Broad phase II and pharmacokinetic study of methoxy-morpholino doxorubicin (FCE 23762-MMRDX) in non-small-cell lung cancer, renal cancer and other solid tumour patients

Abstract

Summary The aim was to perform a broad phase 11 and pharmacokinetic study of methoxymorpholino-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 six cycles. Plasma, urine and leucocyte MMRDX and its 1 3-dihydro metabolite 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 primary) received 132 cycles of MMRDX. Common toxicity criteria (CTC) grade III/IV thrombocytopenia (12% of cycles) and neutropenia (27% of cycles) occurred with median nadir on day 22. Transient transaminases elevation 2 grade III/IV was observed in 7% of cycles, late and prolonged nausea 2 grade 11 in 34% and vomiting . grade 11 in 39%. In two patients, the left ventricular ejection fraction was reduced 2 15%. Of 37 evaluable patients, one out of 17 NSCLC had a partial response. Mean (± s.d.) MMRDX AUCo, calculated up to 24 h after dosing was 20.4 ± 6.2 ,ug h 1-' (n = 11) and tf/2,3 was 44.2 h. Mean plasma clearance (± s.d.) was 37.2 ± 7.3 h-' m-2 and volume of distribution 1982 ± 64 m-2. MMRDX leucocyte levels 2 and 24 h after infusion were 450 to 600-fold higher than corresponding MMRDX plasma levels. In urine, 2% of the MMRDX dose was 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 and haematological toxicity. MMRDX is characterized by extensive clearance and rapid and extensive distribution into tissues. A low response rate was observed in patients with tumours with intrinsic chemotherapy resistance.

A prolonged methoxymorpholino doxorubicin (PNU-152243 or MMRDX) infusion schedule in patients with solid tumours: a phase 1 and pharmacokinetic study

“…infusion during 3 h every 28 days for a maximum of six cycles. The starting dose was 1 mg m -2 for the first three patients, and was extrapolated from the results obtained in the previous studies with bolus administration (Vasey et al, 1995;Bakker et al, 1998). If no DLT occurred, dose was escalated with 0.25 mg m -2 for the next cohort of three patients.…”

“…Samples were immediately centrifuged at 1200 g for 10 min at 4°C and plasma was stored in polypropylene tubes at -20°C until analysis. Determination of levels of MMRDX and its 13-dihydro metabolite (FCE 26176, 13-dihydro-3′-deamino-3′-(2(S)-methoxy-4-morpholinyl) doxorubicin) in plasma and urine was carried out by using high performance liquid chromatography with fluorescence detection by method of Breda et al (1992), with some modifications, as described by Bakker et al (1998). The detection limits for MMRDX and the 13-dihydro metabolite were 0.1 µg l -1 in plasma and 0.5 µg l -1 in urine.…”

“…Furthermore, both studies showed late and prolonged nausea, vomiting and transient elevations of hepatic transaminases. No signs of severe cardiotoxicity were observed in both human studies, although two patients had to be taken off study due to a decrease in left ventricular ejection fraction (LVEF) in the phase II study (Vasey et al, 1995;Bakker et al, 1998). In addition, MMRDX showed no substantial cardiotoxicity in rats (Danesi et al, 1993).…”

“…In animal studies, MMRDX showed activity against MDR xenografts (Ripamonti et al, 1992). However, in patients with various intrinsically anthracycline resistant solid tumours only a few tumour responses were observed (Vasey et al, 1995;Bakker et al, 1998). A phase I study (Vasey et al, 1995) with bolus injection of MMRDX, showed a maximum tolerated dose (MTD) at 1.5 mg m -2 every 3 weeks and myelosuppression (neutropenia and thrombocytopenia) as dose-limiting toxicity (DLT).…”

“…Nadirs occurred in the third week after treatment. A broad phase II study (Bakker et al, 1998) with 1.5 mg m -2 MMRDX administered as bolus every 4 weeks also showed myelosuppression as major toxicity. Furthermore, both studies showed late and prolonged nausea, vomiting and transient elevations of hepatic transaminases.…”