Venetoclax as Consolidation in CLL Patients Treated With BTK Inhibitor Monotherapy

NCT ID: NCT06958705

Last Updated: 2025-11-25

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 79 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-12-01
• Study Completion Date: 2028-02-01

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.

Conditions

Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL)

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

CLL/SLL patients on ibrutinib monotherapy for ≥ 6 months

Group Type: EXPERIMENTAL

Venetoclax combined with Ibrutinib

Intervention Type: DRUG

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.

CLL/SLL patients on zanubrutinib monotherapy for ≥ 6 months

Group Type: EXPERIMENTAL

Venetoclax combined with Zanubrutinib

Intervention Type: DRUG

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.

CLL/SLL patients on acalabrutinib monotherapy for ≥ 6 months

Group Type: EXPERIMENTAL

Venetoclax combined with Acalabrutinib

Intervention Type: DRUG

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.

CLL/SLL patients on orelabrutinib monotherapy for ≥ 6 months

Group Type: EXPERIMENTAL

Venetoclax combined with Orelabrutinib

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AbbVie

INDUSTRY

Sponsor Role: collaborator

The First Affiliated Hospital with Nanjing Medical University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Department of Haematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital

Nanjing, Jiangsu, China

Site Status: RECRUITING

Countries

China

Central Contacts

Jianyong Li, PhD, MD

Role: CONTACT

lijianyonglm@126.com

86-13951877733

Huayuan Zhu, PhD, MD

Role: CONTACT

huayuan.zhu@hotmail.com

86-13813810650

Facility Contacts

Jianyong Li, PhD, MD

Role: primary

lijianyonglm@126.com

86-13951877733

Huayuan Zhu, PhD, MD

Role: backup

huayuan.zhu@hotmail.com

86-13813810650

Other Identifiers

2024-SR-1147

Identifier Type: -

Identifier Source: org_study_id