A phase II, single-arm study of the anti-α5β1 integrin antibody volociximab as monotherapy in patients with platinum-resistant advanced epithelial ovarian or primary peritoneal cancer

Abstract

Objective: This phase II, multicenter, single-arm, two-stage study in platinum-resistant, advanced epithelial ovarian or primary peritoneal cancer evaluated the efficacy, safety, and tolerability of weekly single-agent volociximab. Pharmacokinetic/pharmacodynamic (PK/PD) studies were also performed.

Methods: Sixteen patients were enrolled in Stage 1. Volociximab was administered at 15mg/kg IV qwk until progression of disease or drug intolerability. Tumor response was assessed every 8weeks. Serum samples for PK or whole blood for the evaluation of circulating tumor cells, endothelial cells, and endothelial progenitor cells were obtained on Days 1, 8, 15, 29, and 50. Ascites from one patient was collected for volociximab concentration analysis. Archived tumor tissue was analyzed by immunohistochemistry (IHC) for α5 integrin expression.

Results: Safety data are available on all 16 patients; 14 were evaluable for efficacy. One patient had stable disease at 8weeks. The remaining 13 progressed on treatment. Twelve patients (75%) experienced study-related adverse events (AEs); the most common (≥20%) were headache and fatigue. Three patients experienced possible study-related serious AEs (SAEs): reversible posterior leukoencephalopathy syndrome, pulmonary embolism, and hyponatremia. Peak serum concentrations of volociximab increased 2-3 fold from Day 1 to Day 50. Clinically relevant trough levels were achieved (>150μg/mL). IHC analysis of archived tumor sections showed low-to-moderate expression of α5 integrin on all ovarian cancer tissue evaluated.

Conclusion: Despite insufficient clinical activity in this refractory patient population to continue the study, weekly volociximab was well tolerated, and the gained understanding of the mechanism of action of volociximab will inform future development efforts.

Fig. 1

Serum volociximab concentrations during treatment cycle 1 (PK population N = 16).

Fig. 2

Analysis of α5 integrin expression on archived tumor tissue by immunohistochemical (IHC) staining. (A)Representative images from IHC staining of archived, formalin-fixed, paraffin-embedded ovarian carcinoma tissue sections demonstrate the range of staining intensity that was observed among all samples analyzed. The control represents IHC staining of serial sections using an isotype control reagent (rabbit IgG). (B) H-scores of α5 expression for all available tumor samples demonstrate an evenly distributed range of low-to-moderate expression (mean H-score 140 ± 40; range, 75–200).

Fig. 3

Changes in circulating cellular biomarkers during treatment with volociximab. A significant increase in circulating tumor cells (CTCs) during the course of treatment with volociximab is seen with the mean values of CTCs for all patients (A) and the baseline compared to post-treatment sample (B). No significant change was seen in the mean values of circulating endothelial cells (CECs) during treatment (C). However, a transient increase in CECs was seen in some patients early in the treatment course (D). Circulating endothelial progenitor cells (CEPCs) did decline significantly over the course of treatment as shown in the mean values (E) in baseline and post-treatment samples (F).