Phase I clinical and pharmacokinetic study of the oral platinum analogue JM216 given daily for 14 days

Background. The oral bis (acetate) ammine dichloro cyclohexylamine platinum (IV) analogue (BMS-182751) was brought into clinical development because i t was shown to be cytotoxic against some human tumour cell lines and to hav e an antitumor activity in murine tumours at least comparable to that of pa renteral cisplatin and carboplatin. In early clinical studies in which the optimal schedule of treatment was daily for five consecutive days, dose-dep endent nausea and vomiting occurred in about two-thirds of patients. Patients and methods. To evaluate if the use of lower daily doses for longe r periods of time could result in a better tolerability, JM216 was given on ce daily for 14 consecutive days every four to five weeks to adult patients with solid tumors. Oral antiemetics were given prophylactically only at th e highest doses. The pharmacokinetics of total and ultrafiltrable platinum were studied on days 1 and 14 of the first cycle by Inductively Coupled-Mas s-Spectrometry (ICP-MS). Results: Forty-six patients were treated at doses ranging from 10 mg/m(2)/d to 50 mg/m(2)/d and 39 were evaluable for hematologic toxicity over 74 cyc les. MTDs were reached at 45 mg/m(2)/d and 50 mg/m(2)/d x 14 repealed every five weeks in patients with extensive, or limited/no prior treatment, resp ectively. The dose-limiting toxicity was neutropenia which was delayed and variable among patients. Other non-hematological toxicities were severe vom iting (22% of cycles), diarrhea (28% of cycles) and drug-associated fever ( 32% of patients), controlled with paracetamol. Subjective improvement with disappearance of tumour-related pain was observed in one patient with chemo therapy-resistant metastatic prostate cancer and in one previously untreate d patient with malignant mesothelioma. C-max and AUC values of both total a nd ultrafiltrable platinum on days 1 and 14 were highly variable among pati ents. Only C-max on day 1 was linearly related to the dose. Total and ultra filtrable platinum were still detectable two weeks after the last dose. No relationship could be established between AUC values and toxicities. Conclusions: Daily doses of JM216 of 40 mg/m(2) and 45 mg/m(2) for 14 conse cutive days every five weeks with oral antiemetic prophylaxis are selected for phase II evaluation of single agent in patients with extensive or limit ed/no prior treatment, respectively. The administration of JM216 on a day x 14 schedule produced nausea and vomiting comparable to that observed with the day x 5 regimen but of longer duration. The variability of pharmacokine tics and pharmacodynamics, even though limited at the doses proposed for ph ase II evaluation of JM216 as single agent, recommend a careful monitoring of the patients.