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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Mantle Cell Lymphoma
• Intervention / Treatment: Drug: Venetoclax; Drug: Bendamustine; Drug: Rituximab

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.

10/11/2021: Due to slower than anticipated enrollment, the study was redesigned to reflect the current historical complete response rate and with a lowered sample size for prompt primary endpoint readout.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Urbana, Illinois, United States, 61801
      • Carle Cancer Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Simon Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • St. Joseph Mercy Hospital Cancer Care Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine Siteman Cancer Center
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Cancer Institute
    • West Reading, Pennsylvania, United States, 19611
      • Reading Hospital/McGlinn Cancer Institute
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia Health System
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 58 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Fluorescence In Situ Hybridization (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.
• 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), 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Induction; Venetoclax, bendamustine and rituximab as induction therapy for 6 cycles of 28 days.

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: ABT-199; GDC-0199; 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 Names: 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: Rituxan; Chimeric anti-CD20 monoclonal antibody

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response (CR) Rate at End of Induction	Complete Response (CR) was assessed in accordance with the Lugano Classification Criteria using PET/CT scans (at baseline) and PET/CT or CT scans (during follow-up). Based on this criteria, a Deauville score ≤ 3 corresponds to a CR, a score of 4 or 5 and ≥ 50% decrease in the sum of lesion measurements corresponds to a Partial Response (PR), a score of 4 or 5 and <50% decrease in sum of lesion measurements corresponds to a Stable Disease (SD), a score of 4 or 5 and >1.5cm increase in a single lesion or presence of new lesions or bone marrow recurrence denotes Progressive Disease (PD).	Complete Response (CR) status was assessed after 6 months of induction treatment, plus an additional 2 months for end of treatment PET/CT scans.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v5.0	Number of participants with abnormal laboratory values and/or adverse events including Tumor Lysis Syndrome (TLS) were assessed using CTCAE v5.0. The adverse events were graded on a scale of 1 to 5 based on severity: grade 1 is mild, grade 2 is moderate, grade 3 is severe, grade 4 is life-threatening, and grade 5 resulted in death.	Adverse events were reported throughout 6 months of induction treatment and up to 2 months following completion of induction treatment
Overall Response	Objective response was assessed in accordance with the Lugano Classification Criteria using PET/CT scans (at baseline) and PET/CT or CT scans (during follow-up). Objective response is defined as the number of patients with a best treatment response of complete (CR) or partial response (PR).	Objective response was assessed after 6 months of induction treatment, plus an additional 2 months for end of treatment PET/CT scans.
Progression-Free Survival (PFS)	Progression-Free Survival (PFS) is a measure of patients that are alive and progression-free. Survival status is ascertained via direct contact and disease progression was assessed in accordance with the Lugano Classification Criteria using PET/CT scans (at baseline) and PET/CT or CT scans (during follow-up).	Progression-Free Survival (PFS) was assessed from the start to completion of induction treatment (6 months) through the completion of maintenance treatment (24 months) for up to 60 months of per-protocol study follow-up.
Overall Survival (OS)	Patients' survival status was measured by direct contact.	Overall survival (OS) was assessed from the start to completion of induction treatment (6 months) through the completion of maintenance treatment (24 months) for up to 60 months of per-protocol study follow-up.

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): January 13, 2020
• Primary Completion (Actual): October 20, 2022
• Study Completion (Estimated): November 1, 2024

Study Registration Dates

• First Submitted: February 6, 2019
• First Submitted That Met QC Criteria: February 6, 2019
• First Posted (Actual): February 8, 2019

Study Record Updates

• Last Update Posted (Actual): January 23, 2024
• Last Update Submitted That Met QC Criteria: January 2, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Rituximab; Venetoclax; Bendamustine; Bcl-2 Family Protein Inhibitor
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, Mantle-Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Venetoclax; Bendamustine Hydrochloride; Rituximab
• Other Study ID Numbers: PrE0405; ML40551 (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
• product manufactured in and exported from the U.S.: No