Trial Details
Trial status:
In set-up (funded)
Recruitment start date:
Chief Investigator:
Dr Toby Eyre
Recruitment target:
EudraCT number:
Contact details:
Lay summary:
Zanubrutinib plus rituximab (Zanu-R) as fixed duration, early intervention versus observation for patients with indolent mantle cell lymphoma: a randomised phase II clinical trial

ZEBRA is a phase II, multicentre, randomised open label study to assess the safety and efficacy of zanubrutinib in combination with rituximab for previously untreated indolent Mantle Cell lymphoma patients.

Patients will be randomised to (1:1) to ongoing observation (control arm: arm A) or fixed-duration zanubrutinib-rituximab (experimental arm: arm B)
  • Patients randomised to the control arm (Arm A) will receive the standard of care: ongoing active observation until clinical progression. Upon clinical progression patients will be treated as per standard of care
  • Patients randomised to the experimental arm (arm B) will receive zanubrutinib 160mg twice daily (BD), orally (PO) on days 1-28 and rituximab 375mg/m2 intravenously (IV)* on day 1 (+/- 3 days) of each 28-day cycle for up to six cycles
*If subcutaneous rituximab is administered the recommended dose is 1400mg
Key inclusion/exclusion criteria:

Inclusion criteria
1. 18 years of age or over
2. Life expectancy  6 months
3. 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
4. Stage II-IV MCL measurable by CT imaging or by white cell count (WCC)/BM infiltration
5. '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)
6. Eastern Cooperative Oncology Group (ECOG) Performance status 0-2
7. Absolute neutrophil count 1.0 x 109/L and platelets 75 x 109/L independent of growth factor support
8. AST and/or ALT 3 x upper limit of normal (ULN)
9. Total Bilirubin 1.5 x ULN unless due to Gilberts syndrome or of non-hepatic origin unless directly attributable to the patient's MCL
10. Calculated creatinine clearance 30mL/min. Glomerular filtration rate (GFR) 30mL/min directly measured with 24hr 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)
11. Able to give voluntary written informed consent
12. Willing and able to participate in all required evaluations and procedures in the study protocol including swallowing capsules without difficulty
13. Negative serum or urine pregnancy test for women of childbearing potential
14. Willing to comply with the contraceptive requirements of the trial

Exclusion criteria
1. Any prior therapy for MCL, including prior radiotherapy
2. Central nervous system (CNS) involvement for MCL
3. 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
4. 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)
5. No progression requiring treatment since initial diagnosis
6. Vaccinated with live vaccines (not including messenger ribonucleic acid (mRNA), viral vector or other non-live COVID19 vaccines) within four weeks prior to randomisation 
7. 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
8. 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
9. 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
10. Requirement for vitamin K antagonists (alternative anticoagulation is allowed (e.g. DOACS), but patients must be properly informed about the potential risk of bleeding under treatment with zanubrutinib).  Requires ongoing treatment with warfarin or warfarin derivatives
11. 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
12. Clinically significant cardiovascular disease such as uncontrolled arrhythmias, 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
13. History of stroke or intracranial haemorrhage within 6 months prior to randomisation
14. Any other severe medical or psychiatric illness that in the opinion of the investigator would interfere with participation in this clinical study
15. 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
16. Women who are pregnant or breastfeeding
17. Male participants with female partners of childbearing potential who are unwilling to use appropriate contraception methods
18. Concurrent treatment with another investigational agent
19. History of severe allergic or anaphylactic reactions to humanised or murine monoclonal antibodies, known sensitivity or allergy to murine products
20. Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial
21. Severe or debilitating pulmonary disease
22. Underlying medical conditions that, in the investigator's opinion, will render the administration of study drug hazardous or obscure the interpretation of toxicity of AEs
23. Concurrent participation in another therapeutic clinical trial
24. Active and/or ongoing autoimmune anaemia and/or autoimmune thrombocytopenia (e.g. idiopathic thrombocytopenia purpura)
Duration of recruitment: 2 years and 6 months
To investigate whether there is a benefit of giving earlier treatment of zanubrutinib and rituximab to patients with indolent mantle cell lymphoma compared to patients not being treated (watchful waiting) which is standard of care
Trial protocols
Trial protocols must not be applied to patients treated outside trials. UCL CTC can only ensure that approved trial investigators are provided with amendments to protocols.
No protocols have been currently made available for download
Trial documents
No documents have been currently made available for download
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