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.

Safety, pharmacokinetics, and activity of ABX-EGF, a fully human anti-epidermal growth factor receptor monoclonal antibody in patients with metastatic renal cell cancer.

PURPOSE: To determine the antitumor activity of ABX-EGF, a fully human monoclonal antibody to the epidermal growth factor receptor (EGFr), in previously treated patients with metastatic renal cell carcinoma, and to characterize its toxicity, immunogenicity, pharmacokinetics, and pharmacodynamics. PATIENTS AND METHODS: The antitumor activity, as well as the toxicity, pharmacokinetics, pharmacodynamics, and immunogenicity of ABX-EGF, were assessed. RESULTS: Eighty-eight patients were treated with ABX-EGF doses of 1.0, 1.5, 2.0, or 2.5 mg/kg weekly with no loading dose. EGFr immunostaining was performed on 76 tumor biopsy specimens (86%), and 69 (91%) scored positive. Major responses occurred in three patients, and two patients had minor responses. Forty-four patients (50%) also had stable disease at their first 8-week assessment, and the median progression-free survival (PFS) was 100 days (95% CI, 58 to 140 days). Low hemoglobin and high alkaline phosphatase predicted for short PFS. The principal toxicity, an acneiform rash, occurred in 68%, 95%, 87%, and 100% of patients who received at least three doses of ABX-EGF at 1.0, 1.5, 2.0, and 2.5 mg/kg/wk, respectively. A trend indicated that the severity of the rash may relate to PFS. No human antihuman antibodies were detected. ABX-EGF pharmacokinetics fit a model that incorporated both linear and saturable EGFr-mediated clearance mechanisms, and interindividual variability was low. At 2.5 mg/kg/wk, ABX-EGF concentrations throughout treatment exceeded those estimated to saturate nonlinear clearance and inhibit xenograft growth by 90%. CONCLUSION: ABX-EGF was generally well tolerated. The objective response rate was low in previously treated patients with metastatic renal cell carcinoma. Although skin rash may be a pharmacodynamic marker of drug action, its potential as a surrogate marker of clinical benefit requires further evaluation.

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.