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. 2000 Feb;82(4):767–771. doi: 10.1054/bjoc.1999.0996

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

E Fokkema 1, J Verweij 2, A T van Oosterom 3, D R A Uges 1, R Spinelli 4, O Valota 4, E G E de Vries 1, H J M Groen 1
PMCID: PMC2374418  PMID: 10732743

Abstract

The aim of this phase I study was to assess feasibility, pharmacokinetics and toxicity of methoxymorpholino doxorubicin (MMRDX or PNU-152243) administered as a 3 h intravenous infusion once every 4 weeks. Fourteen patients with intrinsically anthracycline-resistant tumours received 37 cycles of MMRDX. The first cohort of patients was treated with 1 mg m−2of MMRDX. The next cohorts received 1.25 mg m−2and 1.5 mg m−2respectively. Common toxicity criteria (CTC) grade III/IV nausea and vomiting were observed in 1/18 cycles at 1.25 mg m−2and in 2/11 cycles at 1.5 mg m−2. Transient elevation in transaminases up to CTC grade III was observed in 2/16 cycles at 1.25 mg m−2and 4/11 cycles at 1.5 mg m−2. No cardiotoxicity was observed. At 1.25 mg m−2CTC grade IV neutropenia occurred in 1/17 cycles. At 1.5 mg m−2CTC grade III neutropenia was seen in 2/7 and grade IV in 3/7 evaluable cycles. Thrombocytopenia grade III was observed in 2/9 and grade IV in 1/9 evaluable cycles. One patient treated at 1.5 mg m−2died with neutropenic fever. Therefore, dose-limiting toxicity was reached and 1.25 mg m−2was considered the maximum tolerated dose for MMRDX as 3 h infusion. No tumour responses were observed. Pharmacokinetic parameters showed a rapid clearance of MMRDX from the circulation by an extensive tissue distribution. Renal excretion of the drug and its metabolite was negligible. In conclusion, prolongation of MMRDX infusion to 3 h does not improve the toxicity profile as compared with bolus administration. © 2000 Cancer Research Campaign

Keywords: methoxymorpholino doxorubicin, pharmacokinetics, phase I study

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Selected References

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