A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies Journal Article
| Authors: | Aghajanian, C.; Soignet, S.; Dizon, D. S.; Pien, C. S.; Adams, J.; Elliott, P. J.; Sabbatini, P.; Miller, V.; Hensley, M. L.; Pezzulli, S.; Canales, C.; Daud, A.; Spriggs, D. R. |
| Article Title: | A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies |
| Abstract: | 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/m2/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/m2/dose in Phase II trials. Particular care should be taken with patients with preexisting neuropathy. Further testing in Phase II trials is warranted. |
| Keywords: | signal transduction; adult; clinical article; treatment outcome; aged; middle aged; clinical trial; fatigue; advanced cancer; diarrhea; dose response; drug safety; solid tumor; antineoplastic agents; neurotoxicity; follow up; follow-up studies; antineoplastic agent; anorexia; neoplasm; neoplasms; metabolism; bortezomib; proteasome; proteasome inhibitor; enzyme inhibition; boronic acids; proteasome endopeptidase complex; pyrazines; blood toxicity; lung non small cell cancer; neuropathy; dose-response relationship, drug; time; time factors; fever; pruritus; rash; drug antagonism; nausea and vomiting; headache; phase 1 clinical trial; multienzyme complex; multienzyme complexes; boronic acid derivative; pyrazine derivative; middle age; cysteine proteinase; cysteine endopeptidases; humans; human; male; female; priority journal; article; support, non-u.s. gov't; support, u.s. gov't, p.h.s. |
| Journal Title: | Clinical Cancer Research |
| Volume: | 8 |
| Issue: | 8 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2002-08-01 |
| Start Page: | 2505 |
| End Page: | 2511 |
| Language: | English |
| PUBMED: | 12171876 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 14 November 2014 -- Source: Scopus |
