Phase II trial of bevacizumab and sorafenib in recurrent ovarian cancer patients with or without prior-bevacizumab treatment

Abstract

Objective: To examine whether blocking multiple points of the angiogenesis pathway by addition of sorafenib, a multi-kinase inhibitor against VEGFR2/3, Raf, c-Kit, and PDGFR, to bevacizumab would yield clinical activity in ovarian cancer (OvCa).

Methods: This phase II study tested bevacizumab plus sorafenib in two cohorts; bevacizumab-naïve and bevacizumab-exposed patients. Bevacizumab (5 mg/kg IV every 2 weeks) was given with sorafenib 200 mg bid 5 days-on/2 days-off. The primary objective was response rate using a Simon two-stage optimal design. Progression-free survival (PFS) and toxicity were the secondary endpoints. Exploratory correlative studies included plasma cytokine concentrations, tissue proteomics and dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI).

Results: Between March 2007 and August 2012, 54 women were enrolled, 41 bevacizumab-naive and 13 bevacizumab-prior, with median 5 (2-9) and 6 (5-9) prior systemic therapies, respectively. Nine of 35 (26%) evaluable bevacizumab-naive patients attained partial responses (PR), and 18 had stable disease (SD) ≥ 4 months. No responses were seen in the bevacizumab-prior group and 7 (54%) patients had SD ≥ 4 months, including one exceptional responder with SD of 27 months. The overall median PFS was 5.5 months (95%CI: 4.0-6.8 months). Treatment-related grade 3/4 adverse events (≥5%) included hypertension (17/54 [31%]; grade 3 in 16 patients and grade 4 in one patient) and venous thrombosis or pulmonary embolism (5/54 [9%]; grade 3 in 4 patients and grade 4 in one patient). Pretreatment low IL8 concentration was associated with PFS ≥ 4 months (p = .031).

Conclusions: The bevacizumab and sorafenib combination did not meet the pre-specified primary endpoint although some clinical activity was seen in heavily-pretreated bevacizumab-naive OvCa patients with platinum-resistant disease. Anticipated class toxicities required close monitoring and dose modifications.

Keywords: Bevacizumab; Clinical trial; Ovarian cancer; Post-bevacizumab; Sorafenib.

Conflict of interest statement

Declaration of Competing Interest All authors declared no conflicts of interest.

Published by Elsevier Inc.

Figures

Figure 1.

Consort diagram

Figure 2.. Progression-free survival

Median progression-free survival (PFS) for all patients was 5.5 months (95% CI: 4.0–6.8 months). The censoring times do not reflect additional follow-up; patients were followed at most 1 month post-treatment if treatment was discontinued without progression. Six patients in the bevacizumab-naïve cohort who were not evaluable for the RECIST endpoint were captured for the PFS evaluation. Median follow-up duration was 2.1 months for 9 patients who did not progress during off-treatment follow-up. Thus, these curves reflect the available data only.

Figure 3:. Cytokine concentrations at baseline

Pretreatment plasma cytokine concentrations were evaluated as a function of clinical benefit (PR + SD ≥4months [n=37]) vs no benefit (all others [n=15]) in intention-to-treat patients. Baseline low IL-8 concentrations were associated with clinical benefit (a); other cytokines (b-d) did not correlate with clinical outcome.