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A Phase I clinical and pharmacological study of cis-diamminedichloro(2-methylpyridine) platinum II (AMD473).

Beale P, Judson I, O'Donnell A, Trigo J, Rees C, Raynaud F, Turner A, Simmons L, Etterley L - Br. J. Cancer (2003)

Bottom Line: There was no significant alopecia.Toxicity is predictable with linear pharmacokinetics, as was predicted by preclinical studies.A dose of 120 mg m(-2) every 21 days is recommended for Phase II evaluation although there is evidence that chemo-naive patients and those of good performance status may tolerate a higher dose.

View Article: PubMed Central - PubMed

Affiliation: Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.

ABSTRACT
AMD473 is a novel sterically hindered platinum cytotoxic with demonstrated ability to overcome acquired resistance to cisplatin in vitro and in human tumour xenografts. A single-agent dose escalating Phase I study was performed. AMD473 was initially administered intravenously as a 1 h infusion every 21 days to patients with advanced solid tumours. In total, 42 patients received a total of 147 cycles (median 3, range 1-8) of treatment at doses of 12, 24, 48, 96, 110, 120, 130, and 150 mg m(-2). Dosing intervals of 21 and 28 days were explored at the recommended dose. Neutropenia and thrombocytopenia proved dose limiting. Other toxicities included moderate nausea, vomiting, anorexia, and a transient metallic taste. There was no significant alopecia. The maximum tolerated dose was 150 mg m(-2). Plasma pharmacokinetics were linear. Two patients with heavily pretreated ovarian cancer showed partial response. Five patients (mesothelioma, ovary, nonsmall cell lung, and melanoma) showed prolonged stable disease. AMD473 demonstrates encouraging activity in patients, including those with prior platinum exposure. Toxicity is predictable with linear pharmacokinetics, as was predicted by preclinical studies. A dose of 120 mg m(-2) every 21 days is recommended for Phase II evaluation although there is evidence that chemo-naive patients and those of good performance status may tolerate a higher dose.

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AUC ultrafiltrable platinum vs calculated creatinine clearance at 120 mg m−2.
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fig3: AUC ultrafiltrable platinum vs calculated creatinine clearance at 120 mg m−2.

Mentions: The Cmax (maximum concentration) also increased linearly with dose. The mean terminal half-life (t1/2) for free platinum was 85 h at dose level 120 mg m−2, which was longer than that seen in mice (10 h). At lower dose levels, the t1/2 was also apparently lower, attributable to the insensitivity of the pharmacokinetic assay and underestimation of plasma concentrations at later time points. The mean proportion of free platinum excreted in the urine was 32.9% (±15.9 s.d.) overall over 36 h (34.2±10.3% at 120 mg m−2). At 120 mg m−2, there was a moderate negative correlation between the ultrafiltrable platinum AUC and calculated creatinine clearance. (r2=0.47, P<0.0001) (Figure 3Figure 3


A Phase I clinical and pharmacological study of cis-diamminedichloro(2-methylpyridine) platinum II (AMD473).

Beale P, Judson I, O'Donnell A, Trigo J, Rees C, Raynaud F, Turner A, Simmons L, Etterley L - Br. J. Cancer (2003)

AUC ultrafiltrable platinum vs calculated creatinine clearance at 120 mg m−2.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2376375&req=5

fig3: AUC ultrafiltrable platinum vs calculated creatinine clearance at 120 mg m−2.
Mentions: The Cmax (maximum concentration) also increased linearly with dose. The mean terminal half-life (t1/2) for free platinum was 85 h at dose level 120 mg m−2, which was longer than that seen in mice (10 h). At lower dose levels, the t1/2 was also apparently lower, attributable to the insensitivity of the pharmacokinetic assay and underestimation of plasma concentrations at later time points. The mean proportion of free platinum excreted in the urine was 32.9% (±15.9 s.d.) overall over 36 h (34.2±10.3% at 120 mg m−2). At 120 mg m−2, there was a moderate negative correlation between the ultrafiltrable platinum AUC and calculated creatinine clearance. (r2=0.47, P<0.0001) (Figure 3Figure 3

Bottom Line: There was no significant alopecia.Toxicity is predictable with linear pharmacokinetics, as was predicted by preclinical studies.A dose of 120 mg m(-2) every 21 days is recommended for Phase II evaluation although there is evidence that chemo-naive patients and those of good performance status may tolerate a higher dose.

View Article: PubMed Central - PubMed

Affiliation: Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.

ABSTRACT
AMD473 is a novel sterically hindered platinum cytotoxic with demonstrated ability to overcome acquired resistance to cisplatin in vitro and in human tumour xenografts. A single-agent dose escalating Phase I study was performed. AMD473 was initially administered intravenously as a 1 h infusion every 21 days to patients with advanced solid tumours. In total, 42 patients received a total of 147 cycles (median 3, range 1-8) of treatment at doses of 12, 24, 48, 96, 110, 120, 130, and 150 mg m(-2). Dosing intervals of 21 and 28 days were explored at the recommended dose. Neutropenia and thrombocytopenia proved dose limiting. Other toxicities included moderate nausea, vomiting, anorexia, and a transient metallic taste. There was no significant alopecia. The maximum tolerated dose was 150 mg m(-2). Plasma pharmacokinetics were linear. Two patients with heavily pretreated ovarian cancer showed partial response. Five patients (mesothelioma, ovary, nonsmall cell lung, and melanoma) showed prolonged stable disease. AMD473 demonstrates encouraging activity in patients, including those with prior platinum exposure. Toxicity is predictable with linear pharmacokinetics, as was predicted by preclinical studies. A dose of 120 mg m(-2) every 21 days is recommended for Phase II evaluation although there is evidence that chemo-naive patients and those of good performance status may tolerate a higher dose.

Show MeSH
Related in: MedlinePlus