Continuous Infusion of Cilengitide Plus Chemoradiotherapy for Patients With Stage III Non–Small-cell Lung Cancer: A Phase I Study

Abstract

Introduction

Because of our previous preclinical results, we conducted a phase I study associating the specific αvβ3/αvβ5 integrin inhibitor cilengitide, given as a continuous infusion, with exclusive chemoradiotherapy for patients with stage III non–small-cell lung cancer.

Patients and Methods

A standard 3+3 dose escalation design was used. Cilengitide was given as a continuous infusion (dose levels of 12, 18, 27, and 40 mg/h), starting 2 weeks before and continuing for the whole course of chemoradiotherapy (66 Gy combined with platinum/vinorelbine), and then at a dose of 2000 mg twice weekly in association with chemotherapy. 2-Deoxy-2-[fluorine-18]fluoro-d-glucose positron emission tomography (PET) and computed tomography scans were performed before and after the first 2 weeks of cilengitide administration and then every 3 months.

Results

Of the 14 patients included, 11 were evaluable for evaluation of the dose-limiting toxicities (DLTs). One DLT, a tracheobronchial fistula, was reported with the 40 mg/h dose. No relevant adverse events related to cilengitide were observed overall. At the PET evaluation 2 months after chemoradiotherapy, 4 of 9 patients had a complete response and 4 had a partial response. The median progression-free and overall survival was 14.4 months (95% confidence interval [CI], 8.4 to not reached) and 29.4 months (95% CI, 11.73 to not reached), respectively.

Conclusion

Cilengitide, given continuously with chemoradiotherapy, showed acceptable toxicity and gave encouraging clinical results.

Introduction

Despite recent advances in the planning and delivery of radiation therapy for unresectable stage III non–small-cell lung cancer (NSCLC), the therapeutic index has not been further improved owing to physical limitations and dose-limiting structures, as recently shown by unsuccessful dose-escalating studies.¹ For additional progress to occur, technological innovations must be complemented by biologic innovations, such as the development of novel radiosensitizing agents and biology-driven patient selection.

Based on preclinical data, which demonstrated the role of fibroblast growth factor (FGF-2) and αvβ3 integrin in radioresistance and hypoxia,2, 3, 4, 5 we investigated the predictive value of FGF-2 and αvβ3 integrin expression in NSCLC patients treated with chemoradiotherapy. The results showed that the combined expression of FGF-2 and β3 integrin was related to local relapse, thus confirming the role of these factors in tumor radiosensitivity.⁶

The integrin receptors, αvβ3 and αvβ5, whose presence on both endothelial and tumor cells are crucial for continued cell survival, represent attractive targets for antiangiogenesis strategies and radiosensitization.7, 8, 9 Tumor radiosensitivity is modulated by both tumor cell and endothelial cell pathways.¹⁰

Cilengitide (EMD121974; Merck KGaA, Darmstadt, Germany), the inner salt of a cyclized RGD pentapeptide (cyclo-[Arg-Gly-Asp-Dphe-(NMeVal)]), which has been shown to radiosensitize lung cancer cells and endothelial cells in vitro,¹¹ is a potent and selective αvβ3 and αvβ5 antagonist.¹² Inhibiting αvβ3 and αvβ5 integrins in turn counteracts the endothelial cell invasion and differentiation induced by vascular endothelial growth factor (VEGF)-A or FGF, leading to an antiangiogenic effect.¹³ Moreover, it has been shown in a glioma model that inhibition of αvβ3 or αvβ5 integrins in hypoxic cells decreases the hypoxia-inducible factor 1α intracellular level, which also explains the antiangiogenic effects of cilengitide.⁵

Cilengitide has inhibited tumor growth in a dose-dependent manner in numerous in vivo systems.14, 15, 16 Regarding its combination with chemotherapy, cilengitide exerted in vitro and in vivo synergistic antiproliferative action in preclinical studies with different cytotoxic agents,17, 18, 19 with promising results for the association in early clinical trials, especially with cisplatin.20, 21 Several phase I and II studies, conducted on adult patients with advanced solid tumors, have used cilengitide, given as a 1-hour infusion twice weekly, with a good safety profile.22, 23, 24 A randomized phase II study also tested cilengitide at 2000 mg twice weekly or 2000 mg for 5 d/wk combined with temozolomide and radiotherapy to treat glioblastoma.²⁵ Only one of the reported dosing strategies for cilengitide in humans has used continuous administration.²⁶ Most have used intermittent schedules, including within the disappointing phase III CENTRIC study (cilengitide, temozolomide, and radiation therapy in treating patients with newly diagnosed glioblastoma and methylated gene promoter status) of glioblastoma.²⁷ However, cilengitide has a short plasma half-life of 3 to 5 hours, supporting the idea that continuous exposure to cilengitide might be necessary for its optimal efficacy and, thus, warrants investigation.

We designed and conducted a phase I clinical study that combined cilengitide, given as a continuous infusion, with exclusive and concomitant chemoradiotherapy for stage III NSCLC patients.