A phase I study of 9-aminocamptothecin as a colloidal dispersion formulation given as a fortnightly 72-h infusion.
OBJECTIVE
A phase I pharmacologic study was undertaken to determine the maximum tolerated dose (MTD), to characterize the pharmacokinetic profile, and to evaluate all toxicities of the aqueous colloidal dispersion formulation of 9-aminocampothecin (9-AC).


METHODS
9-AC was administered as a constant 72-h i.v. infusion every 2 weeks to adult cancer patients at dose rates ranging from 25 to 59 microg/m2 per hour.


RESULTS
Twenty patients with refractory solid tumors received a total of 86 courses of 9-AC at four dose levels. Myelosuppression, particularly granulocytopenia, was the most common toxicity. Two of six assessable patients entered at 59 microg/m2 per hour had dose-limiting toxicity (grade 3 diarrhea or need for a 2-week treatment delay to permit granulocyte recovery), whereas lower doses were well tolerated. At the recommended dose, 47 microg/m2 per hour, the average steady-state plasma levels (Cpss) and area under the curve (AUC) of 9-AC lactone and total drug were 15 and 75 nM, and 1034 and 4220 nM.h, respectively. A moderate correlation was seen between 9-AC lactone AUC and the percentage decrease in granulocytes.


CONCLUSIONS
The recommended phase II dose of 9-AC colloidal dispersion as a 72-h infusion every 14 days is 47 microg/m2 per hour (1.13 mg/m2 per day). The Cpss of 9-AC lactone at this dose exceeded the 10 nM threshold level for preclinical activity.
Leguizamo
Jorge
J
National Cancer Institute-Navy Medical Oncology, Cancer Therapeutics Branch, Center for Cancer Research, National Naval Medical Center, Bethesda, Maryland, USA.
Quinn
Mary
M
Takimoto
Chris H
CH
Liang
Michael D
MD
Ismail
Abdel-Salam Attia
AS
Pang
Janet
J
Dahut
William
W
Grem
Jean L
JL
D000081:Acetamides; D000328:Adult; D000368:Aged; D000380:Agranulocytosis / Q000097:blood / Q000139:chemically induced; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D001772:Blood Cell Count; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D003102:Colloids; D019008:Drug Resistance, Neoplasm; D005079:Excipients; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
D000081:Acetamides; D000972:Antineoplastic Agents, Phytogenic; D003102:Colloids; D005079:Excipients; C080125:9-aminocamptothecin; C013959:dimethylacetamide; D002166:Camptothecin