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Zanubrutinib Plus Rituximab for Patients With Indolent Mantle Cell Lymphoma (ZEBRA)

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ClinicalTrials.gov Identifier: NCT05635162
Recruitment Status : Not yet recruiting
First Posted : December 2, 2022
Last Update Posted : December 2, 2022
Information provided by (Responsible Party):
University College, London

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)

Condition or disease Intervention/treatment Phase
Mantle Cell Lymphoma Drug: Zanubrutinib Drug: Rituximab Phase 2

Detailed Description:

This 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 MCL patients.

50 patients will be recruited from 15 UK centres over 30 months.

Enrolled patients will be randomised (1:1) to ongoing observation (control arm; arm A) or fixed-duration zanubrutinib-rituximab (experimental arm; arm B). Patients will discontinue zanubrutinib-rituximab after 6 cycles of therapy or sooner in the advent of unacceptable toxicity or any other reason.

All patients will be followed up for a minimum of 2 years after study enrolment. Patients in arm B who develop disease progression and require further therapy after the initial time-limited Zanu-R will receive standard of care therapy according to front line treatment available at that time.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomised
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Estimated Study Start Date : March 1, 2023
Estimated Primary Completion Date : March 31, 2027
Estimated Study Completion Date : April 30, 2027

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
No Intervention: Arm A: Control
Active observation
Experimental: Arm B: Experimental
Time limited Zanubrutinib-R 6 x 28 day cycles
Drug: Zanubrutinib
Zanubrutinib dose is 160 mg twice daily (BD) orally (PO) on days 1-28 of each 28-day cycle.

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

Primary Outcome Measures :
  1. Event free survival [ Time Frame: From date of randomisation until whichever comes first: occurrence of active disease, new MCL treatment or death (any cause) up to 60 months ]
    To determine the effect of fixed-duration Zanu-R on Event-free survival (EFS) compared to active observation

Secondary Outcome Measures :
  1. Progression free survival [ Time Frame: Randomisation until disease progression up to 60 months ]
    To determine the effect of fixed-duration Zanu-R on Progression free survival (PFS) compared to active observation

  2. Overall survival [ Time Frame: Randomisation until date of death up to 60 months ]
    To determine the effect of fixed-duration Zanu-R on overall survival (OS) compared to active observation

  3. Time to next treatment [ Time Frame: Randomisation until date of initiation of subsequent treatment up to 60 months ]
    To determine the effect of fixed-duration Zanu-R on time to next treatment (TTNT) compared to active observation

  4. Overall response rate to Zanu-R [ Time Frame: From start of treatment until 24 weeks post administration of Zanu-R ]
    To determine the effect of fixed-duration Zanu-R on overall response rate (ORR) at the end of 6 cycles of treatment

  5. Overall response rate to re-treatment with covalent BTKi [ Time Frame: From the start of further treatment with a BTKi through to study completion, an average of 60 months ]
    To determine the ORR to re-treatment with covalent BTKi in experimental arm

  6. Safety and Toxicity [ Time Frame: From informed consent until 28 weeks post randomisation ]
    To assess the worst grade of each adverse event for each patient. Grades 1-2 and grades 3-5 will be compared between the arms

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Male or females 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 ≥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) or an equally accurate method.
  11. Able to give voluntary written informed consent.
  12. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.
  13. Negative serum or urine pregnancy test for women of childbearing potential (WOCBP).
  14. Willing to comply with the contraceptive requirements of the trial.

Exclusion Criteria:

  1. Any prior therapy including prior radiotherapy.
  2. Central nervous system (CNS) involvement of MCL.
  3. Known history of infection with HIV or any uncontrolled active systemic infection (e.g., bacterial, viral or fungal).
  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. Progression requiring treatment within 6 months of 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 < 5 years.
  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 alongside zanubrutinib).
  11. Active bleeding or history of bleeding diathesis (e.g. haemophilia or von Willebrand disease).
  12. Clinically significant cardiovascular disease such as uncontrolled arrhythmias, or myocardial infarction within 6 months of screening, 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, or third-degree atrioventricular block at screening.
  13. History of stroke or intracranial haemorrhage within 6 months prior to study enrolment.
  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, 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 humanized 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05635162

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Contact: ZEBRA Trial Coordinator (+44) (0)2076794172 ctc.zebra@ucl.ac.uk
Contact: Hayley Cartwright (+44) (0)2076794172 h.cartwright@ucl.ac.uk

Sponsors and Collaborators
University College, London
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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT05635162    
Other Study ID Numbers: UCL 146660
First Posted: December 2, 2022    Key Record Dates
Last Update Posted: December 2, 2022
Last Verified: November 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action