TY - JOUR
T1 - Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms
AU - Sausville, E. A.
AU - Arbuck, S. G.
AU - Messmann, R.
AU - Headlee, D.
AU - Bauer, K. S.
AU - Lush, R. M.
AU - Murgo, A.
AU - Figg, W. D.
AU - Lahuse, T.
AU - Jaken, S.
AU - Jing, X. X.
AU - Roberge, M.
AU - Fuse, E.
AU - Kuwabara, T.
AU - Senderowicz, A. M.
PY - 2001/4/15
Y1 - 2001/4/15
N2 - Purpose: To define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of the novel protein kinase inhibitor, UCN-01 (7-hydroxystaurosporine), administered as a 72-hour continuous intravenous infusion (CIV). Patients and Methods: Forty-seven patients with refractory neoplasms received UCN-01 during this phase I trial. Total, free plasma, and salivary concentrations were determined; the latter were used to address the influence of plasma protein binding on peripheral tissue distribution. The phosphorylation state of the protein kinase C (PKC) substrate alpha-adducin and the abrogation of DNA damage checkpoint also were assessed. Results: The recommended phase II dose of UCN-01 as a 72-hour CIV is 42.5 mg/m2/d for 3 days. Avid plasma protein binding of UCN-01, as measured during the trial, dictated a change in dose escalation and administration schedules. Therefore, nine patients received drug on the initial 2-week schedule, and 38 received drug on the recommended 4-week schedule. DLTs at 53 mg/m2/d for 3 days included hyperglycemia with resultant metabolic acidosis, pulmonary dysfunction, nausea, vomiting, and hypotension. Pharmacokinetic determinations at the recommended dose of 42.5 mg/m2/d for 3 days included mean total plasma concentration of 36.4 μM (terminal elimination half-life range, 447 to 1176 hours), steady-state volume of distribution of 9.3 to 14.2 L, and clearances of 0.005 to 0.033 L/h. The mean total salivary concentration was 111 nmol/L of UCN-01. One partial response was observed in a patient with melanoma, and one protracted period (> 2.5 years) of disease stability was observed in a patient with alk-positive anaplastic large-cell lymphoma. Preliminary evidence suggests UCN-01 modulation of both PKC substrate phosphorylation and the DNA damage-related G2 checkpoint. Conclusion: UCN-01 can be administered safely as an initial 72-hour CIV with subsequent monthly doses administered as 36-hour infusions.
AB - Purpose: To define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of the novel protein kinase inhibitor, UCN-01 (7-hydroxystaurosporine), administered as a 72-hour continuous intravenous infusion (CIV). Patients and Methods: Forty-seven patients with refractory neoplasms received UCN-01 during this phase I trial. Total, free plasma, and salivary concentrations were determined; the latter were used to address the influence of plasma protein binding on peripheral tissue distribution. The phosphorylation state of the protein kinase C (PKC) substrate alpha-adducin and the abrogation of DNA damage checkpoint also were assessed. Results: The recommended phase II dose of UCN-01 as a 72-hour CIV is 42.5 mg/m2/d for 3 days. Avid plasma protein binding of UCN-01, as measured during the trial, dictated a change in dose escalation and administration schedules. Therefore, nine patients received drug on the initial 2-week schedule, and 38 received drug on the recommended 4-week schedule. DLTs at 53 mg/m2/d for 3 days included hyperglycemia with resultant metabolic acidosis, pulmonary dysfunction, nausea, vomiting, and hypotension. Pharmacokinetic determinations at the recommended dose of 42.5 mg/m2/d for 3 days included mean total plasma concentration of 36.4 μM (terminal elimination half-life range, 447 to 1176 hours), steady-state volume of distribution of 9.3 to 14.2 L, and clearances of 0.005 to 0.033 L/h. The mean total salivary concentration was 111 nmol/L of UCN-01. One partial response was observed in a patient with melanoma, and one protracted period (> 2.5 years) of disease stability was observed in a patient with alk-positive anaplastic large-cell lymphoma. Preliminary evidence suggests UCN-01 modulation of both PKC substrate phosphorylation and the DNA damage-related G2 checkpoint. Conclusion: UCN-01 can be administered safely as an initial 72-hour CIV with subsequent monthly doses administered as 36-hour infusions.
UR - http://www.scopus.com/inward/record.url?scp=0035871444&partnerID=8YFLogxK
U2 - 10.1200/JCO.2001.19.8.2319
DO - 10.1200/JCO.2001.19.8.2319
M3 - Article
C2 - 11304786
AN - SCOPUS:0035871444
SN - 0732-183X
VL - 19
SP - 2319
EP - 2333
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 8
ER -