Phase I trial of rebeccamycin analog (NSC #655649) in children with refractory solid tumors: a pediatric oncology group study.
OBJECTIVE
To conduct a phase 1 trial of rebeccamycin analog (NSC #655649) in children with solid tumors to establish the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD); to establish the pharmacokinetic profile in children, and to document any evidence of antitumor activity.


METHODS
A 1-hour infusion of NSC #655649 was administered every 21 days to 17 patients younger than 21 years who had malignant tumors refractory to conventional therapy. Doses ranged from 450 mg/m2 to 760 mg/m2. Pharmacokinetics were done in at least three patients per dose level. The first course was used to determine DLT and MTD.


RESULTS
Sixteen patients on three dose levels were assessable for toxicities. At 760 mg/m2, four patients had dose-limiting neutropenia and thrombocytopenia. Pharmacokinetics were assessable in 13 patients. Plasma concentrations declined triexponentially and concentrations above the range of in vitro antitumor activity were maintained for 3 days. Analysis of urine extracts revealed the presence of an N-de-ethylated metabolite and probable involvement of cytochrome P450 isoenzyme(s) in the metabolism of NSC #655649. Pharmacodynamic studies showed a relationship between the area under the curve and percentage change in absolute neutrophil count in the E(max) model (r2 = 0.56, P = 0.001).


CONCLUSIONS
The recommended phase 2 dose of NSC #655649 administered as a 1-hour infusion every 21 days to children with solid tumors is 585 mg/m2. Both neutropenia and thrombocytopenia were found to be dose-limiting toxicities.
Langevin
Anne-Marie
AM
University of Texas Health Science Center at San Antonio, Pediatric Hematology Oncology, 333 N. Santa Rosa Street, San Antonio, TX 78207, USA. anne_langevin@srhc.iwhs.org
Weitman
Steven D
SD
Kuhn
John G
JG
Weintraub
Susan T
ST
Baruchel
Sylvain
S
Furman
Wayne
W
Bernstein
Mark
M
Blaney
Susan
S
Vietti
Teresa
T
D000293:Adolescent; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use; D019540:Area Under Curve; D002227:Carbazoles; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005960:Glucosides; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007223:Infant; D008657:Metabolic Clearance Rate; D009369:Neoplasms / Q000097:blood / Q000145:classification / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D018579:Patient Selection; D010976:Platelet Count
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D002227:Carbazoles; D005960:Glucosides; D006454:Hemoglobins; C093269:becatecarin