Overview
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.
Description
This is an open label, phase II, investigator-initiated clinical trial of 50 subjects. Subjects with CLL/SLL who have treatment indications per the 2018 International Workshop for CLL (iwCLL) will be eligible to enroll. The investigators hypothesize that anti-CD20 therapy may not be required for all patients and a response-adapted strategy will prevent over treatment of a significant number of patients and reduce toxicity of treatment while still achieving a high rate of MRD negativity. The investigators also hypothesize that late addition of anti-CD20 therapy can eliminate low burden residual disease in subjects and maximize undetectable MRD negativity in subjects who remain MRD positive.
All subjects will initiate induction therapy with 3 cycles of zanubrutinib monotherapy in order to debulk subjects and mitigate tumor lysis risk. This lead-in period will then be followed by 12 cycles of zanubrutinib and venetoclax combination. Standard ramp-up protocols for venetoclax based on TLS risk assessed prior to C4D1 will be utilized. All subjects will complete 12 cycles of zanubrutinib and venetoclax combination therapy or 15 cycles of total treatment. Peripheral blood and bone marrow MRD assessments will occur at C16D1. Subjects will continue on combination treatment for an additional 1 month while results of MRD testing are obtained. In total, all subjects will be on treatment for at least 16 full cycles. Subjects that meet definition of MRD negativity will stop therapy at C17D1 and enter an observation phase with study visits every 3 months. Subjects that meet definition of MRD positivity will continue combination therapy with zanubrutinib and venetoclax, but will also receive 6 cycles of obinutuzumab starting at C17D1. In this subgroup, peripheral blood and bone marrow MRD assessments will occur after an additional 6 cycles of the triplet combination therapy (C23D1) at which point all subjects will stop study treatment regardless of MRD status.
Eligibility
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.