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

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 cardioto xicity, and antitumor activity after oral administration. Methods: PNU 1522 43 was given orally every 4 weeks to 21 adults with a variety of solid tumo rs at doses ranging from 59 to 940 mu g/m(2) Antiemetic prophylaxis with 5- HT3 antagonists and steroids, given i.v. on day 1 and orally on days 2-8, w as required beginning with the dose of 118 mu g/m(2) The plasma pharmacokin etics of PNU 152243 were determined by an HPLC method with fluorescence det ection. The in vitro myelotoxic effects on granulocyte macrophage-colony fo rming cells (GM-CFC) of the plasma from 11 patients, obtained 4 and 6 h aft er treatment at all dose levels, were also assessed. Results: Neutropenia w as the main hematologic toxic effect and the maximum tolerated dose (MTD) f or myelotoxicity was 940 mu g/m(2) with neutropenia grade 3-4 in two of thr ee patients. Dose-dependent nausea and vomiting were dose-limiting and the MTD for gastrointestinal toxicity was fixed at 820 mu g/m(2), 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. Dos e-dependent Cmax and AUCExp, and significant interpatient variability of th e main pharmaco-kinetic parameters were found. Very low levels of the 13-di hydrometabolite PNU 155051 were detected only at the highest doses. The hem atotoxicity tests showed a <70% colony growth inhibition with no correlatio n between the growth inhibition effect and the degree of myelotoxicity in t he same patient. Plasma concentrations of PNU 152243 were 1000 times lower than the concentration inhibiting the growth of 70% of colonies. No objecti ve tumor responses were seen. Conclusions: Owing to the occurrence of sever e and prolonged nausea and vomiting, the clinical development of oral PNU 1 52243 was discontinued. The higher-than-expected neutropenia and its lack o f relationship with plasma levels of PNU 152243 and its I 3-dihydroderivati ve PNU 155051 might be related to the formation of potent cytotoxic metabol ites present in human plasma at undetectable concentrations and with prolon ged half-life, as suggested by hematotoxicity tests performed with plasma f rom patients in GM-CFC assays.