Venetian: A Phase 2b/3 Study to Evaluate the Risk of Tumor Lysis Syndrome (TLS) and Optimize Initiation of Venetoclax (Ven) in Patients with Previously Untreated Chronic Lymphocytic Leukemia (CLL)
Authors: Wierda William G. , Davids Matthew S. , Sharman Jeff P. , Ghosh Nilanjan , Feng Yang , Fusco Mary Jean , Hilger-Rolfe Jacqueline , Qian Chen , Sinai Wendy J. , Wimberley Sophie , Seymour John F. 
Published: December 2024

Background and Significance: Ven is a highly selective oral BCL-2 inhibitor and among the standard-of-care regimens for patients with previously untreated CLL/small lymphocytic lymphoma (SLL). Due to a potent pro-apoptotic effect and tumor killing activity, BCL-2 inhibitors, including Ven, pose a risk of inducing TLS. Proper adherence to the Ven ramp-up schedule, entailing slowly increasing the daily dose of Ven to reach the target dose, has been shown to gradually reduce tumor burden while minimizing the risk of TLS. Assessment of tumor burden after use of debulking agents (obinutuzumab [Obi] or acalabrutinib [Acala]) enables reduction of tumor burden and TLS risk, thereby maximizing the potential for patients to start Ven in the outpatient setting.

Patients with medium tumor burden (and creatinine clearance [CrCl] ≥80 mL/min) or low tumor burden start Ven in the outpatient setting. For these patients, despite the low incidence of TLS and risk mitigation, TLS prophylaxis requires lab monitoring with pre-dose labs and post-dose labs at 6-8 hours and 24 hours for the first dose on Weeks 1 and 2, with only pre-dose labs assessed on Weeks 3-5. The logistical challenges associated with the post-dose labs during Weeks 1 and 2 may put a burden on patients, oncologists, and healthcare systems, particularly in the community setting. Hence, there is a high unmet need for a simplified Ven initiation strategy that maintains safety. Currently, comprehensive data are lacking on the characteristics of TLS, specifically at each lab monitoring point and at each dose level after debulking.

Here we present the study design of the M24-287 VENETIAN study (NCT06428019). The overall goal of this trial is to assess the incidence of TLS events requiring clinical intervention to evaluate the potential of optimizing initiation while maintaining the excellent safety profile of Ven.

Study Design and Methods: This is a prospective, open-label, international, 2-part, multicenter, Phase 2b/3 study. Part 1, which corresponds to the Phase 2b segment, aims to assess the risk of TLS of Ven in combination with Obi or Acala using different ramp-up schedules in first-line CLL/SLL. Patients aged ≥18 years, with previously untreated CLL/SLL requiring treatment per 2018 International Workshop on CLL criteria, Eastern Cooperative Oncology Group performance status 0-2, and CrCl ≥30 mL/min are eligible.

This study is hypothesis generating and not statistically powered. Part 2, a confirmatory Phase 3 trial, will be planned based on results from Part 1. The enrollment target for Part 1 is 120 patients across 80 sites worldwide. Patients will be randomized in a 1:1:1:1 ratio to 1 of the following 4 arms: Arm A of Ven + Obi, and Arms B, C, and D of Ven + Acala with varying ramp-up periods. Ven and Acala will be administered orally, whereas Obi will be administered by intravenous infusion. The total study duration is approximately 28 months.

The primary endpoint is the incidence of treatment-emergent laboratory TLS or hyperkalemia (potassium &gt;6.0 mmol/L) per Howard criteria requiring a clinical intervention per independent review committee (IRC) assessment during the Ven ramp-up period in patients achieving a medium tumor burden (with CrCl ≥80 mL/min) or low tumor burden (regardless of CrCl level) after debulking therapy. Secondary endpoints include the incidence of laboratory TLS-related events or hyperkalemia per Howard criteria requiring clinical intervention (ie, treating metabolic abnormalities, withholding or reducing the dose of venetoclax) per IRC assessment at each dose level and at each laboratory monitoring point, and assessment of the percentage of patients with reduction of tumor burden from baseline to after debulking. The study is open for enrollment and registered under NCT06428019 at ClinicalTrials.gov.