Phase 1-2 study of docetaxel plus aflibercept in patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer

Abstract

Background: Biologically targeted therapies have been postulated as a viable strategy to improve outcomes for women with ovarian cancer. We assessed the safety, tolerance, pharmacokinetics, relevant circulating and image-derived biomarkers, and clinical activity of combination aflibercept and docetaxel in this population.

Methods: For the phase 1 (pharmacokinetic) study, eligible patients had measurable, recurrent or persistent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with a maximum of two prior chemotherapy regimens. Aflibercept was administered intravenously over three dose levels (2, 4, or 6 mg/kg; one dose every 21 days) to identify the maximum tolerated dose for the phase 2 study. Pharmacokinetics were assessed and dynamic imaging was done during a lead-in phase with single-agent aflibercept (cycle 0) and during combination therapy with intravenous docetaxel (75 mg/m(2)). Eligibility for the phase 2 study was the same as for phase 1. Patients were enrolled in a two-stage design and given aflibercept 6 mg/kg intravenously and docetaxel 75 mg/m(2) intravenously, every 3 weeks. The primary endpoint was objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors version 1.0. The trial has completed enrolment and all patients are now off study. The trial is registered at ClinicalTrials.gov, number NCT00436501.

Findings: From the phase 1 study, the recommended phase 2 doses of aflibercept and docetaxel were found to be 6 mg/kg and 75 mg/m(2), respectively. Log-linear pharmacokinetics (for unbound aflibercept) were observed for the three dose levels. No dose-limiting toxicities were noted. 46 evaluable patients were enrolled in the phase 2 trial; 33 were platinum resistant (15 refractory) and 13 were platinum sensitive. The confirmed ORR was 54% (25 of 46; 11 patients had a complete response and 14 had a partial response). Grade 3-4 toxicities observed in more than two patients (5%) were: neutropenia in 37 patients (80%); leucopenia in 25 patients (54%); fatigue in 23 patients (50%); dyspnoea in ten patients (22%); and stomatitis in three patients (7%). Adverse events specifically associated with aflibercept were grade 1-2 hypertension in five patients (11%), and grade 2 proteinuria in one patient (2%).

Interpretation: Combination aflibercept plus docetaxel can be safely administered at the dose and schedule reported here, and is associated with substantial antitumour activity. These findings suggest that further clinical development of this combination in ovarian cancer is warranted.

Funding: US National Cancer Institute, US Department of Defense, Sanofi-Aventis, Gynecologic Cancer Foundation, Marcus Foundation, and the Commonwealth Foundation.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Dose–response curves for (A) bound aflibercept and (B) unbound aflibercept

A log-linear dose–response was observed for each of the three dose levels. Aflibercept binding to VEGF was rapid and reached asymptote around 7 days after infusion, for all three dose levels. The concentration at this asymptote (dotted line) represents binding of all endogenous VEGF and saturation of the complexed fraction. The concentration at which this saturation is reached is reproduced on the unbound aflibercept dose–concentration graph (B) to show saturation kinetics over time. Only dose level 3 (6 mg/kg) produced an unbound-to-bound ratio of greater than 1 at day 21 on the 3-week intravenous schedule, signifying VEGF binding throughout the treatment cycle.

Figure 2. Waterfall plot of the maximum percent change from baseline in measurable target lesions as defined by RECIST criteria

Solid line represents the minimum increase in the sum of target lesions designating progressive disease as best response; dotted line represents the minimum change in the sum of target lesions designating a response. All measures between these two are classified as stable disease. RECIST=Response Evaluation Criteria in Solid Tumors.

Figure 3

Kaplan-Meier curves for (A) progression-free survival and (B) overall survival for all evaluable patients enrolled in the phase 2 trial