Clinical trial NCT06958705: Venetoclax as Consolidation in CLL Patients Treated With BTK Inhibitor Monotherapy
Official title: Study of the Efficacy and Safety of Venetoclax as Consolidation to Achieve Fix-Duration Treatment in CLL Patients Treated With BTK Inhibitor Monotherapy
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL)
Lead sponsor: The First Affiliated Hospital with Nanjing Medical University
Sponsor class: OTHER
Collaborators: name: AbbVie
First posted: 2025-05-06
Enrollment: 79
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Rate of BM-uMRD after completion of combination therapy (Day 1 of Cycle 16)
timeFrame: On Day 1 of Cycle 16 (each cycle is 28 days)
Secondary outcomes:
measure: Rate of undetected peripheral blood MRD by flow cytometry
timeFrame: 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)
measure: Rate of complete response (CR)
timeFrame: 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)
measure: Progression-free survival (PFS)
timeFrame: 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
measure: Overall survival (OS)
timeFrame: From the first dose of venetoclax until the date of death from any cause, assessed up to 112 months
measure: Time to next treatment (TTNT)
timeFrame: From the first dose of venetoclax to the next CLL-directed therapies due to progression, assessed up to 112 months
measure: Adverse Events
timeFrame: From screening to 30 days after the end of cycle 12 (each cycle is 28 days)
Other outcomes:
measure: MRD relapse
timeFrame: 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
measure: Clearance of BTK C481S mutation
timeFrame: 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)
measure: Occurance of laboratory or clinical TLS
timeFrame: From Day 1 of Cycle 0 to Day 28 of Cycle 0 (dose ramp-up phase)
measure: MRD level detected by NGS IG sequencing
timeFrame: 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)
Locations:
city: Nanjing
country: China
facility: Department of Haematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital
state: Jiangsu
Study officials:
References: