Testing Continuous Versus Intermittent Treatment With the Study Drug Zanubrutinib for Older Patients With Previously Untreated Mantle Cell Lymphoma
Purpose
This phase III trial tests whether continuous or intermittent zanubrutinib after achieving a complete remission (CR) with rituximab works in older adult patients with mantle cell lymphoma (MCL) who have not received treatment in the past (previously untreated). Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Zanubrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. When zanubrutinib is used in MCL, the current standard of care is to continue administering the drug indefinitely until disease progression. This continuous treatment comes with clinical as well as financial toxicity, which could be especially detrimental in older patients. For patients who achieve a CR after initial zanubrutinib plus rituximab therapy, it may be safe and equally effective to stop treatment and restart zanubrutinib upon disease progression rather than continuing indefinitely in previously untreated older adult patients with MCL.
Condition
- Mantle Cell Lymphoma
Eligibility
- Eligible Ages
- Over 60 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Criteria
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
- Archival tissue must be available for submission in all patients for
histopathology review, though participation in correlative substudies is
optional
Study Design
- Phase
- Phase 3
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Induction therapy (Zanubrutinib, rituximab) |
Patients receive zanubrutinib PO and rituximab IV on study. Patients undergo bone marrow biopsy and FDG PET/CT or CT throughout the trial. Patients may also undergo EDG and/or colonoscopy on study as clinically indicated. Patients may optionally undergo blood sample collection throughout the trial. |
|
|
Experimental Arm A (Zanubrutinib) |
Patients receive zanubrutinib PO until first disease progression on study. Patients undergo CT or MRI or FDG PET/CT throughout the trial. Patients may optionally undergo blood sample collection throughout the trial. |
|
|
Active Comparator ARM B (Observation) |
Patients undergo observation until first disease progression and then receive zanubrutinib PO until second disease progression on study. Patients undergo CT or MRI or FDG PET/CT throughout the trial. Patients may optionally undergo blood sample collection throughout the trial. |
|
Recruiting Locations
Kansas City, Kansas 66160
Westwood, Kansas 66205
Kansas City, Missouri 64154
North Kansas City, Missouri 64116
Lee's Summit, Missouri 64064
Overland Park, Kansas 66210
Topeka, Kansas 66606
Site Public Contact
785-295-8000
More Details
- Status
- Recruiting
- Sponsor
- Alliance for Clinical Trials in Oncology
Detailed Description
PRIMARY OBJECTIVE: I. To compare time to first progression or death (progression free survival [PFS]1) with continuous treatment (Arm A) and time to second progression or death (PFS2) with intermittent treatment that is restarted at first progression (Arm B). KEY SECONDARY OBJECTIVE: I. To compare overall survival between patients who achieve a complete remission (CR) with induction therapy subsequently treated with continuous treatment versus (vs.) intermittent treatment as part of maintenance therapy. SECONDARY OBJECTIVES: I. To determine overall response rate (ORR) and CR rate to induction therapy with zanubrutinib and rituximab in previously untreated MCL. II. To determine adverse events during induction and post-induction in each study arm (Arm A and B) by Common Terminology Criteria for Adverse Events (CTCAE) 5.0. III. To determine PFS1, event free survival (EFS) and overall survival (OS) in each study arm (A and B). IV. 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). V. To compare burden of symptomatic adverse events (AEs) as assessed by Patient-Reported Outcome Common Terminology Criteria for Adverse Events (PRO-CTCAE) between patients randomized to Arm A versus Arm B. QUALITY OF LIFE PRIMARY OBJECTIVE: I. To compare health-related quality of life (QOL) at 12 cycles post-randomization as assessed by the Functional Assessment of Cancer Therapy (FACT) Lymphoma Symptom Index-18 (FLYMSI-18) total score between patients randomized to Arm A versus Arm B. QUALITY OF LIFE SECONDARY OBJECTIVES: I. To compare health-related QOL at other time points as assessed by the FLYMSI-18 total score between patients randomized to Arm A versus Arm B. II. To compare burden of symptomatic AEs as assessed by PRO-CTCAE between patients randomized to continuous (Arm A) versus intermittent (Arm B) zanubrutinib treatment. QUALITY OF LIFE EXPLORATORY OBJECTIVES: I. To compare the geriatric functional and cognitive PRO as assessed by Elderly Functional Index (EFLI) and Neurology (Neuro) QOL in Arm A versus Arm B. II. To compare cognitive function at various time points as assessed by the Neuro-QOL between patients randomized to continuous (Arm A) versus intermittent (Arm B) zanubrutinib treatment. EXPLORATORY OBJECTIVES: I. To evaluate the completion rate of a lymphoma-specific patient assessment of life survey (PALS) with patient directed questions on life, health, and social determinants of health (SDH) and assess the impact of the survey collected data on outcomes for all enrolled patients (study arms A and B). II. To evaluate minimal residual disease (MRD) in those patients who achieve a CR after induction therapy (arms A and B) and how detectable MRD status changes after continued therapy vs. discontinuation of therapy (i.e. arms A vs. B). OUTLINE: INDUCTION THERAPY: Patients receive zanubrutinib orally (PO) and rituximab intravenously (IV) on study. Patients undergo bone marrow biopsy and fluciclovine F18 (FDG) positron emission tomography (PET)/ computed tomography (CT) or CT throughout the trial. Patients may also undergo esophagogastroduodenoscopy (EGD) and/or colonoscopy on study as clinically indicated. Patients may optionally undergo blood sample collection throughout the trial. MAINTENANCE THERAPY: Patients achieving a CR after induction therapy are randomized to 1 of 2 arms. ARM A: Patients receive zanubrutinib PO until first disease progression on study. Patients undergo CT or magnetic resonance imaging (MRI) or FDG PET/CT throughout the trial. Patients may optionally undergo blood sample collection throughout the trial. ARM B: Patients undergo observation until first disease progression and then receive zanubrutinib PO until second disease progression on study. Patients undergo CT or MRI or FDG PET/CT throughout the trial. Patients may optionally undergo blood sample collection throughout the trial. After completion of study treatment, patients are followed within 30 days and every 6 months for 10 years.