Phase I and pharmacokinetic study of a daily times 5 short intravenous infusion schedule of 9-aminocamptothecin in a colloidal dispersion formulation in patients with advanced solid tumors.
OBJECTIVE
To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of 9-aminocamptothecin (9-AC) in a colloidal dispersion (CD) formulation administered as a 30-minute intravenous (IV) infusion over 5 consecutive days every 3 weeks.


METHODS
Patients with solid tumors refractory to standard therapy were entered onto the study. The starting dose was 0.4 mg/m(2)/d. The MTD was assessed on the first cycle and was defined as the dose at which > or = two of three patients or > or = two of six patients experience DLT. Pharmacokinetic measurements were performed on days 1 and 5 of the first cycle and on day 4 of subsequent cycles using high-performance liquid chromatography.


RESULTS
Thirty-one patients received 104+ treatment courses at seven dose levels. The DLT was hematologic. At a dose of 1.3 mg/m(2)/d, three of six patients experienced grade 3 thrombocytopenia. Grade 4 neutropenia that lasted less than 7 days was observed in four patients. At a dose of 1.1 mg/m(2)/d, four of nine patients had grade 4 neutropenia of brief duration, which was not dose limiting. Nonhematologic toxicities were relatively mild and included nausea/vomiting, diarrhea, obstipation, mucositis, fatigue, and alopecia. Maximal plasma concentrations and area under the concentration-time curve (AUC) increased linearly with dose, but interpatient variation was wide. Lactone concentrations exceeded 10 nmol/L, the threshold for activity in preclinical tumor models, at all dose levels. Sigmoidal E(max) models could be fit to the relationship between AUC and the degree of hematologic toxicity. A partial response was observed in small-cell lung cancer.


CONCLUSIONS
9-AC CD administered as a 30-minute IV infusion daily times 5 every three weeks is safe and feasible. The recommended phase II dose is 1. 1 mg/m(2)/d.
Herben
V M
VM
Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/the Netherlands Cancer Institute, Amsterdam.
van Gijn
R
R
Schellens
J H
JH
Schot
M
M
Lieverst
J
J
Hillebrand
M J
MJ
Schoemaker
N E
NE
Porro
M G
MG
Beijnen
J H
JH
ten Bokkel Huinink
W W
WW
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D003102:Colloids; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004337:Drug Carriers; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D007783:Lactones / Q000097:blood; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced
C402491:9-aminocamptothecin lactone; D000970:Antineoplastic Agents; D003102:Colloids; D004337:Drug Carriers; D007783:Lactones; C080125:9-aminocamptothecin; D002166:Camptothecin