Phase I biodistribution and pharmacokinetic study of Lewis Y-targeting immunoconjugate CMD-193 in patients with advanced epithelial cancers.

PURPOSE: This phase I study explored the biodistribution and pharmacokinetics of the immunoconjugate CMD-193 [a humanized anti-Lewis Y (Le(y)) antibody conjugated with calicheamicin in patients with advanced cancers expressing the Le(y) antigen. EXPERIMENTAL DESIGN: The primary objectives were to determine biodistribution and pharmacokinetics of CMD-193. Secondary objectives included response rates and change in tumor metabolism. Patients with progressive, measurable, and Le(y) positive malignancies were eligible for enrollment in one of two dose cohorts, 1.0 and 2.6 mg/m(2). The first cycle was trace labeled with (111)In for biodistribution assessment using gamma camera imaging. Subsequent cycles were administered every 3 weeks up to a maximum of six cycles, depending on toxicity and response. Pharmacokinetic analysis was based on radioassay and ELISA. RESULTS: Nine patients were enrolled in the study. Biodistribution images showed initial blood pool activity, followed by markedly increased hepatic uptake by day 2, and fast blood clearance in all patients. There was low uptake in tumor in all patients. The overall T(1/2)beta of (111)In-CMD-193 was 102.88 +/- 35.67 hours, with no statistically significant difference between the two dose levels. One patient had a partial metabolic response on (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG PET) after four cycles, but no radiological responses were observed. Myelosuppression and effects on liver function were the most significant adverse effects. CONCLUSIONS: CMD-193 shows rapid blood clearance and increased hepatic uptake compared with prior studies of the parental antibody hu3S193. These results highlight the importance of biodistribution and pharmacodynamic assessment in early phase studies of new biologics to assist in clinical development.

Phase I clinical trial of the farnesyltransferase inhibitor BMS-214662 administered as a weekly 24 h continuous intravenous infusion in patients with advanced solid tumors.

PURPOSE: BMS-214662 is a novel farnesyltransferase (FT) inhibitor that has shown promising suggestions of single agent activity in patients with advanced solid tumors when administered as a 1 h intravenous (i.v.) infusion every 3 weeks. The degree of FT inhibition in peripheral blood mononuclear cells (PBMCs) was greatest at the end of the infusion and rapidly reversed as the concentration of the drug in the plasma decayed. A second phase I trial of BMS-214662 administered as a weekly 24 h i.v. infusion was initiated to determine if the duration of maximum FT inhibition could be significantly extended by prolonging the infusion time and increasing the frequency of administration. PATIENTS AND METHODS: Infusion of BMS-214662 was prolonged from 2, 4, 8, 16, 24 h in single patient cohorts and repeated weekly for 3 out of 4 weeks. The initial dose was 56 mg/m(2). When the infusion duration reached 24 h, the dose was escalated at a constant multiples of 1.4 in single patient cohorts until the occurrence of toxicity greater than grade 1, upon which groups of at least three patients were evaluated at each dose level. The plasma pharmacokinetics and FT inhibition in PBMCs were measured in all patients at the prospective maximum tolerated dose. RESULTS: Nineteen patients participated in the study (11 males/8 females) and the weekly dose was increased to a maximum of 300 mg/m(2) given as a 24 h i.v. infusion. Drug-related toxicity greater than grade 1 first occurred at 300 mg/m(2), with two patients experiencing dose-limiting toxicity. One patient developed a grade 3 hyponatremia and another developed reversible grade 3 diarrhea, grade 2 renal toxicity, and grade 3 transaminitis. A 275 mg/m(2) dose was then evaluated, where one of the three patients treated experienced reversible grade 4 renal toxicity and grade 3 diarrhea. In view of the identical renal toxicity at 275 mg/m(2) in another study and limited drug availability, there was no further accrual to this dose level and the study was closed. No evidence of antitumor activity was observed. The plasma pharmacokinetics of BMS-214662 was linear with high interpatient variability. In the three patients evaluated at the 275 mg/m(2) dose level, the maximum inhibition of FT activity in PBMCs was 47+/-23% of the baseline. CONCLUSION: Administering BMS-214662 as a weekly 24 h continuous i.v. infusion permitted a considerably greater dose intensity to be delivered as compared to a single 1 h infusion given once every 3 weeks. The more prolonged infusion schedule resulted in a much lower degree of maximum FT inhibition in PBMCs than achieved with the 1 h infusion, although the duration of enzyme inhibition was longer, consistent with the lower peak plasma concentration of the drug provided by comparably tolerated doses when given as a 24 h infusion. Similarly, delivering the drug with increased dose intensity permitted by this weekly administration schedule did not appear to enhance its therapeutic benefit, at least in this phase I trial. Continued development of BMS-214662 may depend upon the potential for using it in combination with other anticancer drugs.

A review and assessment of potential sources of ethnic differences in drug responsiveness.

The International Conference on Harmonization (ICH) E5 guidelines were developed to provide a general framework for evaluating the potential impact of ethnic factors on the acceptability of foreign clinical data, with the underlying objective to facilitate global drug development and registration. It is well recognized that all drugs exhibit significant inter-subject variability in pharmacokinetics and pharmacologic response and that such differences vary considerably among individual drugs and depend on a variety of factors. One such potential factor involves ethnicity. The objective of the present work was to perform an extensive review of the world literature on ethnic differences in drug disposition and responsiveness to determine their general significance in relation to drug development and registration. A few examples of suspected ethnic differences in pharmacokinetics or pharmacodynamics were identified. The available literature, however, was found to be heterologous, including a variety of study designs and research methodologies, and most of the publications were on drugs that were approved a long time ago.