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

NCT05650723 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 22-05024874
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Keywords

Chronic Lymphocytic Leukemia; CLL; Small Lymphocytic Lymphoma; SLL

Outcome Measures

Primary Outcomes (4)

• Percentage of total patients that have achieved undetectable minimal residual disease (MRD) at cycle 16, as assessed via peripheral blood

  The primary endpoint of C16 peripheral blood MRD negativity at cycle 16 will be represented as a percentage of total patients. This will be calculated on both efficacy evaluable and intention to treat basis. These will be estimated with a 90% confidence interval using Clopper-Pearson method based on exact binomial distribution. A cycle is defined as 28 days.

  Cycle 16 (Month 16)

• Percentage of total patients that have achieved undetectable minimal residual disease (MRD) at cycle 16, as assessed via bone marrow aspirate

  The primary endpoint of C16 bone marrow MRD negativity at cycle 16 will be represented as a percentage of total patients. This will be calculated on both efficacy evaluable and intention to treat basis. These will be estimated with a 90% confidence interval using Clopper-Pearson method based on exact binomial distribution.

  Cycle 16 (Month 23)

• Percentage of eligible patients that have achieved undetectable minimal residual disease (MRD) at cycle 23, as assessed via peripheral blood

  The co-primary endpoint of C23 peripheral blood MRD negativity rate will be presented as a percentage of patients that achieve undetectable MRD at C23, who were found to be MRD positive at C16 and went on to receive at least one dose of obinutuzumab. This will be calculated on both efficacy evaluable and intention to treat basis. These will be estimated with a 90% confidence interval using Clopper-Pearson method based on exact binomial distribution.

  Cycle 23 (Month 23)

• Percentage of eligible patients that have achieved undetectable minimal residual disease (MRD) at cycle 23, as assessed via bone marrow aspirate

  The co-primary endpoint of C23 bone marrow MRD negativity rate will be presented as a percentage of patients that achieve undetectable MRD at C23, who were found to be MRD positive at C16 and went on to receive at least one dose of obinutuzumab. This will be calculated on both efficacy evaluable and intention to treat basis. These will be estimated with a 90% confidence interval using Clopper-Pearson method based on exact binomial distribution.

  Cycle 23 (Month 23)

Secondary Outcomes (10)

• Percentage of total participants who experience adverse events (AEs) through cycle 16

  Cycle 16 (Month 16)

• Percentage of participants receiving triplet therapy who experience AEs through cycle 23

  Cycle 23 (Month 23)

• 36-month Progression Free Survival (PFS)

  36 months

• 36-month Overall Survival (OS)

  36 months

• Percentage of patients treated with doublet therapy (zanubrutinib and venetoclax) that have achieved undetectable minimal residual disease (MRD) at 24-months, as assessed via peripheral blood

  24 months

Study Arms (2)

Double Therapy (Zanubrutinib plus Venetoclax)

EXPERIMENTAL

All participants will receive an initial 3 cycles of zanubrutinib monotherapy. This lead-in period will then be followed by 12 cycles of zanubrutinib and venetoclax combination therapy. All participants 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. Participants will continue on double combination treatment for an additional 1 month while results of MRD testing are obtained. In total, all participants will be on treatment for at least 16 full cycles. Participants that meet definition of MRD negativity will stop therapy at C17D1 and enter an observation phase with study visits every 3 months. Participants that remain MRD positive at C16D1 will enter the triple therapy (zanubrutinib, venetoclax, and obinutuzumab) arm.

Drug: Zanubrutinib Pill; Drug: Venetoclax Pill

Triple Therapy (Zanubrutinib, Venetoclax, and Obinutuzumab)

EXPERIMENTAL

Participants that meet definition of MRD positivity at C16D1 will enter the triple therapy arm (zanubrutinib, venetoclax, and obinutuzumab). These participants 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 participants will stop study treatment regardless of MRD status.

Drug: Zanubrutinib Pill; Drug: Venetoclax Pill; Drug: Obinutuzumab Injection

Interventions

Venetoclax Pill DRUG

400 mg once per day by mouth following the standard ramp-up schedule (20mg daily PO week 1, 50mg daily PO week 2, 100mg daily PO week 3, 200mg daily PO week 4, followed by 400mg PO daily week 5)

Also known as: Venclexta

Double Therapy (Zanubrutinib plus Venetoclax); Triple Therapy (Zanubrutinib, Venetoclax, and Obinutuzumab)

Obinutuzumab Injection DRUG

1000 mg IV given every 28 days

Also known as: Gazyva

Triple Therapy (Zanubrutinib, Venetoclax, and Obinutuzumab)

Zanubrutinib Pill DRUG

320 mg once per day by mouth

Also known as: Brukinsa

Double Therapy (Zanubrutinib plus Venetoclax); Triple Therapy (Zanubrutinib, Venetoclax, and Obinutuzumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject must be able to voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures.
• Subject must be ≥ 18 years of age.
• Subject must have confirmed diagnosis of CLL/SLL based upon 2018 iwCLL Guidelines.
• a. Please note, participants with SLL must have identifiable B-cells in peripheral blood or bone marrow consistent with CLL/SLL immuno-phenotype, based on flow-cytometry, in order to be enrolled
• Subject must have indications for treatment per the 2018 iwCLL Guidelines.
• Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.
• Subject must have adequate organ function defined as:
• Creatinine clearance ≥ 30 mL/min (as estimated by the Cockcroft-Gault equation or the Modification of Diet in Renal Disease equation, or as measured by nuclear medicine scan or 24-hour urine collection).
• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase ≤ 2.5 × upper limit of normal (ULN) unless due to CLL/SLL.
• Serum total bilirubin \< 3.0 × ULN (unless documented Gilbert's syndrome)
• Subject must have adequate bone marrow function and meet the below thresholds unless approved by sponsor if cytopenias are felt to be due to significant marrow involvement of CLL:
• Absolute neutrophil count ≥ 1.0 x103/μL
• Hemoglobin ≥ 7 g/dL (can be transfused up to 1 week prior to study enrollment)
• Platelets ≥ 75,000 cells/μL OR platelets ≥ 30,000 cells/μL if clearly due to disease under study (per investigator discretion)
• Subjects of childbearing potential must be willing to comply with pregnancy prevention interventions (as defined in Section 4.4)

You may not qualify if:

• A subject will be ineligible for the study if he/she meets the following 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.
• Subject with a history of malignancy except for non-melanoma skin cancers. Subjects treated with curative intent via methods of local resection and or locally targeted anticancer treatment and are free of malignancy for at least 35 years from treatment end will be allowed to enroll. Adjuvant hormonal therapy will be allowed at time of enrollment if the subject otherwise is not excluded by the 3-year waiting period.
• Subject requires chronic immunosuppressive therapy for any reason or was treated with immunosuppressive therapy within 6 months of study entry.
• Subjects with active autoimmune hemolytic anemia or immune thrombocytopenia purpura.
• Subject with prolymphocytic leukemia or Richter's Transformation.
• Active bleeding, or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease).
• Subject requires warfarin or equivalent vitamin K antagonist.
• Uncontrolled or active significant infection requiring systemic treatment, subjects are eligible if they have completed antibiotic therapy 2 weeks prior to study enrollment.
• History of suspected or confirmed PML
• Clinically significant cardiovascular disease including the following:
• 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).

Sponsors & Collaborators

• BeiGene: collaborator
• Genentech, Inc.: collaborator
• Weill Medical College of Cornell University: lead

Study Sites (1)

Weill Cornell Medicine/NewYork-Presberteryian Hospital

New York, New York, 10021, United States

Location

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

zanubrutinib; venetoclax; obinutuzumab

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• John Allan, M.D.

  Weill Medical College of Cornell University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 6, 2022
• First Posted: December 14, 2022
• Study Start: May 8, 2023
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: February 25, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)