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A phase I pharmacokinetic and pharmacodynamic study of BGC9331 and carboplatin in relapsed gynaecological malignancies.

Benepal T, Jackman A, Pyle L, Bate S, Hardcastle A, Aherne W, Mitchell F, Simmons L, Ruddle R, Raynaud F, Gore M - Br. J. Cancer (2005)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, The Royal Marsden Hospital, 203 Fulham Road, London SW3 6JJ, UK. timbenepal@gmail.com

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.

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Dose administration schedule of BGC9331 and carboplatin.
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fig1: Dose administration schedule of BGC9331 and carboplatin.

Mentions: This was a phase I dose escalation study of BGC9331 in gynaecological malignancies with a fixed dose of carboplatin in patients with greater than 6 months platinum free treatment period. Three patients were planned at each dose level and the MTD was defined as the dose at which two or more patients experienced dose-limiting toxicities. The dose level below MTD was to be expanded to six patients. There were six dose levels in the trial. The carboplatin was administered at a fixed dose of AUC5, as determined by the formula: AUC=(glomerular filtration rate (GFR)+25) × 5 (Calvert et al, 1989) at all dose levels. The GFR was determined in all patients by 51CrEDTA (Chantler et al, 1969). The planned starting BGC9331 dose was 40 mg m−2, then escalated to 65, 85, 100 and finally 130 mg m−2, the recommended single-agent phase II dose (Plummer et al, 2003) (Table 1). As a precaution, a reduced BGC9331 dose level was included in the event of severe toxicities being observed at early dose levels (30 mg m−2). The carboplatin was administered at AUC5 on day 1 of a 21-day cycle, with BGC9331 administered on days 1 and 8 of a 21-day cycle (Figure 1).


A phase I pharmacokinetic and pharmacodynamic study of BGC9331 and carboplatin in relapsed gynaecological malignancies.

Benepal T, Jackman A, Pyle L, Bate S, Hardcastle A, Aherne W, Mitchell F, Simmons L, Ruddle R, Raynaud F, Gore M - Br. J. Cancer (2005)

Dose administration schedule of BGC9331 and carboplatin.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361661&req=5

fig1: Dose administration schedule of BGC9331 and carboplatin.
Mentions: This was a phase I dose escalation study of BGC9331 in gynaecological malignancies with a fixed dose of carboplatin in patients with greater than 6 months platinum free treatment period. Three patients were planned at each dose level and the MTD was defined as the dose at which two or more patients experienced dose-limiting toxicities. The dose level below MTD was to be expanded to six patients. There were six dose levels in the trial. The carboplatin was administered at a fixed dose of AUC5, as determined by the formula: AUC=(glomerular filtration rate (GFR)+25) × 5 (Calvert et al, 1989) at all dose levels. The GFR was determined in all patients by 51CrEDTA (Chantler et al, 1969). The planned starting BGC9331 dose was 40 mg m−2, then escalated to 65, 85, 100 and finally 130 mg m−2, the recommended single-agent phase II dose (Plummer et al, 2003) (Table 1). As a precaution, a reduced BGC9331 dose level was included in the event of severe toxicities being observed at early dose levels (30 mg m−2). The carboplatin was administered at AUC5 on day 1 of a 21-day cycle, with BGC9331 administered on days 1 and 8 of a 21-day cycle (Figure 1).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, The Royal Marsden Hospital, 203 Fulham Road, London SW3 6JJ, UK. timbenepal@gmail.com

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.

Show MeSH
Related in: MedlinePlus