title: A prolonged methoxymorpholino doxorubicin (PNU-152243 or MMRDX) infusion schedule in patients with solid tumours: a phase 1 and pharmacokinetic study.
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(-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.
authors.affiliation: Department of Pulmonology, University Hospital Groningen, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Fokkema
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: A T
authors.initials: AT
authors.lastname: van Oosterom
authors.forename: D R
authors.initials: DR
authors.lastname: Uges
authors.forename: R
authors.initials: R
authors.lastname: Spinelli
authors.forename: O
authors.initials: O
authors.lastname: Valota
authors.forename: E G
authors.initials: EG
authors.lastname: de Vries
authors.forename: H J
authors.initials: HJ
authors.lastname: Groen
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000932:Antiemetics / Q000008:administration & dosage; D019540:Area Under Curve; D015331:Cohort Studies; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D000932:Antiemetics; C066998:methoxy-morpholinyl-doxorubicin; D004317:Doxorubicin