Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms.
OBJECTIVE
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).


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/m(2)/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/m(2)/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/m(2)/d for 3 days included mean total plasma concentration of 36.4 microM (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 G(2) checkpoint.


CONCLUSIONS
UCN-01 can be administered safely as an initial 72-hour CIV with subsequent monthly doses administered as 36-hour infusions.
Sausville
E A
EA
Developmental Therapeutics Program Clinical Trials Unit, Medicine Branch, and Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD 20852, USA. Sausville@nih.gov
Arbuck
S G
SG
Messmann
R
R
Headlee
D
D
Bauer
K S
KS
Lush
R M
RM
Murgo
A
A
Figg
W D
WD
Lahusen
T
T
Jaken
S
S
Jing
X
X
Roberge
M
M
Fuse
E
E
Kuwabara
T
T
Senderowicz
A M
AM
D000328:Adult; D000368:Aged; D000470:Alkaloids / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced; D007022:Hypotension / Q000139:chemically induced; D007262:Infusions, Intravenous; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy; D019311:Staurosporine / Q000031:analogs & derivatives; D014839:Vomiting / Q000139:chemically induced
D000470:Alkaloids; D000970:Antineoplastic Agents; C054852:7-hydroxystaurosporine; D019311:Staurosporine