Phase I clinical and pharmacokinetic study of NSC 655649, a rebeccamycin analogue, given in both single-dose and multiple-dose formats.
OBJECTIVE
NSC 655649 was given in both single- and multiple-dose formats, to characterize maximum tolerated dose (MTD), toxicity, and pharmacokinetic profile.


METHODS
Patients with advanced malignancies were treated with escalating doses of NSC 655649 in either a single-dose format (step 1) or a multiple-dose format (step 2). In step 1, NSC 655649 was given as a 30-60 min infusion. In step 2, the NSC 655649 dose was divided into three consecutive daily doses. Plasma and urine were sampled to assess the pharmacokinetic and excretory characteristics of NSC 655649. A total of 12 patients were enrolled at the MTD for the purpose of gender equity.


RESULTS
Forty-three patients were treated with NSC 655649 for a total of 108 cycles in step 1, and 26 patients were treated for a total of 41 cycles in step 2. The MTD for both steps 1 and 2 was determined to be 572 mg/m(2). Myelosuppression was the dose-limiting toxicity. Local venous irritation was generally grade 1-2 in severity but could only be adequately prevented by administration of study drug through central i.v. access. One patient with adenocarcinoma of unknown primary experienced a partial response on step 1. Four patients experienced stable disease of >100 days duration.


CONCLUSIONS
NSC 655649 may be safely given at an MTD of 572 mg/m(2) in both single-dose and multiple-dose formats. Optimally, this drug should be administered through central i.v. access.
University of Wisconsin Comprehensive Cancer Center, Experimental Therapeutics Program, Madison, Wisconsin 53792, USA.
Joseph
J
Merchant
Kendra
K
Tutsch
Amy
A
Dresen
Rhoda
R
Arzoomanian
Dona
D
Alberti
Chris
C
Feierabend
Kim
K
Binger
Rebecca
R
Marnoccha
James
J
Thomas
Jim
J
Cleary
George
G
Wilding
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002227:Carbazoles; D004305:Dose-Response Relationship, Drug; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D005960:Glucosides; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009503:Neutropenia / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D002227:Carbazoles; D005960:Glucosides; C093269:becatecarin