A phase I study of two different schedules of nab-paclitaxel (Nab-p) with ascending doses of vandetanib (V) in patients (pts) with advanced solid tumors.

Abstract

3059 Background: Nab-p is an albumin bound paclitaxel. V is a potent inhibitor of VEGFR 2 and EGFR. Preclinical data reveal enhanced Nab-p activity with concurrent VEGF inhibition. Primary objective was to determine the maximum tolerated dose (MTD). Methods: Pts were randomized to one of 2 cohorts. Dose of Nab-p was fixed (Cohort A: Nab-p 100 mg/m2 IV weekly for 3 wks q 28 days; Cohort B: Nab-p 260 mg/m2 IV q 3 wks) while 3 doses of V were evaluated in both cohorts (100 mg, 200 mg, 300 mg PO daily). A standard 3+3 design was used. Expansion at the MTD was planned for both cohorts. Results: 46 pts were treated: 21 (cohort A), 13 (cohort B), 12 (cohort B expansion). Median age 56 (range 26-81), Karnofsky PS 100% (6), 90% (21), 80% (17), <70% (2). 17 males, 29 females. Median number of prior treatments 2 (range 1-7). Most common disease sites: pancreatic 15 (33%), ovarian 8 (17%), gastric 7 (15%), endometrial 3 (6%), lung 3 (6%). There was one DLT at each dose level in cohort A (grade 3 rash in 2 pts, grade 4 neutropenia in 1 pt). No DLTs in cohort B. MTD was Nab-p 100 mg/m2 IV weekly for 3/4 wks and V 300 mg daily in cohort A; Nab-p 260 mg/m2 IV q 3 wks and V 300 mg daily in cohort B. No grade 4 toxicities in cycle 1. Toxicities in all cycles were comparable to those in cycle 1 and will be reported at the time of presentation. 4 pts (3 with pancreatic ca and 1 with unknown primary ca) had a PR; 24 pts had SD (pancreatic 8, ovarian 7, prostate 2, lung 2, other 5). The median duration of SD was 5.7 mo (95% CI: 3.9-6.7). Conclusions: Both schedules of Nab-p with V are safe and well tolerated. The MTD for both cohorts was the maximum planned dose. Accrual to the expansion phase at the MTD in cohort A is ongoing and restricted to pts with advanced pancreatic cancer. Exploratory analysis of SPARC genomic polymorphisms as potential markers of efficacy is in progress. Cycle 1 grade 3 toxicities (other than DLT) Cohort A (n= 21) Cohort B dose escalation + expansion (n= 25) Neutropenia 19% 12% Nausea 5% — Vomiting 5% — Mucositis 5% — Hypertension 10% 8% Prolonged QT (asymptomatic) 5% 8% Arthralgia — 4% Diarrhea — 4% Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca Abraxis BioScience, AstraZeneca