A Phase I Trial of the Novel Proteasome Inhibitor PS341 in Advanced Solid Tumor Malignancies

• Published in: Clinical cancer research 2002-08, Vol.8 (8), p.2505-2511
• Main Authors: AGHAJANIAN, Carol, SOIGNET, Steven, CANALES, Christina, DAUD, Adil, SPRIGGS, David R, DIZON, Don S, PIEN, Christine S, ADAMS, Julian, ELLIOTT, Peter J, SABBATINI, Paul, MILLER, Vincent, HENSLEY, Martee L, PEZZULLI, Sandra
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Antineoplastic Agents - toxicity; Biological and medical sciences; Boronic Acids - pharmacokinetics; Boronic Acids - therapeutic use; Boronic Acids - toxicity; Bortezomib; Chemotherapy; Cysteine Endopeptidases - metabolism; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Male; Medical sciences; Middle Aged; Multienzyme Complexes - antagonists & inhibitors; Multienzyme Complexes - metabolism; Neoplasms - drug therapy; Pharmacology. Drug treatments; Proteasome Endopeptidase Complex; Pyrazines - pharmacokinetics; Pyrazines - therapeutic use; Pyrazines - toxicity; Signal Transduction; Time Factors
• ISSN: 1078-0432; 1557-3265

Purpose: The purpose of this study was to evaluate the toxicity and pharmacodynamic behavior of the novel proteasome inhibitor PS341 administered as a twice weekly i.v. bolus for 2 weeks, followed by a 1-week recovery period in patients with advanced solid tumor malignancies. Experimental Design: In this Phase I trial, 43 patients were treated with PS341 in doses ranging from 0.13 to 1.56 mg/m 2 /dose. A standard Phase I design was used. Pharmacodynamic studies were performed to access 20S proteasome activity. Results: Forty-three patients were treated with 89 cycles of PS341. Patients were heavily pretreated. Dose-limiting toxicities on this schedule were diarrhea and sensory neurotoxicity. Other side effects seen were fatigue, fever, anorexia, nausea, vomiting, rash, pruritus, and headache. There was no dose-limiting hematological toxicity. A dose-related inhibition of 20S proteasome activity with increasing dose of PS341 was seen. There was one major response in a patient with refractory non-small cell lung carcinoma. Conclusions: Given the results of this trial, it is safe and reasonable to recommend treatment with PS341 on the schedule used in this trial at 1.56 mg/m 2 /dose in Phase II trials. Particular care should be taken with patients with preexisting neuropathy. Further testing in Phase II trials is warranted.