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

Br J Cancer. 1998;77(1):139-46. doi: 10.1038/bjc.1998.22.


The aim was to perform a broad phase II 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 13-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 > grade III/IV was observed in 7% of cycles, late and prolonged nausea > or = grade II in 34% and vomiting > or = grade II in 39%. In two patients, the left ventricular ejection fraction was reduced > or = 15%. Of 37 evaluable patients, one out of 17 NSCLC had a partial response. Mean (+/- s.d.) MMRDX AUC0-infinity calculated up to 24 h after dosing was 20.4 +/- 6.2 microg h l(-1) (n = 11) and t(1/2, gamma) was 44.2 h. Mean plasma clearance (+/- s.d.) was 37.2 +/- 7.3 l h(-1) m(-2) and volume of distribution 1982 +/- 64 l 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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antibiotics, Antineoplastic / adverse effects
  • Antibiotics, Antineoplastic / chemistry
  • Antibiotics, Antineoplastic / pharmacokinetics*
  • Antibiotics, Antineoplastic / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Doxorubicin / adverse effects
  • Doxorubicin / analogs & derivatives*
  • Doxorubicin / chemistry
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / therapeutic use
  • Female
  • Humans
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / metabolism
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Middle Aged
  • Nausea / chemically induced
  • Neutropenia / chemically induced
  • Thrombocytopenia / chemically induced
  • Treatment Outcome


  • Antibiotics, Antineoplastic
  • methoxy-morpholinyl-doxorubicin
  • Doxorubicin