A Phase I and pharmacological study of the platinum polymer AP5280 given as an intravenous infusion once every 3 weeks in patients with solid tumors.
OBJECTIVE
This Phase I study was designed to determine the maximum tolerated dose, profile of adverse events, and dose-limiting toxicity of AP5280 in patients with solid tumors. Furthermore, the platinum (Pt) pharmacokinetics after AP5280 administration and preliminary antitumor activity were evaluated. AP5280 is a Pt agent linked to the water-soluble, biocompatible copolymer N-(2-hydroxypropyl)methacrylamide, which potentially increases Pt accumulation in tumors via the enhanced permeability and retention effect. In this way, it is anticipated that a higher activity of therapeutic Pt can be reached. The pharmaceutical product contains approximately 8.5% of Pt by weight and has a molecular weight of approximately 25,000.


METHODS
Adult patients with solid tumors received AP5280 as a 1-h i.v. infusion every 21 days. Pharmacokinetics of total and unbound Pt were determined during the first treatment course and before the start of each new cycle using noncompartmental pharmacokinetic analysis. Pt-DNA adduct concentrations in WBCs and, if available, in tumor tissue were quantified using a sensitive (32)P postlabeling assay.


RESULTS
Twenty-nine patients were treated at eight dose levels (90-4500 mg Pt/m(2)). The dose-limiting toxicity was Common Toxicity Criteria grade 3 vomiting and was experienced at 4500 mg Pt/m(2) in two of six patients. The maximum tolerated dose on this schedule was therefore 4500 mg Pt/m(2), and the recommended dose for a Phase II study is 3300 mg Pt/m(2). Renal toxicity and myelosuppression, toxicities typically observed with cisplatin and carboplatin, were minimal for AP5280. The area under the curve of total Pt increased with increasing AP5280 dose. Plasma clearance of total Pt was 644 +/- 266 ml/h, and the terminal half-life was 116 +/- 46.2 h. After AP5280 administration, Pt-guanine-guanine DNA adduct concentrations in WBCs ranged from 70 to 1848 amol/microg DNA, concentrations that were substantially lower than concentrations measured after administration of therapeutic doses of cisplatin.


CONCLUSIONS
AP5280 can be administered safely as a 1-h i.v. infusion at a dose of 3300 mg Pt/m(2) once every 3 weeks and produces prolonged plasma exposure compared with any of the free Pt-containing drugs. However, it remains to be determined whether AP5280 can actually increase Pt delivery to the DNA of tumor cells in man as has been shown in experimental models.
Rademaker-Lakhai
Jeany M
JM
The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Terret
Catherine
C
Howell
Stephen B
SB
Baud
Christiane M
CM
De Boer
Richard F
RF
Pluim
Dick
D
Beijnen
Jos H
JH
Schellens
Jan H M
JH
Droz
Jean-Pierre
JP
D000178:Acrylamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D019540:Area Under Curve; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010984:Platinum / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D013997:Time Factors
D000178:Acrylamides; D000970:Antineoplastic Agents; C438846:HPMA copolymer-platinate; D009944:Organoplatinum Compounds; D011108:Polymers; D010984:Platinum; D004247:DNA; D002945:Cisplatin