Safety, Pharmacokinetics, Pharmacodynamics, and Activity of Navitoclax, a Targeted High Affinity Inhibitor of BCL-2, in Lymphoid Malignancies

By W. Wilson, O. O'Connor, M. Czuczman, A. LaCasce, J. Gerecitano, J. Leonard, A. Tulpule, K. Dunleavy, H. Xiong, Y. Chiu and 7 more. The Lancet Oncology, 2010

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SUMMARY Background BCL-2 family proteins play a central role in regulating clonal selection and survival of lymphocytes and are frequently over expressed in lymphomas. Navitoclax (ABT-263) is a targeted high-affinity small molecule that occupies the BH3 binding groove of BCL-2 and BCL-XL and inhibits their anti-apoptotic activity. Experimentally, navitoclax kills cells in a BAX/BAK-dependent manner and results in regression of lymphoid tumors in xenograft models. Methods This is a phase I dose-escalation study of navitoclax in patients with relapsed or refractory lymphoid malignancies. Study endpoints included safety, maximum tolerated dose (MTD), pharmacokinetic profile and clinical activity. In addition, mechanism-based pharmacodynamic effects on platelets and lymphocytes were assessed. Navitoclax was orally administered and assessed on an intermittent schedule of once daily for 14 days followed by 7 days off (14/21 days) or on a continuous once daily schedule (21/21 days). This trial is registered with ClinicalTrials.gov, number NCT00406809. Findings Fifty-five patients were enrolled, (median age 59 years, IQR 51–67), of whom two did not complete the first cycle and were not evaluable for assessment of dose-limiting toxicity (DLT). Common toxicities included grade 1/2 diarrhea and fatigue in 31 and 21 patients, respectively. Thrombocytopenia and neutropenia were the serious common toxicities with grade 3/4 observed in 29 and 17 patients, respectively. On the intermittent schedule (14/21), 5 DLT’s were observed; two due to hospitalizations for bronchitis and pleural effusion, and one each due to grade 3 transaminase elevation, grade 4 thrombocytopenia and grade 3 cardiac arrhythmia. Navitoclax caused a rapid and dose-dependent decline in peripheral platelets following initial drug exposure, followed by a rebound. To reduce the platelet nadir associated with intermittent dosing, a lead-in dose followed by continuous dosing (21/21 schedule) was examined. Three DLT’s were observed on this schedule (21/21); one each due to grade 4 thrombocytopenia, grade 3 transaminase elevation and grade 3 gastrointestinal bleed. Navitoclax showed a pharmacodynamic effect on circulating platelets and T-cells. Based on these findings, a 150 mg 7-day lead-in dose followed by 325 mg dose administered on a continuous (21/21) schedule was selected for phase II study. Clinical responses occurred at all dose levels and in multiple histologies. Partial responses were observed in 10 of 46 patients with evaluable disease, and the responders had a median progression-free survival of 455 days (IQR 40-218).

Subfields: Genetics, Molecular Biology, Public Health, Environmental and Occupational Health

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