title: A phase I pharmacokinetic and pharmacodynamic study of BGC9331 and carboplatin in relapsed gynaecological malignancies.
abstract: BGC9331 is a rationally designed, specific nonpolyglutamatable thymidylate synthase (TS) inhibitor that is active in gynaecological malignancies. In the light of the sensitivity of human ovarian tumour cell lines to BGC9331 and non-cross resistance to platinum drugs, we studied the combination BGC9331/carboplatin (BCA) in a phase I (PI) pharmacokinetic (PK) and pharmacodynamic (PD) study in platinum pretreated gynaecological malignancies. Patients were >or=18 years or over, with a histologically confirmed gynaecological malignancy, radiological evidence of relapse, and a platinum treatment free interval of at least 6 months. Up to three prior lines of chemotherapy were permitted. Carboplatin (AUC5) and BGC9331 were administered on day 1, and BGC9331 was also given on day 8 of a 21-day cycle. In total, 14 patients were enrolled, and treated with BGC9331 at four dose levels, 40, 65, 85 and 100 mg m-2. The principal grade 3 and 4 haematological toxicity was neutropaenia. The principal nonhaematological toxicities were lethargy and nausea. Dose-limiting toxicities were seen in two patients at 100 mg m-2 BGC9331 (grade 4 neutropaenia>7 days, and grade 4 fatigue>7 days). Plasma BGC9331 was measured by an ELISA that was adapted for use in humans. Carboplatin was assayed by flameless atomic absorption spectrometry. There was no PK interaction between the two drugs. Plasma deoxyuridine was elevated indicating TS inhibition to at least day 12. Antitumour activity was observed in four out of 14 (28%) of patients. In conclusion, the combination of BGC9331 and carboplatin is well tolerated with no significant PK interaction between the two drugs. There is evidence of TS inhibition with the combination. We have demonstrated antitumour activity in platinum pretreated gynaecological malignancy. Further exploration of this combination in this disease is warranted.
authors.affiliation: Department of Medicine, The Royal Marsden Hospital, 203 Fulham Road, London SW3 6JJ, UK. timbenepal@gmail.com
authors.forename: T
authors.initials: T
authors.lastname: Benepal
authors.forename: A
authors.initials: A
authors.lastname: Jackman
authors.forename: L
authors.initials: L
authors.lastname: Pyle
authors.forename: S
authors.initials: S
authors.lastname: Bate
authors.forename: A
authors.initials: A
authors.lastname: Hardcastle
authors.forename: W
authors.initials: W
authors.lastname: Aherne
authors.forename: F
authors.initials: F
authors.lastname: Mitchell
authors.forename: L
authors.initials: L
authors.lastname: Simmons
authors.forename: R
authors.initials: R
authors.lastname: Ruddle
authors.forename: F
authors.initials: F
authors.lastname: Raynaud
authors.forename: M
authors.initials: M
authors.lastname: Gore
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D016190:Carboplatin / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy*; D006801:Humans; D007262:Infusions, Intravenous; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D016190:Carboplatin; D013940:Thymidylate Synthase