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

The aim of this phase I study was to assess feasibility pharmacokinetics an d toxicity of methoxymorpholino doxorubicin (MMRDX or PNU-152243) administe red as a 3 h intravenous infusion once every 4 weeks. Fourteen patients wit h intrinsically anthracycline-resistant tumours received 37 cycles of MMRDX . The first cohort of patients was treated with 1 mg m(-2) of MMRDX, The ne xt cohorts received 1.25 mg m(-2) and 1.5 mg m(-2) respectively. Common tox icity criteria (CTC) grade III/IV nausea and vomiting were observed in 1/18 cycles at 1.25 mg m(-2) and in 2/11 cycles at 1.5 mg m(-2). Transient elev ation in transaminases up to CTC grade III was observed in 2/16 cycles at 1 .25 mg m(-2) and 4/11 cycles at 1.5 mg m(-2). No cardiotoxicity was observe d. At 1.25 mg m(-2) CTC grade IV neutropenia occurred in 1/17 cycles. At 1. 5 mg m(-2) CTC grade III neutropenia was seen in 2/7 and grade IV in 3/7 ev aluable 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(-2) died with neu tropenic fever. Therefore, dose-limiting toxicity was reached and 1.25 mg m (-2) was considered the maximum tolerated dose for MMRDX as 3 h infusion. N o tumour responses were observed. Pharmacokinetic parameters showed a rapid clearance of MMRDX from the circulation by an extensive tissue distributio n. Renal excretion of the drug and its metabolite was negligible. In conclu sion, prolongation of MMRDX infusion to 3 h does not improve the toxicity p rofile as compared with bolus administration. (C) 2000 Cancer Research Camp aign.