PRIMARY OBJECTIVE:
I. To determine the proportion of patients who have treatment-free remission 6 months after
discontinuation of zanubrutinib.
SECONDARY OBJECTIVES:
I. To determine clinical factors associated with a treatment-free remission of more than 6
months after discontinuation of zanubrutinib.
II. To determine the treatment-free remission length. III. To evaluate the efficacy of
re-treatment with zanubrutinib plus rituximab in patients who relapse.
OUTLINE:
FRONTLINE THERAPY: Patients receive zanubrutinib orally (PO) twice daily (BID) on days 1-28.
Patients also receive rituximab intravenously (IV) over 3-4 hours on days 1, 8, 15, and 22 of
cycle 1 and on day 1 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles
in the absence of disease progression or unacceptable toxicity. Beginning cycle 7, patients
with complete response (CR) continue zanubrutinib PO BID on days 1-28 for up to 6 additional
cycles in the absence of disease progression or unacceptable toxicity. Beginning cycle 7,
patients with partial response (PR) or stable disease (SD) continue zanubrutinib PO BID on
days 1-28 and rituximab IV over 3-4 hours on day 1 for up to 6 additional cycles in the
absence of disease progression or unacceptable toxicity. Beginning cycle 13, patients with CR
continue zanubrutinib PO BID on days 1-28 for up to 6 additional cycles in the absence of
disease progression or unacceptable toxicity. Beginning cycle 13, patients with PR or SD
continue zanubrutinib PO BID on days 1-28 for up to 12 additional cycles in the absence of
disease progression or unacceptable toxicity. Patients who do not have a PR after 24 cycles
either continue zanubrutinib if there is a clinical benefit, or pursue alternative therapy
per treating physician discretion.
RE-TREATMENT FOR RELAPSED DISEASE: Patients with disease relapse and active disease that
requires salvage therapy may restart zanubrutinib PO BID on days 1-28 and rituximab IV over
3-4 hours on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of
disease progression or unacceptable toxicity. Beginning cycle 7, patients continue
zanubrutinib PO BID on days 1-28 for up to 18 additional cycles in the absence of disease
progression or unacceptable toxicity and then discontinue if in CR. Beginning cycle 25,
patients with PR or SD may continue zanubrutinib PO BID on days 1-28 for up to 36 additional
cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 60 days, and then every 120
days for up to 5 years or until disease progression or start of a new treatment.
Inclusion Criteria:
- Patients must have a diagnosis chronic lymphocytic leukemia (CLL)/small lymphocytic
lymphoma (SLL) and be previously untreated
- Patients must have an indication for treatment by 2018 International Workshop on
Chronic Lymphocytic Leukemia (IWCLL) Criteria
- Patients must understand and voluntarily sign an informed consent, and be able to
comply with study procedures and follow-up examinations
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- Patients of childbearing potential must be willing to practice highly effective birth
control (e.g., condoms, implants, injectables, combined oral contraceptives,
intrauterine devices [IUDs], sexual abstinence, or sterilized partner) during the
study and for 30 days after the last dose of study drug. Women of childbearing
potential include any female who has experienced menarche and who has not undergone
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or
bilateral oophorectomy) or is not postmenopausal
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) except for patients
with bilirubin elevation due to Gilbert's disease who will be allowed to participate
- An alanine aminotransferase (ALT) =< 2.5 x ULN
- An estimated creatinine clearance (CrCl) of > 30 mL/min, as calculated by the
Cockcroft-Gault equation unless disease related
- Free of prior malignancies for 3 years with exception of currently treated basal cell
or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or
breast. If patients have another malignancy that was treated within the last 3 years,
such patients can be enrolled, after consultation with the principal investigator, if
the likelihood of requiring systemic therapy for this other malignancy within 2 years
is less than 10%, as determined by an expert in that particular malignancy
- A urine pregnancy test (within 7 days of day 1) is required for women with
childbearing potential
Exclusion Criteria:
- Pregnant or breast-feeding females
- Prior therapy with zanubrutinib or other kinase inhibitors that target BCR signaling
(such as ibrutinib, idelalisib)
- Prior CLL-directed treatment including chemotherapy, chemo-immunotherapy, monoclonal
antibody therapy, radiotherapy, high-dose corticosteroid therapy (more than 60 mg
prednisone daily or equivalent), or immunotherapy within 21 days prior to enrollment
or concurrent with this trial. Patients that receive zanubrutinib salvage therapy
cannot have received any other CLL-directed therapy besides frontline zanubrutinib
plus rituximab
- Investigational agent received within 30 days prior to the first dose of study drug.
If received any investigational agent prior to this time point, drug-related
toxicities must have recovered to grade 1 or less prior to first dose of study drug
- Systemic fungal, bacterial, viral, or other infection not controlled by antimicrobial
therapy, in the assessment of the treating physician(s) and/or the principal
investigator
- Patients with uncontrolled autoimmune hemolytic anemia (AIHA) or autoimmune
thrombocytopenia (ITP), i.e. with laboratory signs of active hemolysis or
thrombocytopenia, requiring support with blood products and/or with rapid decline in
hemoglobin (> 1 gram/dL per day) or platelet counts (> 10,000/uL per day)
- Patients with severe hematopoietic insufficiency, as defined by an absolute neutrophil
count of less than 500/uL, unless disease-related, and/or a platelet count of less
than 30,000/uL at time of screening for this protocol
- Any other severe concurrent disease, or have a history of serious organ dysfunction or
disease involving the heart, kidney, liver or other organ system that may place the
patient at undue risk to undergo therapy with zanubrutinib and rituximab
- Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias,
congestive heart failure, or myocardial infarction within 6 months of screening, or
any class 3 or 4 cardiac disease as defined by the New York Heart Association
Functional Classification. Patients with a history of paroxysmal atrial fibrillation
(PAF) or deep vein thrombosis or pulmonary embolism (DVT/PE) can be included if they
had no signs of PAF or DVT/PE in the last 6 months before enrolment. Patients with
ongoing atrial fibrillation (AFib) or ongoing PAF or DVT/PE should be excluded
- History of stroke or cerebral hemorrhage within 6 months
- Evidence of bleeding diathesis or coagulopathy within 3 months
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to day 1, anticipation of need for major surgical procedure during the course of
the study
- Minor surgical procedures, fine needle aspirations or core biopsies within 7 days
prior to day 1. Bone marrow aspiration and/or biopsy are allowed
- Serious, non-healing wound, ulcer, or bone fracture
- Treatment with warfarin (Coumadin) or any other vitamin K antagonist. Patients who
recently received warfarin must be off warfarin for at least 7 days prior to start of
the study. Patients receiving novel oral anticoagulant (NOAC), also termed direct oral
anticoagulant (DOAC) are permitted to enroll. Patients who are currently on a vitamin
K antagonist must be switched to a non-vitamin K antagonist, such as a NOAC/DOAC
- Patients with active hepatitis B (hepatitis B virus [HBV]) or hepatitis C
- Patients with known human immunodeficiency virus (HIV) infection
