Phase I and Pharmacokinetic Study of Paclitaxel by 24-Hour Intravenous Infusion

Paclitaxel, a new antitubular agent, appears to be one of the most promising single agents for the chemotherapy of various solid tumors. The primary objectives of this phase I study of paclitaxel using 24-h continuous intravenous infusions were to determine the maximum tolerated dose of paclitaxel administered by this schedule to Japanese patients with solid tumors and to evaluate the pharmaco-kiiietics of paclitaxel. Eighteen patients received one of five doses of paclitaxel, 49.5, 75, 105, 135 or 180 mg/m². Prcmedication with diphenhydramine, dexamethasone, and ranitidine was used to prevent acute hypersensitivity reactions. Pharmacokinetic data were obtained from all 18 patients. Dose-limiting toxicities observed at 180 mg/m² consisted of grade 4 granulocytopenia associated with grade 3 infection. No severe HSRs or cardiac toxicity were detected. Reversible toxicities observed included liver dysfunction, alopecia, peripheral neuropathy and myalgias. Pharmacokinetic studies performed using high-performance liquid chromatography demonstrated that plasma concentrations of paclitaxel increased during the 24-h infusion and declined immediately upon cessation of the infusion with a half life of 13.1-24.6 h (75-180 mg/m²). Less than 10% of paclitaxel was excreted in the urine within 72 h. The peak plasma concentrations and the areas under the concentration-versus-time curves increased linearly with the dose administered. Antitumor activity was observed in one patient with pulmonary metastasis from pharyngeal cancer. Based on these studies a phase II trial dose of 135 mg/m² administered over 24 h was chosen.     

Phase II Study of Carboplatin in Non-small Cell Lung Cancer

Forty four patients with advanced non-small cell lung cancer(NSCLC) were treated with carboplatin (CBDCA; cis-diammine-1,1-cyclobutane dicarboxylate platinum II) at a dose of 400–450mg/m² intravenously every four weeks in a phase II study. Fortythree patients were evaluated for response and toxicity. Twopatients achieved responses resulting in an overall responserate of 4.7% (95% confidence limits: 0.6–15.8%); one ofthese had not been treated previously and the other had beentreated previously with vinblastine. The durations of theirresponses were 5 and 7 months, respectively. The response ratein 28 previously untreated patients was 3.6% (1/28; 95% confidencelimits: 0.1–18.3%). Myelosuppression was the most commonlyfound toxicity, and thrombocytopenia especially was dose-limiting.Thrombocytopenia (<75,000/mm³) was observed in 12 patients(28%). Leukopenia (<3,000/mm³) was observed in 14 patients(33%). No serious infection or bleeding occurred, however. Treatmentwith 400–450 mg CBDCA/m² was well tolerated in the goodrisk patients in this study. Mild to moderate emesis was observedin 28 patients (65%). No renal toxicity, neurotoxicity or ototoxicitywas seen. It was demonstrated that CBDCA had little efficacyin NSCLC at the dose and schedule given in the present study.     

Phase I and pharmacokinetic study of KW-2170, a novel pyrazoloacridone compound,in patients with malignant tumors

Purpose The primary purposes of this study were to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD), to recommend a dose for phase II studies, and to analyze the pharmacokinetics of KW-2170. A secondary purpose was to assess tumor response to KW-2170.Experimental design KW-2170 was given as a 30-min i.v. infusion every 4 weeks. Doses were escalated from 1.0 mg/m² according to a modified Fibonacci method.Results A total of 45 cycles of KW-2170 were delivered to 41 patients at doses ranging from 1.0 to 53.0 mg/m². The primary DLT was neutropenia which was observed in two of six patients treated at 32.0 mg/m² and in two of two patients treated at 53.0 mg/m²; therefore, the MTD was 53.0 mg/m². Although no patients showed a complete response (CR) or partial response (PR), 15 patients were evaluated as having freedom from progression at the 1-month time-point, with two demonstrating slight tumor shrinkage in their metastatic lesions. None of the patients experienced significant cardiotoxicity. The plasma concentration of KW-2170 declined in a triphasic manner. The half-life, total clearance (CL_tot) and volume of distribution (V_dss) were nearly constant and independent of dose, and showed a relatively small interpatient variability. A linear relationship was observed between dose and maximum plasma concentration (C_max) and area under the concentration–time curve (AUC_0–). In addition, there was a good correlation between neutropenia and AUC_0–. This suggests that toxicity may be dependent on systemic exposure to the drug. Two oxidative metabolites were observed in the patients plasma and urine.Conclusions The primary DLT of KW-2170 in this study was neutropenia, with a MTD of 53 mg/m². A significant linear relationship was observed between neutropenia and AUC_0–. We estimate the recommended dose for phase II studies to be 41.0 mg/m².     

Phase I study of liposomal annamycin

Annamycin is a highly lipophilic anthracycline with the ability to bypass the MDR-1 mechanism of cellular drug resistance. In this phase I study, annamycin entrapped in liposomes was administered by a 1- to 2-h intravenous infusion at 3-week intervals. Thirty-six patients with relapsed solid tumors were treated and 109 courses were administered at doses ranging from 3 to 240 mg/m². The dose-limiting toxicity was thrombocytopenia. Five patients had a probable allergic reaction, requiring discontinuation of treatment in one. Treatment was well tolerated otherwise. No cardiac toxicity was seen on endomyocardial biopsy of four patients studied. There was limited gastrointestinal toxicity and no alopecia. No objective tumor responses were observed. Pharmacokinetic studies at 24, 120 and 240 mg/m² showed a biexponential plasma concentration-versus-time profile. There was a linear relationship between the dose and the maximal plasma concentration with relatively constant plasma clearance values. The maximum tolerated dose (MTD) for liposomal annamycin defined in this study is 210 mg/m². Because of a subsequent change in the formulation of the drug, future studies will use 190 mg/m² as the MTD. Received: 28 December 1999 / Accepted: 29 June 2000     

放射治疗合并盐酸拓普替康治疗局部晚期非小细胞肺癌的Ⅰ期临床研究

 目的 通过局部晚期非小细胞肺癌放射治疗合并盐酸拓普替康(TPT)的综合治疗，进行Ⅰ期临床研究，观察其毒性、耐受剂量及临床可行性。方法 局部晚期肺癌16例，病理或细胞学证实为非小细胞肺癌。放射治疗肺部原发灶及淋巴引流区。化疗(TPT)：放射治疗开始应用拓普替康，每周2次。每个剂量水平治疗4个星期。拓普替康分3个剂量级，0．5mg／m²，0.75mg／m²，1mg／m²，每个剂量级至少入选3个病人，如无明显毒副反应进入下一个剂量水平，直至找到最大耐受量(MTD)。结果 主要毒副反应为骨髓抑制和放射性食管炎。MTD为0．75mg／m²。结论 局部晚期非小细胞肺癌合并TPT综合治疗具有临床可行性，最大耐受剂量0．75mg／m²，推荐Ⅱ期临床剂量为0．5mg／m²。     

Phase II Study of Carboplatin in Small Cell Lung Cancer

Carboplatin (CBDCA; cis-diammine-1, 1-cyclobutane dicarboxylateplatinum II), a new platinum analogue, was administered to 18patients with small cell lung cancer (SCLC) at a dose of 300–450mg/m² intravenously every four weeks, in a phase II study. Allpatients could be evaluated to assess response and 17 for toxicity.The overall response rate was 28% (5/18), including one completeresponse. Of eight patients previously untreated, four (50%)showed a response, including one complete response. The responserate in patients with no previous cisplatintreatment was 50%(5/10). Response durations in five responders were 2, 3, >4,> 10 and 11 months. Toxicity was primarily hematologic,with thrombocytopenia being dose-limiting. Thrombocytopenia(<75,000/mm³) was observed in 12 patients (71%), six requiringplatelet transfusion. Leukopenia (<3,000/mm³) was observedin 11 patients (65%). There were no episodes of serious infectionor bleeding, however. Myelosuppression was more severe in heavilypretreated patients than in patients previously untreated. Dosereductions were required following multiple treatments for cumulativemyelotoxicity. Mild to moderate nausea and vomiting occurredin seven patients (44%). Nephrotoxicity and ototoxicity werenot observed. Carboplatin was demonstrated to be an active agentagainst SCLC. Further investigation into dose and schedule ofCBDCA in combination chemotherapy is warranted.