Zanubrutinib and Rituximab for the Treatment of Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

BTK Inhibitor Zanubrutinib (BGB-3111) in Combination With Rituximab for Previously Untreated Patients With Chronic Lymphocytic Leukemia (CLL)

This phase II trial studies how well zanubrutinib and rituximab work in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma for which the patient has not received treatment in the past (previously untreated). Zanubrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. The study is being done to find out if zanubrutinib combined with rituximab can help control previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.

Study Overview

• Status: Recruiting
• Conditions: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
• Intervention / Treatment: Biological: Rituximab; Drug: Zanubrutinib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • M D Anderson Cancer Center
      • Contact: Jan A. Burger; Phone Number: 713-563-1487; Email: jaburger@mdanderson.org
      • Principal Investigator: Jan A. Burger

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (zanubrutinib, rituximab); See Detailed Description.

Biological: Rituximab; Given IV; Other Names: Rituxan; MabThera; ABP 798; BI 695500; C2B8 Monoclonal Antibody; Chimeric Anti-CD20 Antibody; CT-P10; IDEC-102; IDEC-C2B8; IDEC-C2B8 Monoclonal Antibody; Monoclonal Antibody IDEC-C2B8; PF-05280586; Rituximab ABBS; Rituximab Biosimilar ABP 798; Rituximab Biosimilar BI 695500; Rituximab Biosimilar CT-P10; Rituximab Biosimilar GB241; Rituximab Biosimilar IBI301; Rituximab Biosimilar JHL1101; Rituximab Biosimilar PF-05280586; Rituximab Biosimilar RTXM83; Rituximab Biosimilar SAIT101; rituximab biosimilar TQB2303; rituximab-abbs; RTXM83; Truxima; Drug: Zanubrutinib; Given PO; Other Names: Brukinsa; BGB-3111; BTK-InhB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Success rate	Will estimate the proportion of patients who have treatment-free remission 6 months after discontinuation of zanubrutinib. Success rate will be estimated with 95% credible interval and confidence interval.	At 6 months after discontinuation of zanubrutinib

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical factors associated with a treatment-free remission of more than 6 months after discontinuation of zanubrutinib	To assess the contribution of various factors to relapse risk, will use Cox's proportional hazards analysis of predictors that have a p value < 0.2 in the univariate analysis.	Up to 5 years after discontinuation of zanubrutinib
Treatment-free remission length	The median treatment-free remission duration will be calculated by Kaplan-Meier analysis, and stratified groups will be compared with the log-rank test.	Up to 5 years after discontinuation of zanubrutinib
Overall response	Defined as complete response or partial response after patients received 6 cycles of treatments.	After 6 cycles of treatment (each cycle is 28 days)

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Jan A Burger, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• MD Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): May 26, 2020
• Primary Completion (Estimated): May 26, 2024
• Study Completion (Estimated): May 26, 2024

Study Registration Dates

• First Submitted: July 2, 2020
• First Submitted That Met QC Criteria: July 2, 2020
• First Posted (Actual): July 7, 2020

Study Record Updates

• Last Update Posted (Actual): April 8, 2024
• Last Update Submitted That Met QC Criteria: April 5, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Hematologic Diseases; Leukemia, B-Cell; Chronic Disease; Lymphoma; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Antibodies; Immunoglobulins; Rituximab; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Zanubrutinib
• Other Study ID Numbers: 2019-0012 (Other Identifier: M D Anderson Cancer Center); NCI-2020-05053 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No