Phase I clinical and pharmacological study of oral methoxymorpholinyl doxorubicin (PNU 152243)

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Abstract
Purpose: The methoxymorpholinyl doxorubicin analogue PNU 152243 was brought into clinical studies because of preclinical observations of its non-cross-resistance in mdr tumor cells, dose-limiting neutropenia, lack of cardiotoxicity, and antitumor activity after oral administration. Methods: PNU 152243 was given orally every 4 weeks to 21 adults with a variety of solid tumors at doses ranging from 59 to 940 μg/m2. Antiemetic prophylaxis with 5-HT3 antagonists and steroids, given i.v. on day 1 and orally on days 2–8, was required beginning with the dose of 118 μg/m2. The plasma pharmacokinetics of PNU 152243 were determined by an HPLC method with fluorescence detection. The in vitro myelotoxic effects on granulocyte macrophage-colony forming cells (GM-CFC) of the plasma from 11 patients, obtained 4 and 6 h after treatment at all dose levels, were also assessed. Results: Neutropenia was the main hematologic toxic effect and the maximum tolerated dose (MTD) for myelotoxicity was 940 μg/m2, with neutropenia grade 3–4 in two of three patients. Dose-dependent nausea and vomiting were dose-limiting and the MTD for gastrointestinal toxicity was fixed at 820 μg/m2, with grade 4 vomiting in one of two patients. Other frequent toxic effects were diarrhea and fatigue. Peak levels of PNU 152243 were achieved 4 h after dosing. Dose-dependent Cmax and AUCExp, and significant interpatient variability of the main pharmacokinetic parameters were found. Very low levels of the 13-dihydrometabolite PNU 155051 were detected only at the highest doses. The hematotoxicity tests showed a Conclusions: Owing to the occurrence of severe and prolonged nausea and vomiting, the clinical development of oral PNU 152243 was discontinued. The higher-than-expected neutropenia and its lack of relationship with plasma levels of PNU 152243 and its 13-dihydroderivative PNU 155051 might be related to the formation of potent cytotoxic metabolites present in human plasma at undetectable concentrations and with prolonged half-life, as suggested by hematotoxicity tests performed with plasma from patients in GM-CFC assays.

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