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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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Related in: MedlinePlus

BGC9331 plasma concentration (mean±s.d. μg ml−1) in three patients at dose level 2 (BGC9331 65 mg m−2).
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fig2: BGC9331 plasma concentration (mean±s.d. μg ml−1) in three patients at dose level 2 (BGC9331 65 mg m−2).

Mentions: No matrix effects were observed at these dilutions of drug in human plasma. Recovery of BGC9331 fortified into normal plasma (concentrations) was 121%. Interassay variation as determined using a control sample included in each assay was 20.1% (coefficient of variation). Recovery of BGC9331 from plasma was not affected by the presence of carboplatin (data not shown). PK measurements were performed at dose levels 1 and 2 (Figure 2). Mean clearance and Cmax are shown in Table 4, and individual patient PK parameters for dose level 2 are shown in Table 5. Plasma BGC9331 levels were measured on a total of six patients at dose level 1 and 2 during their first cycle of chemotherapy. There was wide interpatient variability. The mean±s.d. total plasma clearance of BGC9331 after day 1 administration at 40 mg m−2 was 478 ml h−1±61.3. Following the day 8 dose the mean clearance±s.d. was 971 ml h−1±265. At dose level 2 of 65 mg m−2 BGC9331, the mean±s.d. total plasma clearance of BGC9331 after day 1 administration was 1197 ml h−1±580. Following the day 8 dose the mean clearance±s.d. was 746 ml h−1±584.


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)

BGC9331 plasma concentration (mean±s.d. μg ml−1) in three patients at dose level 2 (BGC9331 65 mg m−2).
© Copyright Policy
Related In: Results  -  Collection

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

fig2: BGC9331 plasma concentration (mean±s.d. μg ml−1) in three patients at dose level 2 (BGC9331 65 mg m−2).
Mentions: No matrix effects were observed at these dilutions of drug in human plasma. Recovery of BGC9331 fortified into normal plasma (concentrations) was 121%. Interassay variation as determined using a control sample included in each assay was 20.1% (coefficient of variation). Recovery of BGC9331 from plasma was not affected by the presence of carboplatin (data not shown). PK measurements were performed at dose levels 1 and 2 (Figure 2). Mean clearance and Cmax are shown in Table 4, and individual patient PK parameters for dose level 2 are shown in Table 5. Plasma BGC9331 levels were measured on a total of six patients at dose level 1 and 2 during their first cycle of chemotherapy. There was wide interpatient variability. The mean±s.d. total plasma clearance of BGC9331 after day 1 administration at 40 mg m−2 was 478 ml h−1±61.3. Following the day 8 dose the mean clearance±s.d. was 971 ml h−1±265. At dose level 2 of 65 mg m−2 BGC9331, the mean±s.d. total plasma clearance of BGC9331 after day 1 administration was 1197 ml h−1±580. Following the day 8 dose the mean clearance±s.d. was 746 ml h−1±584.

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