Primary Analysis of a Phase 1b Combination Study of Motesanib (AMG 706) with Paclitaxel or Docetaxel for the Treatment of Locally Recurrent, Unresectable or Metastatic Breast Cancer.
Authors: de Boer R. , Kaufman P. , White S. , Mainwaring P. , Koczwara B. , Chan A. , Urquhart L. , Ye Y. , Sun Y. , Adewoye H. , Kotasek D. 
Published: December 2010

Abstract
Background: Motesanib is an oral inhibitor of VEGF receptors 1, 2 and 3; PDGF and Kit receptors that is under investigation as an antiangiogenic agent. The primary objective of this phase 1b study was to determine the maximum-tolerated dose (MTD) of motesanib in combination with either paclitaxel (P) or docetaxel (D) in patients (pts) with advanced breast cancer. Here we report data from 16 weeks after the last patient was enrolled.Methods: Eligible pts with ECOG ≤1 and ≤1 prior chemotherapy for metastatic breast cancer received escalating doses of motesanib (50 or 125mg orally QD) continuously from day 3 of cycle 1 with 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 combined with motesanib MTD (125mg QD). Objective response rate (ORR) per RECIST was assessed every 8 (Arm A) or 6 weeks (Arm B).Results: 45 pts have received ≥1 dose of motesanib (Arms A/B, n=10/35). Median (range) age is 51 (28-81) years. Dose-limiting toxicities occurred in 3 pts (fatigue, 2 pts; migraine, 1 pt), all grade 3 and all in Arm B (100mg/m2 D, motesanib at 125mg QD). The motesanib target dose was 125mg QD; the MTD was not reached. Motesanib-related adverse events (AEs) were reported in 40 pts (Arms A/B, n=8/32) with diarrhea (Arms A/B, n=7/24; highest grade 3, n=0/6), fatigue (n=3/15; highest grade 3, n=1/4), nausea (n=2/10; no grade ≥3) and hypertension (n=2/9; highest grade 3, n=1/1) being the most common. Motesanib-related AEs of interest included deep vein thrombosis (Arms A/B, n=1/0; grade 3), epistaxis (n=2/8, all grade 1) and cholecystitis (n=1/1, both grade 3). No motesanib-related grade 4 AEs were reported. Three deaths occurred on study; two were grade 5 AEs not related to motesanib (multiorgan failure and bronchopneumonia; Arm B 100mg/m2 D, 125mg QD and 50mg QD, respectively); one death was due to disease progression (Arm B 75mg/m2 D, 125mg QD). Motesanib PK parameters were generally within the range previously described for single-agent motesanib. Geometric least square mean (GLSM) point estimates for Cmax and AUC0-inf suggest an increase in exposure of P by 20-45% after coadministration with motesanib. PK profiles of D showed high interpatient variability, with AUC higher in some pts after motesanib coadministration. In the 32 pts with measurable disease at baseline (Arms A/B, n=7/25) the best ORR (95% CI) at last data cut-off was 57% (18.4, 90.1%) in Arm A, 56% (29.9%, 80.2%) in Arm B with 100mg/m2 D, and 56% (21.2%, 86.3%) in Arm B with 75mg/m2 D. No complete responses were observed. The clinical benefit rate (CR+PR+durable SD≥24 weeks) was 57% in Arm A, 69% in Arm B with 100mg/m2 D, and 78% in Arm B with 75mg/m2 D. Two out of 4 responders in Arm A later progressed with a duration of response (DOR) of 4 and 6 months. In Arm B, 11 out of 14 responders later progressed with a median (range) DOR of 5.7 (2.3 to 12.7) months.Conclusions: In this phase 1b study of pts with advanced breast cancer, the combination of motesanib and P or D was tolerable with evidence of antitumor activity. The MTD was not reached. Coadministration of P or D had no major effect on motesanib PK.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 205.