Phase 1b study of motesanib diphosphate (AMG 706) in combination with paclitaxel or docetaxel for the treatment of locally recurrent, unresectable or metastatic breast cancer.

Abstract

#4117 Background: Motesanib is a novel oral angiogenesis inhibitor designed to selectively target the tyrosine kinase activity of VEGF 1, 2 and 3; PDGF and Kit receptors. Here we report safety, preliminary efficacy and pharmacokinetics (PK) from an ongoing phase 1b dose-finding study of motesanib plus either paclitaxel (P) or docetaxel (D) in patients (pts) with advanced breast cancer.
 Methods: Eligible pts with ECOG 0 or 1 and ≤1 prior chemotherapy regimen for metastatic breast cancer received (until toxicity or disease progression) escalating doses of motesanib (50 or 125mg) QD orally continuously from day 3 of cycle 1 plus either P (Arm A) at 90mg/m2 on days 1, 8 and 15 of each 28-day cycle; or D (Arm B) at either 100mg/m2 on day 1 of every 21-day cycle or at 75mg/m2 with motesanib maximum tolerated dose (125mg QD). Objective response (OR) per RECIST was assessed every 8 (Arm A) or 6 wks (Arm B).
 Results: To date, 33 pts have received ≥1 dose of motesanib: Arm A, n=10; Arm B, n=23. Median age is 51 (range, 28-66) years. There were 5 DLTs (all grade 3) in 4 pts: abnormal liver function tests and deep vein thrombosis (Arm A, 125mg QD), fatigue (Arm A, 125mg QD), gallbladder enlargement (Arm B, 125mg QD+75mg/m2 D) and migraine (Arm B, 125mg QD). 28 pts (85%) had motesanib-related AEs; the most common were (worst grade): diarrhea, Arm A/B 60%/61% (grade 3, 0%/13%); fatigue, 30%/26% (grade 3, 10%/4%); hypertension, 20%/22% (grade 3, 10%/4%); and nausea, 10%/26% (no grade 3). Treatment-related AEs of interest in Arm A/B included epistaxis (10%/18%; all worst grade 1) and deep vein thrombosis (10%/0%; all worst grade 3). There were no grade 4 or 5 related AEs. Two deaths on study occurred (Arm B; 50 and 125mg QD n=1 each); both were not considered to be motesanib related. Motesanib PK parameters were generally within the range previously described for single-agent motesanib. PK profiles of P and D showed high interpatient variability, with AUC higher in some pts after motesanib coadministration. In pts with measurable disease at baseline (Arms A&B, n=7&18), best OR at time of last data cut-off was: confirmed PR in Arm A n=2 (29%), in Arm B n=5 (28%); SD in Arm A n=2 (29%), in Arm B n=9 (50%); durable SD ≥24 wks in Arm A n=0, in Arm B n=3 (17%). Median (range) duration of response currently is 169 (58-169) days in Arm A and 198 (96-337+) days in Arm B.
 Conclusions: Motesanib combined with P or D appears to be tolerable with evidence of antitumor activity in pts with advanced breast cancer. No marked effect on motesanib PK has been noted with coadministration of either P or D. Updated safety and efficacy data, including PFS, will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4117.