Phase I and pharmacokinetic study of tasidotin hydrochloride (ILX651), a third-generation dolastatin-15 analogue, administered weekly for 3 weeks every 28 days in patients with advanced solid tumors.

PURPOSE: To determine the safety, tolerability, and pharmacokinetics and to seek preliminary evidence of anticancer activity of tasidotin (ILX651), a novel dolastatin analogue, when administered as a 30-minute i.v. infusion weekly for 3 weeks every 4 weeks. EXPERIMENTAL DESIGN: Thirty patients with advanced solid malignancies were treated with 82 courses at six dose levels ranging from 7.8 to 62.2 mg/m2 weekly, initially according to an accelerated dose-escalation scheme, which evolved into a Fibonacci scheme as a relevant degree of toxicity was observed. Plasma and urine were sampled to characterize the pharmacokinetic behavior of tasidotin. RESULTS: A high incidence of neutropenia complicated by fever (one patient), or precluding treatment on day 15 (three patients), was the principal toxicity of tasidotin, at doses above 46.8 mg/m2. At all dose levels, nonhematologic toxicities were generally mild to moderate and manageable. Grade 3 toxicities included diarrhea and vomiting (one patient each). Drug-induced neurosensory symptoms were mild and there was no evidence of cardiovascular toxicity, which has been previously associated with other dolastatins. Tasidotin pharmacokinetics were mildly nonlinear, whereas metabolite kinetics were linear. A patient with non-small cell lung carcinoma experienced a minor response, and a patient with hepatocellular carcinoma had stable disease lasting 11 months. CONCLUSIONS: The recommended dose for phase II studies of tasidotin administered on this schedule is 46.8 mg/m2. The mild myelosuppression and manageable nonhematologic toxicities at the recommended dose, the evidence of antitumor activity, and the unique mechanistic aspects of tasidotin warrant further disease-directed evaluations on this and alternative schedules.

Administration of CI-1033, an irreversible pan-erbB tyrosine kinase inhibitor, is feasible on a 7-day on, 7-day off schedule: a phase I pharmacokinetic and food effect study.

PURPOSE: To determine the maximum tolerated dose of administrating CI-1033, an oral 4-anilinoquinazoline that irreversibly inhibits the tyrosine kinase domain of all erbB subfamilies, on an intermittent schedule, and assess the interaction of CI-1033 with food on the pharmacokinetic behavior. EXPERIMENTAL DESIGN: Escalating doses of CI-1033 from a dose level of 300 mg/day for 7 days every other week were administered to patients with advanced solid malignancies. Plasma concentration-time data sets from all evaluable patients were used to develop a population pharmacokinetic model. Noncompartmental methods were used to independently assess the effect of a high-fat meal on CI-1033 absorption and bioavailability. RESULTS: Twenty-four patients were treated with 69 twenty-eight day courses. The incidence of unacceptable toxicity, principally diarrhea and skin rash, was observed at the 300 mg/day dose level. At the 250 mg/day level, toxicity was manageable, and protracted administration was feasible. A one-compartment linear model with first-order absorption and elimination adequately described the pharmacokinetic disposition. CL/F, apparent volume of distribution (Vd/F), and ka (mean +/- relative SD) were 280 L/hour +/- 33%, 684 L +/- 20%, and 0.35 hour(-1)+/- 69%, respectively. Cmax values were achieved in 2 to 4 hours. Systemic CI-1033 exposure was largely unaffected by administration of a high-fat meal. At 250 mg, concentration values exceeded IC50 values required for prolonged pan-erbB tyrosine kinase inhibition in preclinical assays. CONCLUSIONS: The recommended dose on this schedule is 250 mg/day. Its tolerability and the biological relevance of concentrations achieved at the maximal tolerated dose warrant consideration of disease-directed evaluations. This intermittent treatment schedule can be used without regard to meals.

A phase I and pharmacokinetic study of the nonpolyglutamatable thymidylate synthase inhibitor ZD9331 plus docetaxel in patients with advanced solid malignancies.

PURPOSE: To assess the feasibility of administering ZD9331, a thymidylate synthase (TS) inhibitor that does not undergo polyglutamation and has broad antitumor activity, in combination with docetaxel in patients with advanced solid malignancies. The study also sought to determine the principal toxicities of the regimen and recommend appropriate doses for phase II studies, characterize the pharmacokinetics of the agents, evaluate the possibility of major drug-drug interactions, and seek preliminary evidence of anti-cancer activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of docetaxel as a 60-minute intravenous (IV) infusion followed 30 minutes later by ZD9331 as a 30-minute IV infusion every 3 weeks. At least three patients were treated at each dose level, and the maximum tolerated dose level was defined as the highest dose level that was not associated with an unacceptably high incidence of severe toxicity. The pharmacokinetics of both ZD9331 and docetaxel were also characterized. RESULTS: Nineteen patients were treated with 71 cycles of ZD9331 and docetaxel (ZD9331/docetaxel) at dose levels that encompassed dosing iterations of ZD9331 ranging from 65 to 260 mg/m(2) and docetaxel doses in the range of 50 to 75 mg/m(2). Neutropenia was the principal toxicity of the ZD9331/docetaxel regimen. Since five of six patients treated at the ZD9331/docetaxel dose-level of 260/60 mg/m(2) had grade 4 neutropenia that was brief and uncomplicated in the first course, a rigorous exploration of higher dose levels was not undertaken. Nonhematologic toxicities, consisting of malaise, diarrhea, rash, nausea, and vomiting, were also observed, but these effects were rarely severe. No major antitumor responses were observed. The pharmacokinetics of both ZD9331 and docetaxel were similar to those reported in previous studies of each agent administered alone, suggesting the lack of major drug-drug interactions. CONCLUSION: The combination regimen, consisting of ZD9331 and docetaxel, is feasible and well tolerated at single-agent doses that are clinically-relevant. This ZD9331/docetaxel regimen does not appear to be associated with either major pharmacokinetic or toxicologic drug-drug interactions. A ZD9331/docetaxel dose level of 260/60 mg/m(2) is recommended as an initial dose level in disease-directed studies of the regimen, with further dose escalation of docetaxel to 75 mg/m(2) if the initial treatment is well tolerated. Further studies with this regimen are warranted in tumor types that have demonstrated sensitivity to both agents.

A phase I, pharmacokinetic, and biological study of the farnesyltransferase inhibitor tipifarnib in combination with gemcitabine in patients with advanced malignancies.

PURPOSE: To assess the feasibility of administering tipifarnib, an oral nonpeptidomimetic competitive inhibitor of farnesyltransferase, in combination with gemcitabine and recommend doses for disease-directed clinical trials. The study also sought to identify drug-drug pharmacokinetic interactions, evaluate effects on protein farnesylation, and seek preliminary evidence for clinical activity. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with tipifarnib at doses of 100, 200, and 300 mg twice daily continuously and 1000 mg/m(2) gemcitabine i.v. on days 1, 8, and 15 every 4 weeks. To identify pharmacokinetic interactions, the treatment and plasma sampling schemes were designed to permit comparisons of the pharmacokinetic behavior of each agent administered alone and together. The proportions of unfarnesylated and farnesylated HDJ2, a chaperone protein that undergoes farnesylation, were measured in peripheral blood mononuclear cells. RESULTS: Nineteen evaluable patients were treated with 74 courses of tipifarnib/gemcitabine (mg/mg/m(2)). Myelosuppression was the principal toxicity. Dose-limiting myelosuppression occurred in 2 of 5 patients at the 300/1000 dose level, whereas 2 of 11 evaluable patients at the 200/1000 dose level experienced dose-limiting toxicity. There was no evidence of clinically relevant pharmacokinetic interactions between tipifarnib and gemcitabine. Inhibition of farnesylation of HDJ2, a potential surrogate for Ras and/or other potentially relevant farnesylated proteins, was demonstrated in peripheral blood mononuclear cells at all dose levels. Partial responses were noted in patients with advanced pancreatic and nasopharyngeal carcinomas. CONCLUSIONS: On the basis of the results of this study, the tipifarnib/gemcitabine dose level of 200/1000 is recommended for disease-directed studies. At this dose level, biologically relevant plasma concentrations of tipifarnib that consistently inhibit protein farnesylation in vitro are achieved and drug-induced inhibition of protein farnesylation is measured in most patients.

A Phase I and pharmacokinetic study of squalamine, an aminosterol angiogenesis inhibitor.

PURPOSE: The purpose of this study was to assess the feasibility and characterize the pharmacokinetics of squalamine administered as a continuous i.v. infusion daily for 5 days every 3 weeks. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with escalating doses of squalamine as a 5-day continuous i.v. infusion every 3 weeks. Doses were initially escalated in 100% increments from a starting dose of 6 mg/m(2)/day, with a single patient treated at each dose level until moderate toxicity was observed, at which time additional patients were treated. RESULTS: Thirty-three patients were treated with 73 courses of squalamine at 13 dose levels ranging from 6 to 700 mg/m(2)/day. Hepatotoxicity, characterized by brief, asymptomatic elevations in transaminases and hyperbilirubinemia, was the principal dose-limiting toxicity of squalamine. At 700 mg/m(2)/day, two of three patients developed grade 4 hyperbilirubinemia, which precluded further dose escalation. At 500 mg/m(2)/day, one of seven patients experienced dose-limiting grade 4 hyperbilirubinemia and grade 3 neurosensory changes, which resolved soon after treatment. Squalamine pharmacokinetics were dose-proportional. At 500 mg/m(2)/day, the mean (percentage coefficient of variation) clearance, half-life, and volume of distribution of squalamine were 2.67 liters/h/m(2) (85%), 9.46 h (81%), and 36.84 liters/m(2) (124%), respectively, and steady-state concentrations [20.08 micro g/ml (13%)] were well above those that inhibit angiogenesis in preclinical models. CONCLUSIONS: At the recommended Phase II dose of 500 mg/m(2)/day, squalamine is well tolerated and results in plasma concentrations at least an order of magnitude higher than those required for prominent antiangiogenic effects in preclinical studies.

Synthesis and binding affinity of neuropeptide Y at opiate receptors.

Neuropeptide Y and several metabolic fragments were synthesized and evaluated for binding affinity at non-selective opiate receptors. Neuropeptide Y and several C-terminal fragments were shown to bind to non-selective opiate receptors with an affinity similar to that of Leu-enkephalin.