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Phase I Study of Inhaled Doxorubicin for Patients with Metastatic Tumors to the Lungs

Gregory A. Otterson¹, Miguel A. Villalona-Calero¹, Sunil Sharma³, Mark G. Kris³, Anthony Imondi², Mirjam Gerber², Dorothy A. White³, Mark J. Ratain⁴, Joan H. Schiller⁵, Alan Sandler⁶, Michael Kraut⁷, Sridhar Mani⁸ and John R. Murren^9,

Authors' Affiliations: ¹ The Ohio State University Comprehensive Cancer Center and ² Zivena, Inc., Columbus, Ohio; ³ Memorial Sloan Kettering Comprehensive Cancer Center, New York, New York; ⁴ University of Chicago, Chicago, Illinois; ⁵ University of Wisconsin Cancer Center, Madison, Wisconsin; ⁶ Vanderbilt Medical Center, Nashville, Tennessee; ⁷ Karmanos Cancer Center, Detroit, Michigan; ⁸ Montefiore Medical Center, Weiler Division, Bronx, New York; and ⁹ Yale University Comprehensive Cancer Center, New Haven, Connecticut

Requests for reprints: Gregory A. Otterson, Division of Hematology/Oncology, The Ohio State University, B420 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH 43210. Phone: 614-293-2887; Fax: 614-293-7529; E-mail: greg.otterson{at}osumc.edu.

Purpose: To evaluate the toxicity profile of inhalational doxorubicin in patients with malignant disease in the lung.

Experimental Design: The OncoMyst Model CDD-2a inhalation device aerosolizes compounds to particles of 2 to 3 µm and prevents exhaled aerosol from escaping into the environment. Deposition efficiency of inhaled Technetium 99m was used to predict deposition of doxorubicin and calculate dose. Treatment was repeated every 3 weeks. No more than moderate pulmonary dysfunction was permitted (forced expiratory volume in 1 s, forced vital capacity, and diffusing capacity for carbon monoxide, all >50% predicted; resting SaO₂ >90%).

Results: Fifty-three patients were enrolled at 13 dose levels ranging from 0.4 to 9.4 mg/m². The most common histologic diagnoses were sarcoma (n = 19) and non–small cell lung cancer (n = 16). Dose-limiting toxicity (DLT) was observed at the 9.4 mg/m² dose level when two of four patients experienced pulmonary DLT. Of 11 patients treated at the 7.5 mg/m² dose level, only one showed DLT consisting of a decline in forced vital capacity of >20% from baseline. No significant systemic drug-related toxicity was observed. Several patients experienced declines in pulmonary function test variables, which were attributed to progressive disease. Observed activity included a partial response in a patient with metastatic soft tissue sarcoma previously treated with i.v. doxorubicin and ifosfamide.

Conclusions: Inhaled doxorubicin is safe up to a dose of 7.5 mg/m² every 3 weeks in patients with cancer who had normal to moderately impaired pulmonary function.