Phase I trial of oral ABT-751 in pediatric patients: Preliminary evidence of activity in neuroblastoma (NBL)

Abstract

8527 Background: ABT-751 is an orally bioavailable sulfonamide that binds to the colchicine site on β-tubulin and inhibits microtubule polymerization. In adults, the maximum tolerated dose (MTD) is 250 mg daily x 7 days (d) or 200 mg daily x 21d. Dose limiting toxicities (DLTs) were ileus and peripheral neuropathy. Methods: Forty children ages 4 to 18 (median 13 yrs) with refractory solid tumors were enrolled, including 16 with NBL. For each cycle, patients received ABT-751 orally once daily for 7 consecutive days followed by a 14-day break or for 21 consecutive days followed by a 7-day break. Dose levels were 100 (n=4), 130 (n=6), 165 (n=6), 200 (n=7), and 250 (n=2) mg/m2/d on the 7d schedule and 75 (n=3), 100 (n=4), 130 (n=5), and 165 (n=3) mg/m2/d on the 21d schedule. PK sampling was performed on Day 1 of Cycle 1, and plasma concentrations were assayed using HPLC with tandem mass spectrometric detection method. Results: The MTD is 200 mg/m2/d (adult equivalent 375 mg) on the 7d schedule. DLTs included Grade (Gr) 2 motor neuropathy (n=1) at 130, Gr 3 constipation (n=1) at 165, and asymptomatic decrease left ventricular shortening fraction (n=2), neuropathic pain (n=1), fatigue (n=2), and neutropenia (n=1) at 250 mg/m2/d. On the 21d schedule, DLTs included Gr 4 neuropathy (n=1), vomiting and dehydration (n=1), Gr 3 fatigue (n=3), pain (n=1), and Gr 3 transaminase elevation (n=1) at 165 mg/m2/d. Accrual on the 21d schedule continues at 130 mg/m2/d (adult equivalent 260 mg). ABT-751 is rapidly absorbed (Tmax= 2.5 ± 1.2 h) and eliminated (t1/2 = 6.0 ± 2.5 h) (mean ± SD, N = 33). AUC and Cmax increase in proportion to the dose. Patients with NBL experienced prolonged disease stabilization. The median duration for evaluable patients with NBL (n=13) was 5 cycles (range 1–40); 7 patients continue on treatment and 3 are too early to evaluate. Three have had resolution of 123I-meta-iodobenzylguanidine (MIBG) positive lesions. Conclusions: ABT-751 is well tolerated in children at doses exceeding the adult MTD on the 7d and 21d schedules. Absorption after oral administration is rapid and exposure is dose proportional. Disease stabilization and improvement in MIBG scans suggests ABT-751 activity in neuroblastoma. A Phase 2 trial is in development. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories