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 15 mg/kg IV qwk until progression of disease or drug intolerability. Tumor response was assessed every 8 weeks. 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 8 weeks. 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 (>150 µg/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.

Proteolytic fragments of fibronectin function as matrikines driving the chemotactic affinity of prostate cancer cells to human bone marrow mesenchymal stromal cells via the α5β1 integrin

“…The a5b1monoclonal antibody volociximab has been in clinical trials but was abandoned in the absence of discernible clinical efficacy in a range of solid tumors, both as single agent and in combination with cytotoxic chemotherapy. [21][22][23][24] Only a few patients with prostate cancer were included in these studies and the data are insufficient to draw conclusions.…”

WOMEN IN CANCER THEMATIC REVIEW: Ovarian cancer–peritoneal cell interactions promote extracellular matrix processing

“…Phase I and II trials with Vitaxin showed some efficacy in solid cancers and metastatic melanoma (reviewed in Desgrosellier & Cheresh 2010). Volociximab was well tolerated and showed promising results in phase I trials with various solid tumours (Ricart et al 2008); however, it has shown insufficient clinical activity in ovarian cancer patients with platinum resistant disease (Bell-McGuinn et al 2011). Although promising in phase I trials, Cilengitide, an inhibitor of both αvβ3 and αvβ5 integrins, has shown limited clinical efficacy in phase II/III trials in patients with glioblastoma (Eisele et al 2014, Stupp et al 2014) and metastatic castrate-resistant prostate cancer (Bradley et al 2011).…”

Revisiting the Complexity of the Ovarian Cancer Microenvironment—Clinical Implications for Treatment Strategies

“…For example, multicellular aggregated formation is mediated via b1-integrins and their subsequent attachment to the mesothelium is partially dependent on a5b1-integrins (63,64). Efforts to antagonize a5b1-integrin interactions were implemented in phase II clinical trials, using a chimeric antibody, Volociximab (Table 1), in patients with platinum-resistant advanced EOC, although clinical efficacy was not accomplished (65). Moreover, targeting of a v b 3 with antibodies and radiolabeled nucleotides in xenografts has opened up new avenues and opportunities for therapeutic intervention (66)(67)(68).…”