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

David I. Rosenthal, Sue S. Yom, Li Liu, Mitchell Machtay, Kenneth Algazy, Randal S. Weber, Gregory S. Weinstein, Ara A. Chalian, Linda K. Miller, Kenneth Rockwell, Margaret Tonda, Edward Schnipper, Diane Hershock

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)343-349
Number of pages7
JournalInvestigational New Drugs
Volume20
Issue number3
DOIs
StatePublished - Aug 8 2002

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Head and Neck Neoplasms
Radiotherapy
Cisplatin
Radiation
Transaminases
liposomal SPI-77
Exanthema
Neutropenia
Half-Life
Therapeutics
Skin
Liver
Pharmaceutical Preparations
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Rosenthal, David I. ; Yom, Sue S. ; Liu, Li ; Machtay, Mitchell ; Algazy, Kenneth ; Weber, Randal S. ; Weinstein, Gregory S. ; Chalian, Ara A. ; Miller, Linda K. ; Rockwell, Kenneth ; Tonda, Margaret ; Schnipper, Edward ; Hershock, Diane. / A phase I study of SPI-077 (Stealth® liposomal cisplatin) concurrent with radiation therapy for locally advanced head and neck cancer. In: Investigational New Drugs. 2002 ; Vol. 20, No. 3. pp. 343-349.
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title = "A phase I study of SPI-077 (Stealth{\circledR} liposomal cisplatin) concurrent with radiation therapy for locally advanced head and neck cancer",
abstract = "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{\circledR} 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.",
author = "Rosenthal, {David I.} and Yom, {Sue S.} and Li Liu and Mitchell Machtay and Kenneth Algazy and Weber, {Randal S.} and Weinstein, {Gregory S.} and Chalian, {Ara A.} and Miller, {Linda K.} and Kenneth Rockwell and Margaret Tonda and Edward Schnipper and Diane Hershock",
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Rosenthal, DI, Yom, SS, Liu, L, Machtay, M, Algazy, K, Weber, RS, Weinstein, GS, Chalian, AA, Miller, LK, Rockwell, K, Tonda, M, Schnipper, E & Hershock, D 2002, 'A phase I study of SPI-077 (Stealth® liposomal cisplatin) concurrent with radiation therapy for locally advanced head and neck cancer', Investigational New Drugs, vol. 20, no. 3, pp. 343-349. https://doi.org/10.1023/A:1016201732368

A phase I study of SPI-077 (Stealth® liposomal cisplatin) concurrent with radiation therapy for locally advanced head and neck cancer. / Rosenthal, David I.; Yom, Sue S.; Liu, Li; Machtay, Mitchell; Algazy, Kenneth; Weber, Randal S.; Weinstein, Gregory S.; Chalian, Ara A.; Miller, Linda K.; Rockwell, Kenneth; Tonda, Margaret; Schnipper, Edward; Hershock, Diane.

In: Investigational New Drugs, Vol. 20, No. 3, 08.08.2002, p. 343-349.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A phase I study of SPI-077 (Stealth® liposomal cisplatin) concurrent with radiation therapy for locally advanced head and neck cancer

AU - Rosenthal, David I.

AU - Yom, Sue S.

AU - Liu, Li

AU - Machtay, Mitchell

AU - Algazy, Kenneth

AU - Weber, Randal S.

AU - Weinstein, Gregory S.

AU - Chalian, Ara A.

AU - Miller, Linda K.

AU - Rockwell, Kenneth

AU - Tonda, Margaret

AU - Schnipper, Edward

AU - Hershock, Diane

PY - 2002/8/8

Y1 - 2002/8/8

N2 - 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.

AB - 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.

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