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 X18 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 À2 . 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 À2 BGC9331 (grade 4 neutropaenia 47 days, and grade 4 fatigue 47 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.

Metformin, at Concentrations Corresponding to the Treatment of Diabetes, Potentiates the Cytotoxic Effects of Carboplatin in Cultures of Ovarian Cancer Cells

“…This concentration of carboplatin was previously reported by Benepal et al as the maximal plasmatic concentration obtained with a dose-corrected area under curve (AUC) of 5.4. 31 Currently, in clinical use, the dose of carboplatin is determined by the method of Calvert, which considers the rate of glomerular filtration, where the dose is adjusted by AUC to 5 or 6. 32 However, carboplatin is given cyclically every 21 days Figure 5A.…”

A Hierarchical Bayesian Design for Phase I Trials of Novel Combinations of Cancer Therapeutic Agents

“…Phase I trials of combination cancer therapies have been published for a variety of cancer types, including small-cell lung cancer (Rudin et al, 2004), gastric cancer (Inokuchi et al, 2006), melanoma (Azzabi et al, 2005), ovarian cancer (Benepal et al, 2005), and renal cell carcinoma (Amato, Morgan, and Rawat, 2006). Unfortunately, all of these trials, and many others similar to them, suffer from poor study designs that have two distinct limitations.…”