Zanubrutinib and Venetoclax as Initial Therapy for Chronic Lymphocytic Leukemia (CLL) With Response-based Obinutuzumab

• Status: Not yet recruiting
• Trial end date: 2028-03-01
• Target enrollment: 0
• Participant gender: All

Summary

Bruton's tyrosine kinase inhibitors (BTKi), anti-CD20 antibodies, and the B cell lymphoma 2 inhibitor (BCL-2i) venetoclax are drug classes used to treat patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL). Anti-CD20 therapy may not be required for all patients. The investigators hypothesis is that it may be better to give anti-CD20 therapy (obinutuzumab) only to patients that still have detectable cancer in their blood (minimal residual disease [MRD]) after being treated with a combination of two oral medications, zanubrutinib (a BTKi ) and venetoclax (a BCL-2i), instead of giving a combination of three drugs to all patients from the start of treatment. This strategy, if effective, will prevent overtreatment with anti-CD20 antibodies; reduce side effects of treatment while potentially increasing MRD negativity rates; and will possibly make the anti-CD20 antibody therapy more effective given the low tumor burden present when utilized. This study will test this hypothesis by treating subjects with 3 cycles of a zanubrutinib monotherapy lead-in, in order to debulk and mitigate tumor lysis risk, followed by 13 cycles of zanubrutinib and venetoclax combination therapy. Subjects who are both peripheral blood and bone marrow MRD negative at the completion of the 13 cycles of combination therapy will stop treatment and enter an observation phase every 3 months. Subjects that are MRD positive will continue combination therapy with zanubrutinib and venetoclax for an additional 6 cycles but also receive 6 cycles of obinutuzumab in order to augment response and increase MRD negative rates for the overall treated cohort.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Weill Medical College of Cornell University
• Collaborators: BeiGene; Genentech, Inc.
• Treatments: Obinutuzumab; Venetoclax; Zanubrutinib

Criteria

Inclusion Criteria:

• Participant must have confirmed diagnosis of CLL/SLL

• Participant must have indications for treatment

• Participants of childbearing potential must be willing to comply with pregnancy prevention interventions

Exclusion Criteria:

• Previous exposure to any systemic anti-cancer therapy as a treatment for CLL/SLL, including but not limited to chemotherapy, immunotherapy, radiotherapy, hormone therapy (other than contraceptives, hormone-replacement therapy or megestrol acetate) or investigational therapy.

• History of malignancy except for non-melanoma skin cancers. Participants treated with curative intent via methods of local resection and or locally targeted anticancer treatment and are free of malignancy for at least 5 years from treatment end will be allowed to enroll.

• Requires chronic immunosuppressive therapy for any reason or was treated with immunosuppressive therapy within 6 months of study entry.

• Participants with active autoimmune hemolytic anemia or immune thrombocytopenia purpura.

• Prolymphocytic leukemia or Richter's Transformation.

• Active bleeding, or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease).

• Participant requires warfarin or equivalent vitamin K antagonist.

• Uncontrolled or active significant infection requiring systemic treatment

• History of suspected or confirmed PML

• Myocardial infarction within 6 months before screening.

• Unstable angina within 3 months before screening.

• 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).

• Patients with stroke or CNS hemorrhage within 6 months.

• Pregnant or breastfeeding.

• Major surgical procedure within 28 days of first dose of study drug.

• Has difficulty with or is unable to swallow oral medication or has significant gastrointestinal disease that would limit absorption of oral medication.

• Participant is positive for human immunodeficiency virus (HIV).

• Known hypersensitivity reactions (e.g., anaphylaxis) to obinutuzumab or any of the excipients, including serum sickness with prior obinutuzumab use.

• Vaccination with live vaccine ≤28 days prior to start of treatment.