Venetoclax as Consolidation in CLL Patients Treated With BTK Inhibitor Monotherapy

Phase 2

Recruiting

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

• Registration Number: NCT06958705
• Lead Sponsor: The First Affiliated Hospital with Nanjing Medical University

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Status Verified: 2025-04
• Study First Submitted: 2025-04-08
• Study First Submitted QC: 2025-04-27
• Last Update Submitted: 2025-04-27
• Study First Posted: 2025-05-06
• Last Update Posted: 2025-05-06
• Study Start: 2025-06-01
• Primary Completion: 2027-12-01
• Study Completion: 2028-02-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 79

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CLL/SLL patients on ibrutinib monotherapy for ≥ 6 months	Venetoclax combined with Ibrutinib	-
CLL/SLL patients on zanubrutinib monotherapy for ≥ 6 months	Venetoclax combined with Zanubrutinib	-
CLL/SLL patients on acalabrutinib monotherapy for ≥ 6 months	Venetoclax combined with Acalabrutinib	-
CLL/SLL patients on orelabrutinib monotherapy for ≥ 6 months	Venetoclax combined with Orelabrutinib	-

Primary Outcome Measures

Name	Time	Method
Rate of BM-uMRD after completion of combination therapy (Day 1 of Cycle 16)	On Day 1 of Cycle 16 (each cycle is 28 days)	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.

Secondary Outcome Measures

Name	Time	Method
Rate of undetected peripheral blood MRD by flow cytometry	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 undetected peripheral blood MRD is defined by negative MRD in the peripheral blood by flow cytometry at a sensitivity of 10\^-4.
Rate of complete response (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)	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.
Progression-free survival (PFS)	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	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.
Overall survival (OS)	From the first dose of venetoclax until the date of death from any cause, assessed up to 112 months	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.
Time to next treatment (TTNT)	From the first dose of venetoclax to the next CLL-directed therapies due to progression, assessed up to 112 months	TTNT is defined as the time from the first dose of venetoclax to the next CLL-directed therapies.
Adverse Events	From screening to 30 days after the end of cycle 12 (each cycle is 28 days)	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.

Trial Locations

Locations (1)

Department of Haematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital; 🇨🇳 Nanjing, Jiangsu, China