PHASE-I CLINICAL AND PHARMACOKINETIC STUDY OF 3'-DEAMINO-3'-(2-METHOXY-4-MORPHOLINYL)DOXORUBICIN (FCE-23762)

Methoxymorpholinyldoxorubicin (FCE 23762) is a novel, highly lipophili c doxorubicin analogue, It possesses potent in vitro and in vivo antit umor activity including efficacy in multidrug-resistant tumor cell Lin es, It is also metabolically activated in vivo resulting in an 80-fold increase in potency over the parent drug. In this phase I study the d rug was administered by i.v. bolus injection at 3 week intervals, Fift y-three patients with refractory solid tumors were treated; 133 course s of FCE 23762 were administered at doses ranging from 30 to 2250 mu g /m(2). The dose limiting toxicity was reversible myelosuppression (gra nulocytopenia and thrombocytopenia), demonstrating a delayed nadir and recovery in comparison to doxorubicin. Other toxicities included tran sient elevation of hepatic transaminases, delayed and prolonged nausea and vomiting, mucositis, anorexia, fatigue, and diarrhea, Heavily pre treated patients demonstrated more myelosuppression than previously un treated patients at 1250 mu g/m(2). No cardiotoxicity was observed, Fo ur objective tumor responses were seen: one complete response in a pat ient with pelvic recurrence of cervical cancer; one partial response i n a patient with cutaneous and lymph gland metastases from head and ne ck cancer; and two minor responses in patients with liver metastases f rom colorectal cancer, Plasma concentrations of FCE 23762 and its 13-d ihydro metabolite, FCE 26176, were measured in 20 patients at doses gr eater than or equal to 675 mu g/m(2), using HPLC with fluorescence det ection, The area under the plasma concentration-time curve ranged from 30 to 80 ng/h/ml; plasma data suggested linear kinetics in the range of tested doses (although there was considerable interpatient variabil ity), The maximum tolerated dose defined in this study using this sche dule is 1500 mu g/m(2). A safe phase II dose for previously untreated patients using this schedule is 1250 mu g/m(2); however, this may actu ally be below the optimal dose for this patient population.