendamustine improves the response (the tumor shrinks or disappears) in patients with follicular lymphoma.

As of 9/5/2018, a higher than expected incidence of tumor lysis syndrome (TLS) was experienced among patients receiving venetoclax, obinutuzumab and bendamustine on Cycle 1, Day 1 of treatment. TLS is caused by the fast breakdown of cancer cells. These patients developed an increase in some of their blood tests (uric acid, phosphorus, potassium and/or creatinine). They received a medication called rasburicase and continued with treatment. It is unclear if the TLS was due to the venetoclax or the standard treatment of obinutuzumab and bendamustine. For the remaining patients, venetoclax will start on Cycle 2, Day 1 (previously Cycle 1, Day 1).

As of 9/16/2021, additional maintenance therapy has been suspended for those patients who remain on study. These patients will not receive any further treatment and will move on to the two year survival follow-up.

Condition or disease Intervention/treatment Phase
Follicular Lymphoma Non-Hodgkin's Lymphoma Follicular Non-Hodgkin's Lymphoma, Adult High Grade Drug: Induction Venetoclax Drug: Maintenance Venetoclax Phase 2

Detailed Description:

Follicular lymphoma (FL) is the most common low grade lymphoma comprising 70% of low-grade non-Hodgkin's lymphoma (NHL) and 22% of all cases of NHL. The survival rates for patients with indolent NHL remained unchanged from the 1950s through the early 1990s, but recent evidence suggests that outcomes continue to improve. High-risk patients with FL, defined as having advanced stage and high tumor burden have significantly shorter progression free survival despite significant advances.

This is an open-label phase II study of venetoclax in combination with obinutuzumab and bendamustine. Patients will receive induction therapy with obinutuzumab and bendamustine for six cycles (1 cycle = 28 days). Venetoclax will start with 2nd cycle of induction therapy (previously started with cycle 1). There will be a formal, detailed toxicity evaluation after 21 patients complete 3 cycles of treatment.

Patients who achieve partial response or stable disease will receive therapy with obinutuzumab every 2 months for 12 cycles and venetoclax every month for 24 cycles. Patients who achieve a complete response will receive obinutuzumab every 2 months for 12 cycles. Patients with progressive disease will not continue onto the maintenance arm.

Tumor assessments will be performed approximately every 12 weeks during induction and every 6 months during maintenance therapy.

Mandatory pre-treatment tumor tissue sample (i.e., obtained during a previous procedure or biopsy) will be required for research (if sufficient tissue is available). Optional tumor biopsy samples obtained during treatment or post-treatment will also be requested for research.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 56 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of Venetoclax (ABT-199/GDC-0199) in Combination With Obinutuzumab and Bendamustine in Patients With High Tumor Burden Follicular Lymphoma as Front Line Therapy
Actual Study Start Date : December 27, 2017
Actual Primary Completion Date : May 3, 2021
Actual Study Completion Date : January 6, 2023

Arm Intervention/treatment
Experimental: Induction Venetoclax
Cycle 1-6: Obinutuzumab intravenously (IV) and bendamustine IV. Cycle 2-6: Venetoclax (oral)
Drug: Induction Venetoclax

1 cycle = 28 days.

  • Cycle 1-6: Obinutuzumab IV. Cycle 1, Day 1 obinutuzumab 100 mg and Cycle 1, Day 2 obinutuzumab 900 mg for total dose of 1000 mg. On Cycle 1, Day 8 and Day 15 obinutuzumab 1000 mg. Starting with Cycle 2, obinutuzumab 1000 mg on Day 1 only of each cycle.
  • Cycle 1-6: Bendamustine 90 mg/m² IV on Days 1 and 2 of each cycle over 15 minutes after obinutuzumab.
  • Cycle 2-6: Venetoclax 800 mg by mouth daily on Days 1-10 administered before obinutuzumab and/or bendamustine.
Other Names:
  • GDC-0199
  • ABT-199
  • RO5537382

Experimental: Maintenance Venetoclax
Patients with stable or improved disease will receive venetoclax by mouth daily for 24 cycles (1 cycle=1 month) and obinutuzumab IV every 2 months for 12 cycles. Patients with no evidence of disease will receive obinutuzumab IV every 2 months for 12 cycles.
Drug: Maintenance Venetoclax
Patients whose disease is the same or improved will receive venetoclax 800 mg by mouth daily for 24 cycles (1 cycle=1 month) and obinutuzumab 1000 mg IV every 2 months for 12 cycles. Patients with no evidence of disease will receive obinutuzumab 1000 mg IV every 2 months for 12 cycles.
Other Names:
  • GDC-0199
  • ABT-199
  • RO5537382

Primary Outcome Measures :
  1. Complete Response (CR) at End of Induction [ Time Frame: After 6 cycles (at 28 days/cycle) of induction therapy. ]
    CR assessed in accordance with Lymphoma Response Criteria (Lugano Criteria)

Secondary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: After 6 cycles (at 28 days/cycle) of induction therapy ]
    ORR assessed in accordance with Lymphoma Response Criteria (Lugano Criteria)

  2. Convert to CR During Maintenance Therapy [ Time Frame: Up to 24 cycles which corresponds to 22 months (at 28 days/cycle) ]
    Conversion to CR during Maintenance Therapy assessed in accordance with Lymphoma Response Criteria (Lugano Criteria)

  3. Progression-Free Survival (PFS) in the Intent to Treat (ITT) Population. [ Time Frame: Up to 24 months ]
    PFS assessed in accordance with Lymphoma Response Criteria (Lugano Criteria)

  4. Overall Survival (OS) in the ITT Population. [ Time Frame: Up to 24 months ]
    OS assessed in accordance with Lymphoma Response Criteria (Lugano Criteria)

  5. Number of Participants With Treatment-related GRADE 3+ Adverse Events as Assessed by CTCAE V4.0 [ Time Frame: Adverse events were captured through 6 cycles of therapy (at 28 days/cycle) and for 30 days after the last dose, for a total assessment period of approximately 7 months. ]
    Number of participants with abnormal laboratory values and/or adverse events related to treatment of GRADE 3 or higher

  6. Patient Compliance in Receiving Induction Therapy [ Time Frame: Up to 6 cycles (at 28 days/cycle) ]
    Off treatment Reasons

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
  • Patient must have a histologically confirmed (biopsy-proven) diagnosis of follicular B-cell non-Hodgkin lymphoma (WHO classification: follicular center grades 1, 2, and 3a [3b patients are not eligible]), with no evidence of transformation to large cell histology.
  • Patient must meet criteria for High Tumor Burden (higher risk) as defined by either the Groupe D'Etude des Lymphomes Follicularies (GELF) criteria [at least one criterion] OR the follicular lymphoma international prognostic index (FLIPI) [score of 3, 4, or 5].
  • Patient must have Stage II, III or IV disease.
  • Baseline measurements and evaluations (PET/ CT) must be obtained within 10 weeks of randomization to the study. Patient must have at least one objective measurable disease parameter.
  • Age ≥ 18 years.
  • Eastern Cooperative Oncology Group (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) for research purposes.
  • Adequate organ function as measured by the following criteria:

    • Absolute Neutrophil Count (ANC) ≥ 1000/mm³
    • Hemoglobin ≥ 8 g/dL
    • Platelets ˃75,000/mm³
    • Creatinine clearance ≥ 50 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
    • Alkaline Phosphatase <5x ULN
  • All females of childbearing potential (not surgically sterilized and between menarche and 1 year post menopause) must have a blood or urine test to rule out pregnancy within 2 weeks prior to registration.
  • Women must not be pregnant or breastfeeding.
  • Patient must have had no prior chemotherapy, radiotherapy or immunotherapy for lymphoma. For purposes of this trial, prednisone or other corticosteroids used for non-lymphomatous conditions will not be considered as prior chemotherapy. In addition, a prior/recent short course (<2 weeks) of steroids for symptom relief of lymphoma-related symptoms will not make a patient ineligible.
  • Patient must have no recent history of malignancy except for adequately treated basal cell or squamous cell skin cancer, Stage I melanoma of the skin, or in situ cervical cancer. Individuals in documented remission without treatment for ≥ 2 years prior to enrollment may be included at the discretion of the investigator.
  • Patient must have no active, uncontrolled infections.
  • Patients must be tested for hepatitis B virus (HBV), hepatitis B surface antigen (HBsAg+) and hepatitis C (HCV) antibody within 6 weeks of registration. Patients who are chronic carriers of HBV with positive HBsAg+ and positive HCV serology are excluded, as chemotherapy and B-cell depleting therapy have been associated with virus reactivation and fulminant hepatitis. NOTE: Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) may be included if HBV DNA is undetectable. If enrolled, patients must be willing to undergo monthly HBV DNA testing. Patients with positive HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation.
  • HIV positive patients are not excluded, but to enroll, must meet all of the below criteria:

    • HIV is sensitive to antiretroviral therapy.
    • Must be willing to take effective antiretroviral therapy if indicated.
    • No history of CD4 prior to or at the time of lymphoma diagnosis <300 cells/mm³.
    • No history of AIDS-defining conditions.
    • If on antiretroviral therapy, must not be taking zidovudine or stavudine.
    • Must be willing to take prophylaxis for Pneumocystis jiroveci pneumonia during therapy and until at least 2 months following the completion of therapy or until the CD4 cells recover to over 250 cells/mm³, whichever occurs later.
  • 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.
  • No major surgery within 2 weeks prior to cycle 1, other than for diagnosis.
  • A condition that precludes oral route of administration (venetoclax).
  • No known allergies to both xanthine oxidase inhibitors and rasburicase.
  • Patient must not require the use of warfarin (because of potential drug-drug interactions that may potentially increase the exposure 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
    • Consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of venetoclax.
  • Patient must not have serious medical or psychiatric illness likely to interfere with participation in this clinical study.

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): NCT03113422

Layout table for location information
United States, Georgia
Winship Cancer Institute of Emory University
Atlanta, Georgia, United States, 30322
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at John Hopkins
Baltimore, Maryland, United States, 21205
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New Jersey
Rutgers Cancer Institute of NJ
New Brunswick, New Jersey, United States, 08903
United States, Pennsylvania
Fox Chase
Philadelphia, Pennsylvania, United States, 19111
United States, Tennessee
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37232
United States, Virginia
University of Virginia
Charlottesville, Virginia, United States, 22908
United States, Wisconsin
Gunderson Health System Cancer Center
La Crosse, Wisconsin, United States, 54601
University of Wisconsin
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
Genentech, Inc.
Layout table for investigator information
Study Chair: Craig Portell, MD University of Virginia
  Study Documents (Full-Text)

Documents provided by PrECOG, LLC.:
Study Protocol  [PDF] October 15, 2021
Statistical Analysis Plan  [PDF] August 13, 2018

Layout table for additonal information
Responsible Party: PrECOG, LLC. Identifier: NCT03113422    
Other Study ID Numbers: PrE0403
ML39161 ( Other Identifier: Genentech )
First Posted: April 13, 2017    Key Record Dates
Results First Posted: July 18, 2022
Last Update Posted: March 28, 2023
Last Verified: February 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Data is proprietary.

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by PrECOG, LLC.:
High Tumor Burden Follicular Lymphoma
Bcl-2 Family Protein Inhibitor
Monoclonal Antibody
Additional relevant MeSH terms:
Layout table for MeSH terms
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Antineoplastic Agents