Abstract A92: A phase 1 safety and pharmacokinetic study of navitoclax in combination with docetaxel in patients with solid tumors.

Abstract

Abstract Background: Navitoclax (N; ABT-263) is a first-in-class orally available Bcl-2 protein inhibitor that in vitro and in vivo potentiates docetaxel (D) activity across a variety of solid tumor types. This ongoing phase I study evaluates the maximum tolerated dose (MTD) and safety and pharmacokinetic (PK) profile of N plus D. Methods: Patients (pts) with advanced solid tumors, adequate organ function and ECOG PS ≤1 were eligible. Pts were treated with (a) N 150 mg or 200 mg PO, QD on days (d) 1–3 or d1–5 q21 plus D 75 mg/m2 IV on d1 q21; or (b) N 150 mg PO, QD on d1–3, d8–10, and d15–17 q28 plus D 30 mg/m2 IV given on d1, 8, and 15 q28. To compare the PK of either agent alone, N was given on d3–5 or d3–7 only in cycle 2 of q21. PK samples were collected for N and D in cycles 1 and 2. Treatment-emergent adverse events (TAEs) were graded by NCI CTCAE V3.0. Results: Of 37 pts (M/F, 24/13) enrolled, data on 31 pts are available for safety, 33 pts for tumor response, and 13 pts for PK analysis. Pts (median age, 59 y; range, 30–83 y) were treated at 3 dose levels of N: 150 mg and 200 mg on d1–5 q21; 200 mg on d1–3 q21; and 150 mg on d1–3, d8–10, and d15–17 q28. Dose-limiting toxicities (DLTs) were grade (gr) 3 febrile neutropenia, and gr 4 thrombocytopenia (TCP) at N 200 mg d1–5 plus D 75 mg/m2 q21; gr 3/4 febrile neutropenia, gr 4 neutropenia, and gr 3 fatigue at N 200 mg d1–3 plus D 75 mg/m2 q21; gr 3 febrile neutropenia, gr 4 TCP, and death at N 150 mg d1–5 plus D 75 mg/m2 q21. The MTD of N with D at 75 mg/m2 q21 was 150 mg on d1–5. Other gr 3/4 TAEs (≥20%) were neutropenia (55%), leukopenia (32%), febrile neutropenia (29%), TCP (29%), and fatigue (13%); frequently occurring TAEs (≥20%) were fatigue (55%), TCP (45%), alopecia (42%), nausea (42%), anemia (36%), constipation (32%), decreased appetite (32%), diarrhea (32%), vomiting (32%), and dyspnoea (26%). Best tumor responses were 3 confirmed partial responses (PR), 2 currently unconfirmed PR, 8 stable disease (SD), 13 progressive disease, and 7 pts had incomplete data. Based on limited data, there was no significant PK interaction between N and D (Table). Conclusions: Navitoclax may be administered safely with D in 2 schedules; 150 mg with D 75 mg/m2 q21 and with D 30 mg/m2 q28. Both combinations were tolerable with no significant PK interactions in the D 75 mg/m2 q21 schedule. Antitumor activity was observed. Exploration of N 200 mg with weekly D is ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A92.