Venetoclax as Consolidation in CLL Patients Treated With BTK Inhibitor Monotherapy

Study of the Efficacy and Safety of Venetoclax as Consolidation to Achieve Fix-Duration Treatment in CLL Patients Treated With BTK Inhibitor Monotherapy

This is an open-label, multicenter, phase 2, non-randomized study aiming to study the efficacy and safety of fixed-duration venetoclax consolidation in CLL patients who are on BTK inhibitor monotherapy. Patients who are on BTK inhibitor monotherapy for ≥ 6 months and still responsive are included. The study includes patients who are treatment-naive before taking BTK inhibitors. Patients will be treated with the BTK inhibitor plus full-dose venetoclax for 12 cycles after a standard 5-week dose ramp-up. Peripheral blood and bone marrow MRD status will be evaluated during and after the treatment. After the completion of combination therapy, patients will stop both BTK inhibitor and venetoclax and be followed.

Study Overview

• Status: Recruiting
• Conditions: Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL)
• Intervention / Treatment: Drug: Venetoclax combined with Ibrutinib; Drug: Venetoclax combined with Zanubrutinib; Drug: Venetoclax combined with Acalabrutinib; Drug: Venetoclax combined with Orelabrutinib

• Study Type: Interventional
• Enrollment (Estimated): 79
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jianyong Li, PhD, MD; Phone Number: 86-13951877733; Email: lijianyonglm@126.com
• Study Contact Backup: Name: Huayuan Zhu, PhD, MD; Phone Number: 86-13813810650; Email: huayuan.zhu@hotmail.com

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • Recruiting
      • Department of Haematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital
      • Contact: Jianyong Li, PhD, MD; Phone Number: 86-13951877733; Email: lijianyonglm@126.com
      • Contact: Huayuan Zhu, PhD, MD; Phone Number: 86-13813810650; Email: huayuan.zhu@hotmail.com
      • Principal Investigator: Jianyong Li, PhD, MD
      • Principal Investigator: Huayuan Zhu, PhD, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 1. Age: 18-80 years-old.
• 2. Patients must have a diagnosis of CLL/SLL.
• 3. Detectable MRD by flow cytometry (10^-4 sensitivity) in the peripheral blood.
• 4. Patients who are on BTK inhibitor monotherapy for more than 6 months. This study includes patients who are taking one of the following BTK inhibitors: ibrutinib, zanubrutinib, orelabrutinib, and acalabrutinib.
• 5. Patients need to have a response of at least PR (CR/PR) to BTK inhibitor monotherapy.
• 6. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.
• 7. Patients must have adequate renal and hepatic function:
• Serum bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for patients with Gilbert's disease;
• Serum creatinine clearance of ≥ 50 ml/min (calculated or measured);
• ALT and AST ≤ 3.0 × ULN, unless clearly due to disease involvement.
• 8. Adequate bone marrow function:
• Platelet count of greater than 50,000/µl, with no platelet transfusion in prior 2 weeks;
• ANC ≥ 1000/µl in the absence of growth factor support unless due to compromised bone marrow production from CLL, indicated by ≥ 80% CLL in marrow;
• Hemoglobin ≥ 8g/dL.
• 9. Adequate cardiac function, as assessed by:
• Absence of uncontrolled cardiac arrhythmia;
• Echocardiogram demonstrating LVEF ≥ 35%;
• NYHA functional class ≤ 2.
• 10. Ability to provide informed consent and adhere to the required follow-up.

Exclusion Criteria:

• 1. Richter transformation.
• 2. Active malignancy requiring systemic therapy, other than CLL, with the exception of: adequately treated in situ carcinoma of the cervix uteri; adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin; previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
• 3. Major surgery, radiotherapy, chemotherapy, biologic therapy, immunotherapy, experimental therapy within 3 weeks prior to the first dose of the study drug.
• 4. Grade 3 or 4 hemorrhage within the past 3 weeks.
• 5. Uncontrolled active infections (viral, bacterial, and fungal).
• 6. Females who are pregnant or lactating.
• 7. Known HIV positive.
• 8. Active hepatitis B infection (defined as the presence of detectable HBV DNA or HBe antigen). Patients who are HBsAg positive or HBcAb positive are eligible, provided HBV DNA is negative. These patients must have monthly monitoring of HBV DNA for the duration of the study.
• 9. Active hepatitis C, defined by the detection of hepatitis C RNA in plasma by PCR.
• 10. Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune thrombocytopenia) requiring steroid therapy > 20 mg prednisone daily or equivalent, within 7 days of starting venetoclax.
• 11. Received other therapeutic agents for CLL/SLL during BTK inhibitor treatment prior to enrollment.
• 12. Concurrent use of warfarin or equivalent vitamin K inhibitor or other oral anticoagulant treatment.
• 13. Received strong CYP3A inhibitors or strong CYP3A inducers within 7 days of starting venetoclax.
• 14. Consuming grapefruit, grapefruit products, Seville oranges, or star fruit within 7 days of starting venetoclax.
• 15. Prior treatment with venetoclax or other Bcl-2 inhibitor.
• 16. Malabsorption syndrome or other condition that precludes enteral route of administration.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CLL/SLL patients on ibrutinib monotherapy for ≥ 6 months	Drug: Venetoclax combined with Ibrutinib; All Patients will be treated with venetoclax for 12 cycles after a standard 5-week dose ramp-up, as an add-on to the primary using ibrutinib. After the completion of combination therapy, patients will stop both the ibrutinib and venetoclax then be followed. Each cycle is 28 days. At the start of cycle 0, patients will start venetoclax by 20mg-50mg-100mg-200mg daily in a weekly dose escalation way. The combination of full dose venetoclax (400mg) and ibrutinib will continue for an additional 12 cycles. Venetoclax and ibrutinib will be continued until the completion of cycle 12, start of new CLL-directed therapies, disease progression or unacceptable toxicities, depending on which comes first. Ibrutinib is intended to be admistratered orally 420mg once daily.
Experimental: CLL/SLL patients on zanubrutinib monotherapy for ≥ 6 months	Drug: Venetoclax combined with Zanubrutinib; All Patients will be treated with venetoclax for 12 cycles after a standard 5-week dose ramp-up, as an add-on to the primary using zanubrutinib. After the completion of combination therapy, patients will stop both the zanubrutinib and venetoclax then be followed. Each cycle is 28 days. At the start of cycle 0, patients will start venetoclax by 20mg-50mg-100mg-200mg daily in a weekly dose escalation way. The combination of full dose venetoclax (400mg) and zanubrutinib will continue for an additional 12 cycles. Venetoclax and zanubrutinib will be continued until the completion of cycle 12, start of new CLL-directed therapies, disease progression or unacceptable toxicities, depending on which comes first. Zanubrutinib is intended to be admistratered orally 160mg twice daily.
Experimental: CLL/SLL patients on acalabrutinib monotherapy for ≥ 6 months	Drug: Venetoclax combined with Acalabrutinib; All Patients will be treated with venetoclax for 12 cycles after a standard 5-week dose ramp-up, as an add-on to the primary using acalabrutinib. After the completion of combination therapy, patients will stop both the acalabrutinib and venetoclax then be followed. Each cycle is 28 days. At the start of cycle 0, patients will start venetoclax by 20mg-50mg-100mg-200mg daily in a weekly dose escalation way. The combination of full dose venetoclax (400mg) and acalabrutinib will continue for an additional 12 cycles. Venetoclax and acalabrutinib will be continued until the completion of cycle 12, start of new CLL-directed therapies, disease progression or unacceptable toxicities, depending on which comes first. Acalabrutinib is intended to be admistratered orally 100mg twice daily.
Experimental: CLL/SLL patients on orelabrutinib monotherapy for ≥ 6 months	Drug: Venetoclax combined with Orelabrutinib; All Patients will be treated with venetoclax for 12 cycles after a standard 5-week dose ramp-up, as an add-on to the primary using orelabrutinib. After the completion of combination therapy, patients will stop both the orelabrutinib and venetoclax then be followed. Each cycle is 28 days. At the start of cycle 0, patients will start venetoclax by 20mg-50mg-100mg-200mg daily in a weekly dose escalation way. The combination of full dose venetoclax (400mg) and orelabrutinib will continue for an additional 12 cycles. Venetoclax and orelabrutinib will be continued until the completion of cycle 12, start of new CLL-directed therapies, disease progression or unacceptable toxicities, depending on which comes first. Orelabrutinib is intended to be admistratered orally 150mg once daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of BM-uMRD after completion of combination therapy (Day 1 of Cycle 16)	Rate of BM-uMRD is defined by negative MRD in the bone marrow by flow cytometry at a sensitivity of 10^-4. The Clopper Pearson method is used to estimate the 95% two-sided confidence interval (CI) of the rate of BM-uMRD.	On Day 1 of Cycle 16 (each cycle is 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of undetected peripheral blood MRD by flow cytometry	Rate of undetected peripheral blood MRD is defined by negative MRD in the peripheral blood by flow cytometry at a sensitivity of 10^-4.	On screening, Day 1 of Cycle 4, Day 1 of Cycle 7, Day 1 of Cycle 10, Day 1 of Cycle 16, Day 1 of Cycle 20, Day 1 of Cycle 24, Day 1 of Cycle 28 and Day 1 of Cycle 34 (each cycle is 28 days)
Rate of complete response (CR)	CR is defined by the 2018 IWCLL criteria. Enhanced contrast CT combined with bone marrow examination will be performed to determine if a patient achieve CR.	On Day 1 of Cycle 7, Day 1 of Cycle 16, Day 1 of Cycle 22, and Day 1 of Cycle 28 (each cycle is 28 days)
Progression-free survival (PFS)	PFS is defined as the time from the first dose of venetoclax to progression, or death due to any cause, whichever occurs first. For subjects without progression, relapse, or death at the time of analysis, EFS will be censored at the last assessment date.	From the first dose of venetoclax until the date of progression or date of death from any cause, whichever came first, assessed up to 112 months
Overall survival (OS)	OS is defined as the time from the first dose of venetoclax to death due to any cause. Subjects who remain alive at the time of analysis will be censored at the last known alive date of the subject.	From the first dose of venetoclax until the date of death from any cause, assessed up to 112 months
Time to next treatment (TTNT)	TTNT is defined as the time from the first dose of venetoclax to the next CLL-directed therapies.	From the first dose of venetoclax to the next CLL-directed therapies due to progression, assessed up to 112 months
Adverse Events	All treatment-emergent AEs will be included in the analysis. For each AE, the number and percentage of subjects who experience at least one occurrence of the given event will be summarized. The number and percent of subjects with TEAEs will be summarized according to intensity (CTCAE, v5) or IWCLL for hematologic toxicity, and drug relationship, as well as categorized by system organ class and preferred term. Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those subjects who die, who discontinue treatment due to an AE, or who experience a severe AE or a SAE.	From screening to 30 days after the end of cycle 12 (each cycle is 28 days)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRD relapse	MRD relapse is now defined as either: (1) conversion of MRD negativity to MRD positivity, independent of the MRD technique, or (2) increase of MRD ≥ 1 log10 between any 2 positive samples measured in the same tissue (PB or BM) in patients with MRD+ CLL.	From the date of MRD negativity to the date of MRD positivity or the occurrence of increase of MRD ≥ 1 log10 between any 2 positive samples measured in the same tissue, assessed up to 112 months
Clearance of BTK C481S mutation	Baseline BTK C418S mutation by droplet digital PCR will performed. Patients with detected baseline BTK C481S mutation will be re-evaluated at C4D1, C7D1, C10D1, and C16D1 to determine the effects of venetoclax on the clearance of BTK C481S mutation.	On Day 1 of Cycle 4, Day 1 of Cycle 7, Day 1 of Cycle 10, and Day 1 of Cycle 16 (each cycle is 28 days)
Occurance of laboratory or clinical TLS	In the dose ramp-up phase, laboratory and clinical monitoring will be regularly performed to determine if TLS occur.	From Day 1 of Cycle 0 to Day 28 of Cycle 0 (dose ramp-up phase)
MRD level detected by NGS IG sequencing	Peripheral blood MRD by NGS of immunoglobulin (IG) will be evaluated at C0D1, C4D1, C7D1, C10D1, and C16D1. NGS of IG for determining bone marrow MRD status will be performed at C0D1, C7D1, and C16D1. At the timepoints, the correlation between MRD by flow cytometry and NGS MRD will be evaluated.	On Day 1 of Cycle 0, Day 1 of Cycle 4, Day 1 of Cycle 7, Day 1 of Cycle 10, and Day 1 of Cycle 16 (each cycle is 28 days)

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital with Nanjing Medical University
• Collaborators: AbbVie

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): February 1, 2028

Study Registration Dates

• First Submitted: April 8, 2025
• First Submitted That Met QC Criteria: April 27, 2025
• First Posted (Actual): May 6, 2025

Study Record Updates

• Last Update Posted (Actual): November 25, 2025
• Last Update Submitted That Met QC Criteria: November 24, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Leukemia, Lymphocytic, Chronic, B-Cell; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; zanubrutinib; acalabrutinib; ibrutinib; orelabrutinib
• Other Study ID Numbers: 2024-SR-1147

Drug and device information, study documents

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