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
Research Highlights
►Volociximab was safe and well tolerated by advanced ovarian cancer patients. ►Volociximab concentrations corresponding with pre-clinical activity were achieved. ►Circulating tumor and endothelial cell populations were evaluated during the study.
Introduction
Volociximab is a high-affinity, chimeric antibody directed against human α5β1 integrin. Integrins are heterodimeric cell surface adhesion receptors consisting of α and β chains, and their ligands are often components of the extracellular matrix (ECM). Integrins are highly expressed on tumor vascular endothelial cells. While growth factors are required to elicit new blood vessel growth, interactions between cell surface integrin receptors and their ECM protein ligands provide migration, adhesion, and survival signals to activated endothelial cells [1], [2]. Recent evidence suggests that the interaction between α5β1 integrin and its ligand fibronectin plays a pivotal role in the initial process of neovascularization. Antagonists of this interaction, such as volociximab, inhibit endothelial cell survival and proliferation in vitro and in vivo even when endothelial cells adhere to the ECM through other integrins [3], [4].
Ovarian carcinoma is a highly vascular tumor type that expresses α5β1 integrin on its vasculature [5]. In addition, α5 integrin is also found on ovarian tumor cells [6]. Interfering with integrin–ligand binding may affect the ability of ovarian cancer tumor cells to spread and grow within the peritoneal cavity. Adhesion and migration of ovarian cancer cells are regulated by integrin-dependent mechanisms involving the interaction of integrins with the ECM and CD44 [7]. In the mouse SKOV-3ip1 ovarian cancer xenograft model, treatment with the murine parent antibody of volociximab IIA1 showed significant benefit compared with control IgG treatment [6]. The number of metastases, total tumor burden, and ascites production in mice treated with IIA1 was significantly decreased, while overall survival was increased compared with controls.
The phase I study of volociximab in solid tumors showed that volociximab could be safely administered at a dose of 15 mg/kg intravenously per week [8]. Of the 21 patients enrolled, one minor response was seen in a renal carcinoma patient, and stable disease was seen in one melanoma patient. There were no ovarian carcinoma patients enrolled in the phase I study. The present phase II study in platinum-resistant, advanced epithelial ovarian cancer or primary peritoneal cancer was warranted based on the strong preclinical data to evaluate the efficacy and safety of weekly infusions of single-agent volociximab at a dose of 15 mg/kg. Correlative studies were performed to evaluate the prevalence of α5-integrin expression in patients' tumors and to analyze the effects of volociximab on circulating tumor cells (CTCs), circulating endothelial cells (CECs), and circulating endothelial progenitor cells (CEPCs).
Section snippets
Patient eligibility
Patients age 18 or older with advanced, histologically documented epithelial ovarian cancer or primary peritoneal cancer that had progressed during or within 6 months of discontinuing platinum-based chemotherapy and that had progressed during or following treatment with topotecan or liposomal doxorubicin were eligible to participate. Additional eligibility criteria included the presence of at least one measurable lesion in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) [9]
Patient characteristics
Sixteen patients were enrolled from 9/2007 to 4/2008 (Table 1). All 16 patients received at least one volociximab infusion and were included in the safety analysis. Fifteen patients (94%) received 8 or fewer weekly infusions of volociximab. The median number of infusions was 7.5 (range, 1–16).
Response evaluation
Fourteen patients were evaluable for response. Of the 2 remaining patients, 1 withdrew consent after 1 infusion and opted for supportive care; the other was removed from study by the treating physician
Discussion
Advanced ovarian cancer carries a poor overall prognosis [15]. While platinum-based chemotherapy may be initially effective, responses to additional chemotherapy are limited when ovarian cancer recurs within 3–6 months after initial treatment [12], [13], [16], [17], [18], [19], [20]. Standard FDA-approved therapeutic options for patients who recur within 6 months of initial therapy include liposomal doxorubicin or topotecan. There are no approved therapies for use after the development of
Conflict of interest statement
Katherine M. Bell-McGuinn: None.
Carolyn M. Matthews: None.
Steffan N. Ho: Employed by Biogen Idec.
Minal Barve: None.
Lucy Gilbert: None.
Richard T. Penson: Research funds from PDL Biopharma Inc.
Ernst Lengyel: Received funding from PDL for experiments with the antibody. (Cancer Res. 2008 Apr 1;68(7):2329–39.)
Rameshraja Palaparthy: Employed by Biogen Idec. Owns stock of Biogen Idec.
Kye Gilder: Employed by Biogen Idec. Owns stock of Biogen Idec.
Artemios Vassos: Employed by Biogen Idec.
William
Acknowledgments
We would like to thank all participating 206OC201 study investigators, research staff, and patients. Biogen Idec would like to thank their development partner, Facet Biotech, for all their contributions to the program.
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2022, Biomedicine and PharmacotherapyCitation Excerpt :Additionally, Cianfrocca et al. demonstrated that ATN-161 had no effect on tumor regression in patients with solid tumors in a phase I trial [115]. Moreover, Volociximab, another α5β1 integrin inhibitor, showed no improvement in a phase II trial for patients with platinum-resistant advanced epithelial ovarian or primary peritoneal cancer [107]. Whether monotherapies or combination therapies, clinical trials have revealed obvious shortcomings of integrin-targeted therapy.