BRAZAN: A Randomized Phase 2 Study of Bendamustine, Rituximab, Cytarabine (AraC) Induction With Zanubrutinib (BRAZAN) Followed by Zanubrutinib/Rituximab +/- Sonrotoclax Maintenance in Treatment-Naïve Mantle Cell Lymphoma

NCT06854003 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 24-654
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 7

Brief Summary

This study aims to evaluate the efficacy and safety of an induction regimen combining Bendamustine, Rituximab, Cytarabine (AraC), and Zanubrutinib (BRAZAN), followed by maintenance therapy with Zanubrutinib and Rituximab with or without Sonrotoclax in participants with Mantle Cell Lymphoma (MCL). The names of the study drugs involved in this study are:

• bendamustine (a type of alkylating agent)
• rituximab (a type of monoclonal antibody)
• cytarabine (a type of antineoplastic)
• zanubrutinib (a type of kinase inhibitor)
• sonrotoclax (a type of BCL2 inhibitor)

Conditions

Mantle Cell Lymphoma; Lymphoma

Keywords

Mantle Cell Lymphoma; Lymphoma

Outcome Measures

Primary Outcomes (1)

• Complete Response Rate (CRR) after 1-year of Maintenance Treatment

  CRR after maintenance treatment is defined as the proportion of participants who experienced complete response (CR) with peripheral blood (PB) MRD-negativity after 1-year of maintenance therapy.

  Up to 125 weeks

Secondary Outcomes (40)

• Grade 4 Treatment-Related Toxicity Rate of zanubrutinib in combination with sonrotoclax and rituximab

  Up to 125 weeks

• Grade 4 Treatment-Related Toxicity Rate of zanubrutinib in combination with BR

  Up to 125 weeks

• Complete Response Rate (CRR) after Maintenance Treatment in doublet arm

  Up to 125 weeks

• Complete Response Rate (CRR) after Maintenance Treatment in triplet arm

  Up to 125 weeks

• Best Overall Response (BRR)

  Up to 125 weeks

Study Arms (4)

Induction Therapy (All Patients)

EXPERIMENTAL

Enrolled participants will complete: * Baseline visit with PET/CT, lymph node biopsy, and bone marrow biopsy * Cycles 1 through 3 (28-day cycles): * Days 1 - 28: Predetermined dose of Zanubrutinib 2x daily * Days 1 and 2: Predetermined dose of Bendamustine 1x daily * Day 1: Predetermined dose of Rituximab 1x daily * PET/CT scan * Cycles 4 through 6 (21-day cycles): * Day 1: Predetermined dose of Rituximab 1x daily * Days 1 and 2: Predetermined dose of Cytarabine 2x daily * PET/CT scan Participants without disease progression will proceed to randomization to either Arm A or Arm B for maintenance therapy.

Drug: Bendamustine; Drug: Rituximab; Drug: Cytarabine; Drug: Zanubrutinib

Maintenance Arm A: Zanubrutinib + Rituximab

EXPERIMENTAL

Following randomization participants with a complete response to induction therapy will complete: * Cycles 1 - 24 (28-day cycles): * Days 1 through 28: Predetermined dose of Zanubrutinib 2x daily * Day 1 every other cycle: Predetermined dose of Rituximab 1x daily * PET/CT on Cycles 7, 12, 19, and at end of treatment * Post-treatment follow up: every 6 months. PET/CT every 12 months

Drug: Rituximab; Drug: Zanubrutinib

Maintenance Arm B: Zanubrutinib + Rituximab + Sonrotoclax

EXPERIMENTAL

Following randomization participants with a complete response to induction therapy will complete: * Cycles 1 - 24 (28-day cycles): * Days 1 through 28: Predetermined dose of Zanubrutinib 2x daily * Days 1 through 28: Predetermined dose of Sonrotoclax 1x daily * Day 1 every other cycle: Predetermined dose of Rituximab 1x daily * PET/CT on Cycles 7, 12, 19, and at end of treatment * Post-treatment follow up: every 6 months. PET/CT every 12 months

Drug: Rituximab; Drug: Zanubrutinib; Drug: Sonrotoclax

Maintenance Arm B with Sonrotoclax Ramp-Up: Zanubrutinib + Rituximab + Sonrotoclax

EXPERIMENTAL

Following randomization participants with an incomplete response to induction therapy will require a ramp-up initiation of sonrotoclax and will complete: * Cycles 1 - 24 (28-day cycles): * Days 1 through 28: Predetermined dose of Zanubrutinib 2x daily * Days 1 through 28: Predetermined dose of Sonrotoclax 1x daily \*\*Cycles 1 and 2: Predetermined dose of Sonrotoclax 1x daily will be increased weekly. * Day 1 every other cycle: Predetermined dose of Rituximab 1x daily * PET/CT on Cycles 7, 12, 19, and at end of treatment * Post-treatment follow up: every 6 months. PET/CT every 12 months

Drug: Rituximab; Drug: Zanubrutinib; Drug: Sonrotoclax

Interventions

Bendamustine DRUG

An Alkylating agent, multi-dose vial, via intravenous (into the vein) infusion per institutional standard of care.

Also known as: Bendamustine hydrochloride, C16H21Cl2N3O2 · HCl, Bendeka

Induction Therapy (All Patients)

Rituximab DRUG

An Anti-CD20 antibody, single-use vials, via intravenous infusion per institutional standard of care.

Also known as: Riabni, Rituxan, Ruxience, Truxima, ABP 798, IDEC-C2B8, PF-05280586, MabThera

Induction Therapy (All Patients); Maintenance Arm A: Zanubrutinib + Rituximab; Maintenance Arm B with Sonrotoclax Ramp-Up: Zanubrutinib + Rituximab + Sonrotoclax; Maintenance Arm B: Zanubrutinib + Rituximab + Sonrotoclax

Cytarabine DRUG

An Antineoplastic, single dose vial via intravenous infusion per institutional standard of care.

Also known as: AraC

Induction Therapy (All Patients)

Zanubrutinib DRUG

A BTK inhibitor, capsule taken orally per protocol.

Also known as: Brukinsa, BGB-3111, C27H29N5O3

Induction Therapy (All Patients); Maintenance Arm A: Zanubrutinib + Rituximab; Maintenance Arm B with Sonrotoclax Ramp-Up: Zanubrutinib + Rituximab + Sonrotoclax; Maintenance Arm B: Zanubrutinib + Rituximab + Sonrotoclax

Sonrotoclax DRUG

A BCL 2 Protein Inhibitor, immediate release tablet, taken orally per protocol.

Also known as: BGB-11417

Maintenance Arm B with Sonrotoclax Ramp-Up: Zanubrutinib + Rituximab + Sonrotoclax; Maintenance Arm B: Zanubrutinib + Rituximab + Sonrotoclax

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed diagnosis of mantle cell lymphoma, with review of the diagnostic pathology specimen at one of the participating institutions. Whenever possible, the Ki67 fraction should be reported or evaluated, cytogenetics should be performed, and TP53 status should be assessed (preferably by next-generation sequencing; immunohistochemical staining would be next-preferred).
• No prior anti-lymphoma therapy, with the following exceptions:
• Prior radiotherapy for localized disease is permitted.
• A course of radiotherapy for urgent symptomatic disease is also permitted. Short-course systemic corticosteroids is permissible for disease control (must be \< 7 days and ≤ 100mg/day of prednisone or ≤ 20mg/day of dexamethasone, or equivalent). Steroids must be discontinued prior to study treatment.
• Measurable disease, defined as ≥1 measurable nodal lesion (long axis \>1.5 cm or short axis \>1.0 cm) or ≥1 measurable extra-nodal lesion (long axis \>1.0 cm) on PET, CT, or magnetic resonance imaging (MRI). Disease should be FDG-avid based on PET.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. (Appendix A)
• Age ≥18 years and considered a candidate for high-dose cytarabine by the treating physician.
• Adequate hematologic and organ function defined as:
• Absolute neutrophil count ≥ 1.0 x109/L, or ≥ 0.5 x109/L if bone marrow involvement (use of growth factor support allowed).
• Hemoglobin ≥ 8 g/dL and independent of transfusion within 7 days of screening.
• Platelets ≥ 100 x109/L, or ≥ 50 x109/L if bone marrow involvement, and independent of transfusion within 7 days of screening.
• Estimated CrCl ≥ 30mL/min (by Cockcroft-Gault formula or by 24-hour urine collection).
• AST/ALT \< 2.5 X institutional upper limit of normal (ULN), or \< 5.0 X institutional ULN if documented liver involvement of lymphoma.
• Total bilirubin \< 2.0 X ULN (unless active hemolysis); for subjects with Gilbert's Syndrome, direct bilirubin \< 1.5 X ULN.
• Patients with known infection with human immunodeficiency virus (HIV) are eligible, provided all 3 of the following are true: 1) presence of controlled disease, defined as CD4 count ≥ 200/uL and an undetectable viral load, 2) disease control has been stable on anti-retroviral therapy for at least 6 months prior to study enrollment, and 3) there are no prohibitive drug-drug interactions between study drugs and the necessary anti- retroviral therapies.

You may not qualify if:

• Known central nervous system involvement.
• Known active infection requiring systemic antimicrobial therapy at trial enrollment.
• Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia).
• Participants who require warfarin or other vitamin K antagonists for anticoagulation. Other anticoagulants including direct oral anticoagulants (i.e. apixaban, rivaroxaban) and low-molecular weight heparin are allowed.
• History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusions or other medical interventions.
• History of stroke or intracranial hemorrhage within 6 months of first dose of zanubrutinib.
• History of significant or life-threatening hemorrhage within 3 months of first dose of zanubrutinib.
• History of uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia, unless these conditions are related to the underlying malignancy.
• Active hepatitis C infection. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable (NOTE: the limit of detection for HCV RNA must have a sensitivity of \< 15 IU/mL). Subjects who received treatment for HCV that was intended to eradicate the virus and who have an undetectable HCV RNA may participate without serial HCV RNA screening. Other patients may participate if they are willing to undergo every 3- month monitoring for HCV reactivation.
• Active hepatitis B infection. Patients with positive hepatitis B serologies with undetectable HBV DNA (NOTE: the limit of detection for HBV DNA must have a sensitivity of \< 20 IU/mL) are permitted in the trial but should receive prophylactic antiviral therapy (i.e. entecavir) and undergo every 3 month HBV DNA monitoring.
• Prior history of another malignancy unless treated with curative intent and disease-free for at least 3 years at time of screening with expected low risk of recurrence during expected timeframe of study participation. Such patients should first be discussed with the Sponsor-Investigator. Additional exceptions: non-melanoma skin cancer, in situ cervical or breast cancer, or Gleason 6 prostate cancer managed with observation.
• Patients with the following cardiac conditions will be excluded:
• New York Heart Association Class III or IV heart failure.
• Myocardial infarction within 6 months of screening.
• Unstable angina within 3 months prior to screening.

Sponsors & Collaborators

• Christine Ryan: lead
• BeiGene: collaborator

Study Sites (7)

Mayo Clinic Arizona

Phoenix, Arizona, 85054, United States

NOT YET RECRUITING

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

RECRUITING

Brigham and Women's Hospital

Boston, Massachusetts, 02215, United States

ACTIVE NOT RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

RECRUITING

Mayo Clinic

Rochester, Minnesota, 55905, United States

NOT YET RECRUITING

Washington University

St Louis, Missouri, 63110, United States

RECRUITING

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

RECRUITING

MeSH Terms

Conditions

Lymphoma, Mantle-Cell; Lymphoma

Interventions

Bendamustine Hydrochloride; Rituximab; Cytarabine; zanubrutinib

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Christine Ryan, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Dana-Farber Cancer Institute Clinical Trials

CONTACT

877-DF-TRIAL (877-338-7425); DFCILymphomaResearchNurses@partners.org

Clare Phinney

CONTACT

clare_phinney@dfci.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor Investigator

Model Details: Induction therapy phase followed by randomized, maintenance therapy phase. Participants will be randomized to Arms A or B, but Arm B participants requiring ramp up for Sonrotoclax, will be placed in Arm B Ramp Up.

Study Record Dates

• First Submitted: February 25, 2025
• First Posted: March 3, 2025
• Study Start: April 22, 2025
• Primary Completion (Estimated): November 1, 2029
• Study Completion (Estimated): November 1, 2039
• Last Updated: February 20, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (7)