Phase I trial with pharmacokinetics of CB10-277 given by 24 hours continuous infusion.

The dose limiting toxicities of the short infusion trial of the dacarbazine analog, CB10-277, were nausea and vomiting which appeared to be related to the peak plasma level of the parent drug. In addition, based on mouse studies, these dose limiting toxicities occurred at a less than optimal level of the monomethyl metabolite, the presumed species required for antitumour activity. An alternative schedule that would avoid the parent drug peak plasma levels of short infusion, while possibly allowing an increase in the amount of monomethyl metabolite produced was considered. Thus, a 24 h continuous infusion schedule, repeated every 21 days was explored. Twenty-two patients received 42 courses with a dose range of 4,700-15,000 mg m-2. The dose limiting toxicity was myelosuppression (leucopenia and thrombocytopenia). Although nausea and vomiting also occurred, it was manageable with routine antiemetic therapy. Other toxicities included diarrhoea, hallucinations, malaise, muscle ache, headache and flushing and all were < or = WHO grade 2. Pharmacokinetic studies were performed with 13 courses which included all dose levels. The mean t1/2 of the parent drug was 178 min. Area under the concentration x time curve (AUC) at the highest dose for the parent drug and the monomethyl metabolite were 2,350 and 9 mM x minutes, respectively. This monomethyl metabolite AUC and the associated myelosuppression showed a more favourable comparison to the preclinical data determined in mice than the results from the short infusion trial of CB10-277. Therefore, the recommended Phase II dose and schedule of this drug was 12,000 mg m-2 given by 24 h continuous infusion.

Clinical pharmacokinetics of the anthrapyrazole CI-941: factors compromising the implementation of a pharmacokinetically guided dose escalation scheme.

The pharmacokinetics of the anthrapyrazole CI-941 has been investigated in conjunction with the Phase I evaluation of the drug with the intent of applying a pharmacokinetically guided dose escalation strategy. A starting dose of 5 mg/m2 was chosen, based on one-tenth the 10% lethal dose in mice. Due to the steep dose lethality relationship and nonlinear pharmacokinetics in mice, a target area under the CI-941 plasma concentration x time curve (AUC) of 110 microM x min (i.e., 40% of the mouse 10% lethal dose AUC) was chosen. This AUC was achieved in mice at 40 mg/m2. A total of 37 patients received 74 courses of CI-941 (5 to 55 mg/m2), with 26 patients consenting to pharmacokinetic monitoring. CI-941 was rapidly cleared from plasma, and a triexponential open model could be fitted to the data (t1/2 alpha = 7.6 +/- 2 min, t1/2 beta = 65 +/- 27 min, t1/2 zeta = 21 +/- 9 h). CI-941 was subjected to only limited urinary elimination, accounting for 5.2 +/- 2.8% of the administered dose. Wide interpatient variability in plasma CI-941 clearance at the starting dose and subsequent doses precluded the implementation of a pharmacokinetically guided dose escalation scheme, and the dose was escalated in 5-mg/m2 increments until the maximally tolerated dose was achieved. A number of investigations were performed to study potential reasons for variability in CI-941 clearance. However, CI-941 plasma protein binding (95 +/- 1%) and measures of pretreatment renal (51Cr-EDTA clearance), hepatic (plasma alanine transaminase and alkaline phosphatase levels), or cardiac function (left ventricular ejection fractions) did not relate strongly to CI-941 clearance. In patients treated at 40 mg/m2, the AUC values (156 to 415 microM x min) approximated or exceeded the target AUC. Fifty mg/m2 was the Phase II recommended dose. Further prospective studies are warranted to assess the utility of pharmacokinetically guided dose escalation strategies and to determine whether or not the variability encountered in clearance is unique to CI-941.

Phase I trial of the anthrapyrazole CI-941: prospective evaluation of a pharmacokinetically guided dose-escalation.

The development of new drugs in early clinical trials is currently based upon the results of preclinical antitumour and toxicity studies in animals. More recently, the use of preclinical pharmacokinetic information in mice has been proposed to also provide information that might expedite early clinical trials and more specifically phase I studies. The anthrapyrazole CI-941 was one of three chosen for phase I anticancer drug development. In addition, because of the predictability of the preclinical dose limiting toxicity and linear CI-941 pharmacokinetics in mice; a pharmacokinetically guided dose escalation scheme was attempted during the phase I trial, but had to be abandoned. 44 patients were entered who received 95 courses of treatment using a bolus injection every 21 days. The dose range was 5-55 mg/m2. The dose limiting toxicity was leucopenia and other toxicities, which included nausea and vomiting, mucositis, diarrhoea, alopecia and skin discolouration were either mild or manageable. Pharmacokinetic studies were performed with 27 courses. There were wide interpatient variations in the dose-AUC relationship (r = 0.7496) that hampered application of the proposed pharmacokinetically guided dose escalation scheme as planned. No complete or partial responses were observed. The recommended phase II dose using this schedule is 50 mg/m2.