Combination antiangiogenic therapy in advanced breast cancer: a phase 1 trial of vandetanib, a VEGFR inhibitor, and metronomic chemotherapy, with correlative platelet proteomics

Abstract

This phase 1 study evaluated the safety and tolerability of antiangiogenic therapy using vandetanib and metronomic cyclophosphamide and methotrexate in metastatic breast cancer. Eligible patients had metastatic breast cancer with 0-4 prior chemotherapy regimens. All received cyclophosphamide 50 mg daily, methotrexate 2.5 mg days 1-2 weekly, and vandetanib daily in 3 dose-escalation cohorts: 100 mg (C1), 200 mg (C2), and 300 mg (C3). The primary endpoint was safety and tolerability; secondary endpoints included response rate and evaluation of platelet-associated proteins. Twenty three patients were treated and evaluable for toxicity. Common mild toxicities included nausea, vomiting, LFTs abnormalities, fatigue, and rash. Three episodes of dose-limiting toxicity occurred in C3. In all cohorts, 1/3 of patients required vandetanib dose reduction, and 22 % ended therapy for toxicity. Of the 20 response-evaluable patients, 10 % demonstrated partial response and 15 % stable disease ≥24 weeks. Proteomic analyses demonstrated changes in platelet content of angiogenesis regulators, including vascular endothelial growth factor and platelet factor 4, with exposure to therapy. This regimen was tolerable at a maximum vandetanib dose of 200 mg; modest clinical activity was observed in this heavily pretreated population. Changes in the platelet proteome may serve as pharmacodynamic markers of angiogenesis inhibition. Metronomic chemotherapy is an attractive partner with biologics and deserves further study in metastatic breast cancer.

Conflict of interest statement

Conflict of interest None.

Figures

Fig. 1

Waterfall plot describing maximum change in target lesion diameter. A total of 20 patients contributed more than one imaging evaluation. The best overall response is demonstrated

Fig. 2

Longitudinal changes in platelet proteome with therapy. Figures illustrate examples of detectable changes in the levels of platelet-associated proteins by SELDI-ToF analysis. Two examples are presented for differentially expressed proteins in platelet lysates from 6 breast cancer patients treated with vandetanib and metronomic chemotherapy compared with matched normal controls. Time points are pre-treatment (baseline), 4-weeks drug exposure, and 8-weeks drug exposure. Both graphs represent mean ± SEM. a At baseline, levels of a 12.5-kD protein are low, but with subsequent exposure to protocol therapy, protein levels rise, reaching levels comparable to healthy controls at 8 weeks of therapy. b In contrast, the levels of a 53.9-kD polypeptide are high at baseline; by 8 weeks of therapy, levels of this protein decrease to about 50 % normal

Fig. 3

Levels of intra-platelet VEGF and PF4 “normalize” with exposure to therapy. VEGF and PF4 were identified as differentially expressed between platelets of normal subjects and patients with breast cancer, and demonstrated dynamic change with exposure to therapy. All measurements were repeated on 2 separate occasions, and the graph represents the mean of the two measurements ± SEM. At baseline, the levels of VEGF (Fig. 3a) and PF4 (Fig. 3b) were notably higher in platelets of patients with breast cancer than in those of normal controls. With each subsequent cycle, the levels of both of these proteins “normalized,” and by the third cycle VEGF closely approached levels in platelets of normal healthy subjects