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

Abstract

SummaryThe 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 -2 of MMRDX. The next cohorts received 1.25 mg m -2 and 1.5 mg m -2 respectively. Common toxicity 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 elevation 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 observed. 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 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 -2 died with neutropenic 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. 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.

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

“…The response rate was low, but hematologic or hepatic toxicities were frequent; moreover, greater than 15% reduction of LVEF occurred in 2 patients of 48. Essentially similar response rate and noncardiac toxicities were observed when PNU-152243 was given by slow infusion, but cardiotoxicity was apparently negligible (Fokkema et al, 2000). The safety and efficacy of MMRA clearly require further evaluation.…”

Formation and Antitumor Activity of PNU-159682, A Major Metabolite of Nemorubicin in Human Liver Microsomes

“…This is not surprising because based on its extremely higher potency compared with MMDX, and requirement of catalysis by CYP3A for its formation, PNU-159682 plays a role in the in vivo antitumor activity and host toxicity of MMDX (9). A role of metabolism in the activity of MMDX in vivo is also suggested by the lack of correlation between drug plasma area under the curve and hematologic and nonhematologic toxicity observed during phase I and II clinical trials (32,33). Ongoing studies aimed at exploring the molecular mechanism of action of PNU-159682 indicate that it has different effects on cell cycle progression and different DNAinteracting properties, compared with both MMDX and doxorubicin (34).…”

Structural modifications in the sugar moiety as a key to improving the anticancer effectiveness of doxorubicin

“…The phase II study showed one partial response in one of 17 cases of NSCLC [71]. In the studies carried out by Fokkema [72] no tumour responses to MMRDX were observed in patients with histologically confirmed NSCLC, mesothelioma, colorectal, head and neck, renal or cervical cancer or adenocarcinoma of unknown origin.…”