BROAD PHASE-II AND PHARMACOKINETIC STUDY OF METHOXY-MORPHOLINO DOXORUBICIN (FCE 23762-MMRDX) IN NON-SMALL-CELL LUNG-CANCER, RENAL-CANCER AND OTHER SOLID TUMOR PATIENTS

The aim was to perform a broad phase II and pharmacokinetic study of m ethoxymorpholino-doxorubicin (MMRDX), a drug active against multidrug- resistant tumour cells in vitro when given by i.v. bolus at 1.5 mg m(- 2) every 4 weeks, in metastatic or unresectable solid tumour patients with known intrinsic drug resistance. Patients received a maximum of s ix cycles. Plasma, urine and leucocyte MMRDX and its 13-dihydro metabo lite pharmacokinetic analysis was performed in patients without liver metastases. Patients (n = 48, 21 NSCLC, 19 renal cell, three head and neck tumour, three cervical cancer and two adenocarcinoma of unknown p rimary) received 132 cycles of MMRDX. Common toxicity criteria (CTC) g rade III/IV thrombocytopenia (12% of cycles) and neutropenia (27% of c ycles) occurred with median nadir on day 22. Transient transaminases e levation greater than or equal to grade III/IV was observed in 7% of c ycles, late and prolonged nausea greater than or equal to grade II in 34% and vomiting greater than or equal to grade II in 39%. In two pati ents, the left ventricular ejection fraction was reduced greater than or equal to 15%. Of 37 evaluable patients, one out of 17 NSCLC had a p artial response. Mean (+/-s.d.) MMRDX AUC(0-->infinity) calculated up to 24 h after dosing was 20.4 +/- 6.2 mu g h l(-1) (n = 11) and t(1/2, gamma) was 44.2 h. Mean plasma clearance (+/-s.d.) was 37.2 +/- 7.3 l h(-1) m(-2) and volume of distribution 1982 +/- 64 l m(-2). MMRDX leu cocyte levels 2 and 24 h after infusion were 450 to 600-fold higher th an corresponding MMRDX plasma levels. In urine, 2% of the MMRDX dose w as excreted unchanged, and 2% as metabolite. The main side-effects of 1.5 mg m(-2) every 4 weeks of MMRDX are delayed nausea and vomiting an d haematological toxicity. MMRDX is characterized by extensive clearan ce and rapid and extensive distribution into tissues. A low response r ate was observed in patients with tumours with intrinsic chemotherapy resistance.