Phase 1b dose-finding study of motesanib with docetaxel or paclitaxel in patients with metastatic breast cancer

Abstract

The purpose of this study was to investigate the safety, tolerability, and pharmacokinetics of motesanib when combined with docetaxel or paclitaxel in patients with metastatic breast cancer. In this open-label, dose-finding, phase 1b study, patients received motesanib 50 or 125-mg orally once daily (QD), beginning day 3 of cycle 1 of chemotherapy, continuously in combination with either paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 28-day cycle (Arm A) or docetaxel 100 mg/m(2) on day 1 every 21-day cycle (Arm B). Dose escalation to motesanib 125 mg QD occurred if the incidence of dose-limiting toxicities (DLTs, primary endpoint) was ≤ 33 %. If the maximum tolerated dose (MTD) of motesanib was established in Arm B, additional patients could receive motesanib at the MTD plus docetaxel 75 mg/m(2). Forty-six patients were enrolled and 45 received ≥ 1 dose of motesanib. The incidence of DLTs was <33 % in all cohorts; thus, motesanib 125 mg QD was established as the MTD. Seven patients (16 %) had grade 3 motesanib-related adverse events including cholecystitis (2 patients) and hypertension (2 patients). Pharmacokinetic parameters of motesanib were similar to those reported in previous studies. The objective response rate was 56 % among patients with measurable disease at baseline who received motesanib in combination with taxane-based chemotherapy. The addition of motesanib to either paclitaxel or docetaxel was generally tolerable up to the 125-mg QD dose of motesanib. The objective response rate of 56 % suggests a potential benefit of motesanib in combination with taxane-based chemotherapy.

Fig. 1

Study schema. ^aThe sponsor and the principal investigators reviewed the safety data from each cohort to evaluate possible drug effects and DLTs. ^bDisease progression or motesanib intolerability

Fig. 2

Comparison of motesanib C _max (a) and AUC_0-inf (b) values during cycle 1 with C _max and AUC_0-inf values obtained from previous motesanib studies. Study 1 is the first-in-human study of motesanib in patients with advanced solid tumors [7]; study 2 is the phase 1b study of motesanib in combination with chemotherapy or panitumumab in patients with NSCLC [9]

Fig. 3

Mean (±SE) fold change from baseline in PLGF (a) and VEGF (b) among patients receiving motesanib in combination with paclitaxel or docetaxel. No error bars are shown where only 1 or 2 samples were evaluable for a particular time point

Fig. 4

Change from baseline in tumor measurements among patients with measurable disease at baseline. Cohorts: A1 motesanib 50 mg QD + paclitaxel 90 mg/m²; A2 motesanib 125 mg QD + paclitaxel 90 mg/m²; B1 motesanib 50 mg QD + docetaxel 100 mg/m²; B2 motesanib 125 mg QD + docetaxel 100 mg/m²; B3 motesanib 125 mg QD + docetaxel 75 mg/m². One patient in Cohort A2 had no response assessment. SLD sum of longest diameters