Japanese Journal of Clinical Oncology 30:377-384 (2000)
© 2000 Foundation for Promotion of Cancer Research
Pharmacokinetic and Pharmacodynamic Analysis of Bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) Administered Once a Day for Five Consecutive Days: A Phase I Study
,+ 1Thoracic Oncology Division, National Cancer Center Hospital, Tokyo, 2Division of Oncology and Hematology, National Cancer Center Hospital East, Kashiwa, Chiba, 3Department of Respiratory Medicine and Oncology, Osaka City General Hospital, Osaka and 4Fourth Department of Internal Medicine, Kinki University School of Medicine, Osaka, Japan
Background: Bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) is the first orally given platinum complex that shows in vitro cytotoxicity comparable to that of cisplatin and in vivo cytotoxicity superior to those of cisplatin and carboplatin.
Methods: We conducted an escalating-dose (50, 75, 100, 120 mg/m2) phase I study of JM216 administered orally once a day for five consecutive days in patients with solid tumors to establish the toxicity profile, maximum tolerated dose (MTD) and pharmacokinetic profile. Twenty-three patients were enrolled and all were assessable for toxicity.
Results: The MTD was 120 mg/m2/day and the dose-limiting toxicities were leukopenia, thrombocytopenia, anemia and diarrhea. Because of the delayed hematological toxicities, it was difficult to repeat cycles every 26 days in some patients. Tumor shrinkage was observed in two patients with breast cancer, both of whom were resistant to doxorubicin. A pharmacokinetic study showed that the areas under the concentration–time curve (AUC) and peak plasma concentrations (Cmax) for total platinum (Pt) on days 1 and 5 and ultrafiltered Pt (UF-Pt) on day 1 increased in proportion to the dose of JM216. The AUCs for both total and UF-Pt on day 5 were higher than the AUCs on day 1. The AUC for UF-Pt on day 5 showed the best correlation with percentage reduction in leukocyte count and in absolute neutrophil count.
Conclusion: The recommended dose for phase II studies is 100 mg/m2/day every 4–6 weeks. The observation of tumor shrinkage in previously heavily treated breast cancer patients supports a phase II investigation.
+ For reprints and all correspondence : Takayasu Kurata, Thoracic Oncology Division, National Cancer Center Hospital, 1–1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, JapanAbbreviations: MTD, maximum tolerated dose; AUC, area under concentration–time curve; Cmax, peak plasma concentration; Pt, total platinum; UF-Pt, ultrafiltered platinum; CDDP, cis-diammine-dichloro-platinum; CBDCA, cis-diammine-cyclobutane-dicarboxylato-platinum; DLT, dose-limiting toxicity; PS, performance status; WBC, white blood cell; plt, platelet count; AST, aspartate aminotransferase; ALT, alanine aminotransferase; GCP, Good Clinical Practice; 51Cr-EDTA, chromium-51-edathamil; JCOG, Japan Clinical Oncology Group; NCI-CTC, National Cancer Institute Common Toxicity Criteria; CR, complete response; PR, partial response; NC, no change; PD, progression disease; AAS, atomic absorption spectrometry; LOQ, lower limit of quantitation; t, half-life; ANC, absolute neutrophil count; NSCLC, non-small cell lung cancer; pt, patient; BRM, biological response modifier; SD, standard deviation
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