A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies.
OBJECTIVE
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.


METHODS
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.
Aghajanian
Carol
C
The Developmental Chemotherapy Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. aghajanc@mskcc.org
Soignet
Steven
S
Dizon
Don S
DS
Pien
Christine S
CS
Adams
Julian
J
Elliott
Peter J
PJ
Sabbatini
Paul
P
Miller
Vincent
V
Hensley
Martee L
ML
Pezzulli
Sandra
S
Canales
Christina
C
Daud
Adil
A
Spriggs
David R
DR
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D001897:Boronic Acids / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D000069286:Bortezomib; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D015398:Signal Transduction; D013997:Time Factors
D000970:Antineoplastic Agents; D001897:Boronic Acids; D009097:Multienzyme Complexes; D011719:Pyrazines; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex