A phase I study of two different schedules of nab-paclitaxel (nab-P) with ascending doses of vandetanib (V) with expansion in patients (Pts) with pancreatic cancer (PC).

Abstract

4124 Background: nab-P is an albumin bound paclitaxel. V is a potent inhibitor of VEGFR 2, RET and EGFR. Preclinical data reveal enhanced nab-P activity with concurrent VEGF inhibition. Primary objective was to determine the maximum tolerated dose (MTD). A secondary objective was to assess preliminary efficacy in pts with PC. 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 (100 mg, 200 mg, 300 mg orally daily). A 3+3 design was used. Expansion at the MTD (15 pts) was planned in both cohorts. Cohort A expansion was restricted to PC pts who failed gemcitabine based therapy. Two single nucleotide polymorphisms (SNPs), SPARC rs1059829 and rs3210714, were evaluated by PCR-RFLP on genomic DNA extracted from peripheral whole blood in 25 pts. Results: Dose escalation results were presented at ASCO 2010 (J Clin Oncol 28:15s, 2010 suppl; abstr 3059).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 observed 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. 29 pts with PC were treated: 9 (cohort A dose escalation), 15 (cohort A dose expansion) and 5 (cohort B). Median age was 62; 16 males, 13 females. Median number of prior treatments 2 (range 1-4). 22 pts with PC were evaluable for response: 6 (27.5%) PR, 10 (45%) SD and 6 (27.5%) PD. Median PFS was 5.3 mo (95% CI: 3.7-7.3) and median OS 8.2 mo (95% CI: 6.2 -11.5). No statistically significant association was found between SNPs in SPARC and clinical outcome. Conclusions: Both schedules of nab-P with V are well tolerated. The MTD for both cohorts is the maximum planned dose. The preliminary efficacy in a cohort of pts with refractory PC is promising and warrants further evaluation. Grade 3 or 4 toxicities for all pts in all cycles Cohort A% Cohort B% Neutropenia 31 48 Diarrhea 13 12 Leukopenia 10 16 Acneiform rash 15 8 Fatigue 10 4 Hypertension 5 12 Prolonged QTC 5 8 Thombosis 8 4 Joint pain 5 4 Muscle pain 5 4 Anorexia 5 0 Dyspnea 5 0 Nausea 5 0 Pruritus 5 0