title: Phase I and pharmacokinetic study of ormaplatin (tetraplatin, NSC 363812) administered on a day 1 and day 8 schedule.
abstract: Ormaplatin (tetraplatin, NSC 363812) is a platinum(IV) analogue that is active against cisplatin-resistant cell lines in preclinical models. A schedule previously shown to be active and well tolerated for cisplatin was evaluated in 26 patients. Ormaplatin was administered over a dose range of 4.4-60.8 mg/m2 i.v. given over 30 min on a day 1 and day 8 schedule every 28 days. Twenty-three patients had received prior chemotherapy, and the median performance status was 1. Nausea/vomiting (> or = grade 2) occurred in 40% of patients but was well controlled with standard antiemetic therapy. One patient had grade 2 renal toxicity and 1 patient had grade 3 hepatotoxicity (grade 2 pretreatment). No toxicity limited the dose given during the first course. With repeated drug administration delayed severe neurotoxicity developed in 4 patients, manifested as a sensory polyneuropathy in 3 patients and a possible autonomic neuropathy in one. Prospective nerve conduction studies did not detect subclinical neuropathy prior to the onset of symptoms. Patients who received cumulative doses above 200 mg/m2 were at increased risk for developing neurotoxicity. Plasma elimination of ultrafilterable platinum (measured by atomic absorption spectrometry) was biphasic with a harmonic mean terminal half-life of 15.8 h. The mean total body clearance and renal clearance of ultrafilterable platinum were 173 and 29.8 ml/min/m2, respectively. Thus, renal clearance accounted for 16% of total clearance suggesting that extensive protein/tissue binding was responsible for the majority of platinum clearance. Approximately 60% of the platinum is protein bound (one-half irreversibly) at the end of the infusion. Pharmacokinetic parameters were not dose dependent. No pharmacokinetic parameters were more predictive of neurotoxicity than the cumulative ormaplatin dose. A phase II dose cannot be recommended on this schedule because severe and unpredictable neurotoxicity precludes the administration of more than three cycles at the three highest doses levels tested.
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia 19111-2497.
authors.forename: R J
authors.initials: RJ
authors.lastname: Schilder
authors.forename: F P
authors.initials: FP
authors.lastname: LaCreta
authors.forename: R P
authors.initials: RP
authors.lastname: Perez
authors.forename: S W
authors.initials: SW
authors.lastname: Johnson
authors.forename: J M
authors.initials: JM
authors.lastname: Brennan
authors.forename: A
authors.initials: A
authors.lastname: Rogatko
authors.forename: S
authors.initials: S
authors.lastname: Nash
authors.forename: C
authors.initials: C
authors.lastname: McAleer
authors.forename: T C
authors.initials: TC
authors.lastname: Hamilton
authors.forename: D
authors.initials: D
authors.lastname: Roby
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D009431:Neural Conduction / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D014462:Ultrafiltration; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C049777:ormaplatin