A phase I study of SPI-077 (Stealth® liposomal cisplatin) concurrent with radiation therapy for locally advanced head and neck cancer

Background: Liposomal cisplatin preparations have two potential advantages over the free drug when combined with radiation therapy (RT): 1) selective tumor localization, improving the therapeutic ratio, and 2) prolonged half-life, allowing more radiosensitization. We performed a Phase I study of Stealth® liposomal cisplatin (SPI-077) concurrent with RT for head and neck squamous cell carcinoma (HNSCC). Methods: Patients with Stage IVa/b HNSCC were treated with SPI-077, given intravenously twice two weeks apart, concurrent with RT (60-72 Gy in 6-7 weeks). The SPI-077 dose was escalated in standard phase I design. Results: Twenty patients received 38 doses of SPI-077, escalated from 20-200 mg/m² in six dose levels. Two of these patients received one dose because of reversible Grade 3 liver toxicity or rash. Three patients had a Grade 1, and one had a Grade 2 infusion reaction. Four patients had transiently elevated transaminases: Grade 1 (n = 1), Grade 2 (n = 1), and Grade 3 (n = 2). Grade 3 neutropenia occurred in one patient. There was no ototoxicity, neurotoxicity, or nephrotoxicity. In-field radiation skin and mucosal toxicities did not appear to be intensified. Ten of 17 patients (59%) finishing treatment achieved initial complete response. Conclusions: Systemic and in-field radiation toxicities of SPI-077 were minimal. Infusion reactions were minimized with a slower and more dilute initial infusion. Further dose escalation was stopped in the absence of dose-limiting toxicity to address the reformulation of the liposomally bound cisplatin. Nonetheless, this study shows that high doses of SPI-077 can be given safely. The potentially beneficial therapeutic ratio suggests that liposomal radiosensitizer preparations warrant further investigation.