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

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

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.

Study Overview

• Status: Completed
• Conditions: Follicular Lymphoma; Non-Hodgkin's Lymphoma Follicular; Non-Hodgkin's Lymphoma, Adult High Grade
• Intervention / Treatment: Drug: Induction Venetoclax; Drug: Maintenance Venetoclax

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.

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Sidney Kimmel Comprehensive Cancer Center at John Hopkins
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of Nj
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Gunderson Health System Cancer Center
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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: ABT-199; GDC-0199; 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: ABT-199; GDC-0199; RO5537382

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response (CR) at End of Induction	CR assessed in accordance with Lymphoma Response Criteria (Lugano Criteria)	After 6 cycles (at 28 days/cycle) of induction therapy.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	ORR assessed in accordance with Lymphoma Response Criteria (Lugano Criteria)	After 6 cycles (at 28 days/cycle) of induction therapy
Progression-Free Survival (PFS) in the Intent to Treat (ITT) Population.	PFS assessed in accordance with Lymphoma Response Criteria (Lugano Criteria)	Up to 24 months
Overall Survival (OS) in the ITT Population.	OS assessed in accordance with Lymphoma Response Criteria (Lugano Criteria)	Up to 24 months
Number of Participants With Treatment-related GRADE 3+ Adverse Events as Assessed by CTCAE V4.0	Number of participants with abnormal laboratory values and/or adverse events related to treatment of GRADE 3 or higher	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.
Patient Compliance in Receiving Induction Therapy	Off treatment Reasons	Up to 6 cycles (at 28 days/cycle)
Convert to CR During Maintenance Therapy (From PR in Induction)	Conversion to CR during Maintenance Therapy assessed in accordance with Lymphoma Response Criteria (Lugano Criteria)	Up to 24 cycles which corresponds to 22 months (at 28 days/cycle)

Collaborators and Investigators

• Sponsor: PrECOG, LLC.
• Collaborators: Genentech, Inc.
• Investigators: Study Chair: Craig Portell, MD, University of Virginia

Publications and helpful links

General Publications

• Portell CA, Jegede OA, Wagner-Johnston N, Nowakowski GS, Fletcher C, Cohen JB, Evens AM, Rosenstein LJ, Craig JW, Reddy N, Kahl BS. Phase II study of venetoclax added to bendamustine and obinutuzumab in patients with high-risk follicular lymphoma as front-line therapy: PrE0403. Blood Cancer J. 2025 May 12;15(1):93. doi: 10.1038/s41408-025-01300-1.

Study record dates

Study Major Dates

• Study Start (Actual): December 27, 2017
• Primary Completion (Actual): May 3, 2021
• Study Completion (Actual): January 6, 2023

Study Registration Dates

• First Submitted: April 10, 2017
• First Submitted That Met QC Criteria: April 10, 2017
• First Posted (Actual): April 13, 2017

Study Record Updates

• Last Update Posted (Actual): May 23, 2025
• Last Update Submitted That Met QC Criteria: May 14, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Venetoclax; Monoclonal Antibody; Obinutuzumab; Bendamustine; Bcl-2 Family Protein Inhibitor; High Tumor Burden Follicular Lymphoma
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, Follicular; Antineoplastic Agents; Venetoclax
• Other Study ID Numbers: PrE0403; ML39161 (Other Identifier: Genentech)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data is proprietary.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No