Zanubrutinib Plus Rituximab for Patients With Indolent Mantle Cell Lymphoma

NCT05635162 | Recruiting Phase 2 DMC

• 1 other identifier: UCL 146660
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 13

Brief Summary

Phase II, multicentre, randomised, open-label study to assess the benefit of early intervention with fixed duration, time-limited zanubrutinib-rituximab in indolent mantle cell lymphoma (MCL)

Conditions

Mantle Cell Lymphoma

Outcome Measures

Primary Outcomes (1)

• Event free survival

  To determine the effect of fixed-duration Zanu-R on Event-free survival (EFS) compared to active observation

  From date of randomisation until whichever comes first: occurrence of active disease, new MCL treatment or death (any cause) up to 60 months

Secondary Outcomes (7)

• Progression free survival

  Randomisation until disease progression up to 60 months

• Overall survival

  Randomisation until date of death up to 60 months

• Time to next treatment

  Randomisation until date of initiation of subsequent treatment up to 60 months

• Time to second progression

  From date of randomisation or date of first progression until date of second progression or death from any cause up to 60 months

• Overall response rate to Zanu-R

  From start of treatment until 24 weeks post administration of Zanu-R

Study Arms (2)

Arm A: Control

NO INTERVENTION

Active observation

Arm B: Experimental

EXPERIMENTAL

Time limited Zanubrutinib-R 6 x 28 day cycles

Drug: Zanubrutinib; Drug: Rituximab

Interventions

Zanubrutinib DRUG

Zanubrutinib dose is 160 mg twice daily (BD) orally (PO) on days 1-28 of each 28-day cycle.

Arm B: Experimental

Rituximab DRUG

Rituximab 375 mg/m2 intravenous (IV)\* on day 1 (+/-3 days) of each 28-day cycle

Arm B: Experimental

Eligibility Criteria

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

You may qualify if:

• years of age or over.
• Life expectancy ≥ 6 months.
• Pathologically confirmed MCL, with documentation of monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1, D2 or D3.
• Stage II-IV MCL measurable by CT imaging or by white cell count (WCC)/BM infiltration.
• 'Indolent' MCL, defined as 1 or more of the following:
• Observation with no treatment for a minimum of 6 months after the initial diagnosis
• Leukaemic non-nodal variant (lymphocytosis/splenomegaly only without nodal involvement)
• Low tumour volume (largest lymph node ≤ 3cm in maximal diameter), proliferation fraction (Ki67 or equivalent) ≤30% and classical morphology (non-blastoid/pleomorphic)
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2.
• Absolute neutrophil count ≥1.0 x 109/L and platelets ≥75 x 109/L independent of growth factor support.
• AST and/or ALT ≤3 x upper limit of normal (ULN).
• Total Bilirubin ≤1.5 x ULN unless due to Gilberts syndrome or of non-hepatic origin unless directly attributable to the patient's MCL.
• Calculated creatinine clearance ≥30 mL/min. Glomerular filtration rate (GFR) ≥30 mL/min directly measured with 24 hour urine collection, or creatinine clearance calculated according to the modified formula of Cockcroft and Gault (for men: GFR ≈ ((140 - age) x bodyweight)/ (72 x creatinine), for women x 0, 85).
• Able to give voluntary written informed consent.
• Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.

You may not qualify if:

• Any prior therapy for MCL, including prior radiotherapy.
• Central nervous system (CNS) involvement of MCL.
• Uncontrolled infection with HIV or any uncontrolled active systemic infection (e.g., bacterial, viral or fungal). Patients with well-controlled HIV status (undetectable viral load) will not be excluded.
• Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HB core) positive and who are surface antigen (HBsAg) negative will need to have a negative polymerase chain reaction (PCR) test. Those who are hepatitis B HbsAg positive or hepatitis B PCR positive will be excluded. Those who are hepatitis C antibody and PCR positive will be excluded (those who are hepatitis C antibody positive and PCR negative will not be excluded).
• No progression requiring treatment since initial diagnosis.
• Vaccinated with live vaccines (not including messenger ribonucleic acid (mRNA), viral vector or other non-live COVID19 vaccines) within four weeks prior to randomisation.
• Major surgical procedure within 28 days prior to randomisation. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
• Prior malignancy (or any other malignancy requiring active treatment), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, localised prostate cancer or other cancer from which the subject has been disease free for ≥ 2 years or which will not limit survival to \< 5 years.
• Requirement for moderate or strong CYP3A inducers. Moderate and strong CYP3A inhibitors are allowed although these should be switched to agents causing less CYP3A inhibition where possible.
• Requirement for vitamin K antagonists (alternative anticoagulation is allowed (e.g. DOACs), but patients must be properly informed about the potential risk of bleeding alongside zanubrutinib). Requires ongoing treatment with warfarin or warfarin derivatives
• Active bleeding or history of bleeding diathesis (e.g. haemophilia or von Willebrand disease) or history of spontaneous bleeding requiring blood transfusion or other medical intervention.
• Clinically significant cardiovascular disease such as uncontrolled arrhythmias, or history of ventricular tachycardia, ventricular fibrillation, torsades de points or myocardial infarction within 6 months of randomisation, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association (NYHA) Functional Classification, or corrected QT interval (QTc) \> 480 msec, second-degree atrioventricular block Type II, third-degree atrioventricular block at randomisation, unstable angina within 3 months prior to randomisation.
• History of stroke or intracranial haemorrhage within 6 months prior to randomisation.
• Any other severe medical or psychiatric illness that in the opinion of the investigator would interfere with participation in this clinical study.
• Malabsorption syndrome, unable to swallow capsules, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.

Sponsors & Collaborators

• University College, London: lead
• BeiGene: collaborator

Study Sites (13)

Royal Derby Hospital

Derby, United Kingdom

RECRUITING

Beatson West of Scotland Cancer Centre

Glasgow, United Kingdom

RECRUITING

Clatterbridge Cancer Centre

Liverpool, United Kingdom

RECRUITING

Guy's Hospital

London, United Kingdom

RECRUITING

St Bartholomew's Hospital

London, United Kingdom

RECRUITING

University College London Hospital

London, United Kingdom

RECRUITING

Christie Hospital

Manchester, United Kingdom

RECRUITING

Norfolk and Norwich University Hospitl

Norwich, United Kingdom

RECRUITING

Nottingham City Hospital

Nottingham, United Kingdom

RECRUITING

Churchill Hospital

Oxford, United Kingdom

RECRUITING

Derriford Hospital

Plymouth, United Kingdom

RECRUITING

Southampton General Hospital

Southampton, United Kingdom

RECRUITING

Royal Cornwall Hospital

Truro, United Kingdom

RECRUITING

MeSH Terms

Conditions

Lymphoma, Mantle-Cell

Interventions

zanubrutinib; Rituximab

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Central Study Contacts

ZEBRA Trial Manager

CONTACT

(+44) (0)2076799860; ctc.zebra@ucl.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomised

Study Record Dates

• First Submitted: October 31, 2022
• First Posted: December 2, 2022
• Study Start: May 17, 2024
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): October 1, 2028
• Last Updated: April 16, 2025

Record last verified: 2025-04

Locations

GB (13)