A phase I and pharmacology study of GR63178A, a water-soluble analogue of mitoquidone.
GR63178A is a water-soluble analogue of mitoquidone, a pentacyclic pyrroloquinone. This group of drugs exhibit a novel structure and activity against several murine solid tumours and xenografts. In the present phase I study the toxicity and pharmacokinetics of GR63178A given on 5 consecutive days of a 21-day cycle were examined. A total of 24 patients presenting with a wide range of tumours were treated at 5 doses escalated to reach the maximal tolerated dose (MTD). Linear pharmacokinetics was documented over the dose range studied, and there was no difference in parent drug handling between day 1 and day 4 of dosing. A number of metabolites were detected. The toxicity profile was unusual in that pain occurred in 20/24 patients, most often at the site of known disease. This was the dose-limiting toxicity. Other side effects included nausea and vomiting (23/24), phlebitis at the infusion site (6/24) and headache (7/24). No treatment response was seen in this study. The MTD was demonstrated to be 160 mg/m2 daily (total, 800 mg/m2 per treatment cycle). The drug has now entered phase II trials at 120 mg/m2 daily x 5, repeated every 21 days.
Eccles
D M
DM
Medical Oncology Unit, Western General Hospital, Edinburgh, U.K.
Cummings
J
J
Stewart
M E
ME
Nicolson
M
M
Cornbleet
M A
MA
Leonard
R C
RC
Smyth
J F
JF
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage / Q000009:adverse effects* / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology; D012995:Solubility; D013997:Time Factors
D000970:Antineoplastic Agents; D007546:Isoquinolines; D009943:Organophosphorus Compounds; C072687:fosquidone