Citation: European Journal of Cancer Supplements, Vol 7 No 2, September 2009, Page 269

P. Kaufman¹, R. de Boer², S. White³, P. Mainwaring⁴, B. Koczwara⁵, L.M. Urquhart¹, Y. Ye⁶, Y. Sun⁷, H. Adewoye⁸, D. Kotasek<sup>9

1</sup>Dartmouth-Hitchcock Medical Center, Hematology/Oncology, Lebanon NH, USA
²Royal Melbourne and Western Hospitals, Oncology, Parkville and Footscray VIC, Australia
³Austin Health, Medical Oncology, Heidelberg VIC, Australia
⁴Mater Hospital, Medical Oncology, South Brisbane QLD, Australia
⁵Flinders Medical Centre, Medical Oncology, Bedford Park SA, Australia
⁶Amgen Inc., Biostatistics and Epidemiology, Thousand Oaks CA, USA
⁷Amgen Inc., Pharmacokinetics & Drug Metabolism, Thousand Oaks CA, USA
⁸Amgen Inc., Oncology, Thousand Oaks CA, USA
⁹Ashford Cancer Centre, Medical Oncology, Ashford SA, Australia

Background: Motesanib, an oral inhibitor of angiogenesis, selectively targets VEGF receptors 1, 2, and 3; PDGF and Kit receptors. This ongoing phase 1b open-label dose-finding study determines the maximum-tolerated dose (MTD), safety, pharmacokinetics (PK), and efficacy of motesanib plus paclitaxel (P) or docetaxel (D) in patients (pts) with advanced breast cancer (ClinicalTrials.gov ID NCT00322400; sponsor: Amgen Inc.).
Methods: Pts with ECOG 0/1 and ≤1 prior chemotherapy regimen for metastatic breast cancer are eligible. Pts were treated with (until toxicity or disease progression) motesanib (50 or 125 mg) QD orally continuously from cycle 1 day 3 plus either P (Arm A) 90 mg/m² on days 1, 8, and 15 of each 28-day cycle; or D (Arm B) at either 100 mg/m² on day 1 of every 21-day cycle; or at 75 mg/m² with motesanib at MTD (125 mg). Objective response (OR) per RECIST was assessed every 8 (Arm A) or 6 wks (Arm B).
Results: 33 pts (Arm A, n = 10; Arm B, n = 23) have received ≥1 dose of motesanib. Median age is 51 (range 28–66) yrs. 5 dose-limiting toxicities (all grade [gr] 3) occurred in 4 pts: abnormal liver function test and deep vein thrombosis (Arm A, 125 mg), fatigue (Arm A, 125 mg), gallbladder enlargement (Arm B, 125 mg+D 75 mg/m²), and migraine (Arm B, 125 mg). The motesanib MTD has not been reached; the target dose is 125 mg QD. 28 (85%) pts had motesanib-related adverse events (AEs). The most common (highest gr) AEs were: diarrhea, Arm A/B 60%/61% (gr 3, 0%/13%); fatigue, 30%/26% (gr 3, 10%/4%); hypertension, 20%/22% (gr 3, 10%/4%); and nausea, 10%/26% (no gr 3). No related AE ≥gr 4 was reported. 2 deaths occurred on study (Arm B; 50 and 125 mg, n = 1 each); neither was considered to be motesanib-related. Motesanib PK parameters were generally within the range described for single-agent motesanib treatment. PK profiles of P and D showed high interpatient variability; AUC was higher in some pts after motesanib coadministration. Efficacy at data cutoff in pts with measurable disease at baseline is shown (Table).

	Best OR, n (%)
	Arm A (n = 7)	Arm B (n = 18)
Partial response	2 (29)	5 (28)
Stable disease (SD)	2 (29)	9 (50)
SD ≥24 wks	0	3 (17)
Duration of response, median days (range)	169 (58+, 169)	198 (96, 337+)

Conclusions: Motesanib in combination with P or D appears to be tolerable and shows evidence of antitumor activity in pts with advanced breast cancer. Coadministration with either P or D had no major effect on motesanib PK.