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 I (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.
Department of Radiation Oncology, Head and Neck Surgery, Hospital of the University of Pennsylvania, Philadelphia 19104, USA. rosenthal@xrt.upenn.edu
David I
DI
Rosenthal
Sue S
SS
Yom
Li
L
Liu
Mitchell
M
Machtay
Kenneth
K
Algazy
Randal S
RS
Weber
Gregory S
GS
Weinstein
Ara A
AA
Chalian
Linda K
LK
Mille
Kenneth
K
Rockwell
Margaret
M
Tonda
Edward
E
Schnipper
Diane
D
Hershock
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D006801:Humans; D007262:Infusions, Intravenous / Q000009:adverse effects; D017567:Karnofsky Performance Status; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D011446:Prospective Studies
D000970:Antineoplastic Agents; D008081:Liposomes; C422270:SPI-77, liposomal; D002945:Cisplatin