Journal
LANCET ONCOLOGY
Volume 11, Issue 12, Pages 1149-1159Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/S1470-2045(10)70261-8
Keywords
-
Categories
Funding
- Abbott Laboratories
- Genentech
- National Cancer Institute National Institutes of Health
Ask authors/readers for more resources
Background Proteins of the BCL 2 family regulate clonal selection and survival of lymphocytes, and are frequently overexpressed in lymphomas Navitoclax is a targeted high affinity small molecule that inhibits the anti apoptotic activity of BCL 2 and BCL XL We aimed to assess the safety and antitumour activity of navitoclax in patients with lymphoid tumours and establish the drug's pharmacokinetic and pharmacodynamic profiles Methods In this phase 1 dose escalation study patients (aged >= 18 years) with relapsed or refractory lymphoid malignancies were enrolled and treated at seven sites in the USA between November 2006 and November 2009 A modified Fibonacci 3+3 design was used to assign patients to receive oral navitoclax once daily by one of two dosing schedules intermittently for the first 14 days of a 21 day cycle (14/21) at doses of 10 20 40 80 110, 160, 225, 315 or 440 mg/day or continuously for 21 days of a 21 day cycle (21/21) at doses of 200, 275, 325 or 425 mg/day Study endpoints were safety, maximum tolerated dose, pharmacokinetic profile pharmacodynamic effects on platelets and T cells and antitumour activity This trial is registered with ClinicalTrials gov number NCT00406809 Findings 55 patients were enrolled (median age 59 years IQR 51-67), 38 to receive the 14/21 dosing schedule and 17 to receive the 21/21 dosing schedule Common toxic effects included grade 1 or 2 anaemia (41 patients) infection (39) diarrhoea (31) nausea (29) and fatigue (21) and grade 3 or 4 thrombocytopenia (29) lymphocytopenia (18) and neutropenia (18) On the Intermittent 14/21 schedule, dose limiting toxic effects were hospital admissions for bronchitis (one) and pleural effusion (one) grade 3 increase in aminotransferases (one) grade 4 thrombocytopenia (one), and grade 3 cardiac arrhythmia (one) To reduce platelet nadir associated with intermittent 14/21 dosing we assessed a 150 mg/day lead in dose followed by a continuous 21/21 dosing schedule On the 21/21 dosing schedule two patients did not complete the first cycle and were excluded from assessment of dose-limiting toxic effects dose-limiting toxic effects were grade 4 thrombocytopenia (one), grade 3 increase m aminotransferases (one) and grade 3 gastrointestinal bleeding (one) Navitoclax showed a pharmacodynamic effect on circulating platelets and T cells Clinical responses occurred across the range of doses and in several tumour types Ten of 46 patients with assessable disease had a partial response and these responders had median progression free survival of 455 days (IQR 40-218) Interpretation Navitoclax has a novel mechanism of peripheral thrombocytopenia and T cell lymphopenia attributable to high affinity inhibition of BCL XL and BCL 2 respectively On the basis of these findings a 150 mg 7 day lead in dose followed by a 325 mg dose administered on a continuous 21/21 dosing schedule was selected for phase 2 study
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available