A Randomized Phase 3 Trial of Continuous vs. Intermittent Maintenance Therapy with Zanubrutinib as Upfront Treatment in Older Patients with Mantle Cell Lymphoma

Cancer Categories

Hematologic (Blood Cancers)

Karmanos Trial ID

A052101

NCT ID

NCT05976763

Age Group

Adult

Scope

National

Phase

Phase III

Principal Investigator

Dipenkumar
Modi, M.D.
Oncology - Hematology, Oncology - Medical View Profile

Objective:

Primary objective:

To compare time to first progression or death (PFS1) with continuous treatment (Arm A) and time to second progression or death (PFS2) with intermittent treatment that is restarted at first progression (Arm B). PFS1 and PFS2 will be defined as follows for patients who achieve complete remission (CR) with induction therapy and are randomized to a maintenance treatment arm:
- Continuous treatment Arm A: time from randomization until first progression or death from any cause (PFS1)
- Intermittent treatment Arm B: time from randomization until second progression or death from any cause (PFS2)

Key secondary objective:

To compare overall survival between patients who achieve a CR with induction therapy subsequently treated with continuous treatment vs. intermittent treatment as part of maintenance therapy.

Secondary objectives:

To determine overall response rate (ORR) and CR rate to induction therapy with zanubrutinib and rituximab in previously untreated MCL
To determine adverse events during induction and post-induction in each study arm (Arm A and B) by CTCAE 5.0
To determine PFS1, event free survival (EFS) and overall survival (OS) in each study arm (A and B)
To determine the overall response rate (ORR) and complete response rate (CR) after restarting zanubrutinib, following the first progression, in the intermittent treatment arm (Arm B)
To compare burden of symptomatic AEs as assessed by PRO-CTCAE between patients randomized to Arm A versus Arm B.

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Eligibility

Inclusion Criteria:

• Histologically confirmed mantle cell lymphoma with cyclin D1 (BCL1) expression by immunohistochemical stains and/or t(11;14) by cytogenetics or fluorescence in situ hybridization (FISH) as confirmed by the enrolling center

Any stage allowed (stage I-IV)

Presence of measurable disease, defined as >= 1 nodal lesion that is > 1.5 cm in longest diameter or >= 1 extranodal lesion that is > 1 cm in longest diameter
Steroids for management of mantle cell lymphoma are allowed up to a dose of prednisone 100mg/day (or equivalent) for up to 7 days
No prior systemic treatment for mantle cell lymphoma
No prior radiation treatment for stage I MCL
No prior exposure to a BTK inhibitor or anti-CD20 monoclonal antibody
No prior stem cell transplant
Age >= 70 years OR age >= 60 to < 70 years with comorbidities precluding autologous stem cell transplantation (autoSCT) including at least one of the following: a) cardiac ejection fraction (EF) < 45%, b) diffusing capacity for carbon monoxide < 60% predicted; c) creatinine clearance < 70 but > 30ml/minute (min); d) Eastern Cooperative Oncology Group (ECOG) performance status of 2, which poses an unacceptable risk of toxicity for high-dose therapy and stem cell transplantation; or e) Cumulative Illness Rating Scales (CIRS) total score > 6
ECOG Performance Status 0-2
Absolute neutrophil count (ANC) >= 750/mm^3 (without growth factor support within 7 days)
Platelet count >= 75,000/mm^3 (or >= 50,000/mm^3 for patients with bone marrow involvement of lymphoma) without growth factor support or transfusion within 7 days
Creatinine clearance >= 30 mL/ min determined by either: a) Estimation using the Cockcroft-Gault equation or b) Measurement by nuclear medicine scan or 24 hour urine collection
Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless documented Gilbert's syndrome)
Aspartate transferase (AST) / alanine transaminase (ALT) =< 3 x ULN
Patients should not be considered candidates for stem cell transplant or must have declined a stem cell transplant strategy
No clinically significant cardiovascular disease including the following

Unstable angina within 3 months before registration
New York Heart Association class III or IV congestive heart failure
History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes)
QT correction formula (QTcF) > 480 msecs based on Fredericia's formula
History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place

Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
No active Hepatitis B or Hepatitis C infection. Patients with prior hepatitis B virus (HBV) exposure (positive HBV core antibody and/or surface antigen) are eligible if they have no detectable viral load, and are taking appropriate prophylactic antiviral therapy to prevent reactivation. Patients with history of hepatitis C virus (HCV) are eligible if they have an undetectable HCV viral load
Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
No history of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention
No history of stroke or intracranial hemorrhage within 6 months prior to registration
No disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction. Patient must be able to swallow pills
Potential trial participants should have recovered from major surgery
No vaccination with a live vaccine within 35 days prior to registration
No hypersensitivity to zanubrutinib or rituximab or any of the other ingredients of the study drugs
Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study.
Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment
Avoid use of moderate CYP3A4 inhibitors, PGP inhibitors, and moderate CYP3A4 inducers

Locations

Karmanos Cancer Institute - Detroit Headquarters

4100 John R
Detroit, MI 48201
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Phone: 1-800-527-6266

Karmanos Cancer Institute at Weisberg Cancer Center - Farmington Hills

31995 Northwestern Hwy
Farmington Hills, MI 48334
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Phone: 1-800-527-6266

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