[1999]-[BNP7787]-[Possible Protector of Cisplatin-Induced Toxicities]
BNP7787 (DIMESNA) as a Possible Protector of Cisplatin-Induced Toxicities: A Dose-Finding and Pharmacokinetic Study. E. Boven, M. Verschraagen, R. Ruijter, M. Westerman, F.H. Hausheer, H.M. Pinedo, W.J.F. Van der Vijgh. Dept of Medical Oncology, University Hospital Vrije Universiteit, Amsterdam, NL; BioNumerik Pharmaceuticals, San Antonio, TX.
BNP7787 is under investigation as a novel agent to protect against cisplatin-induced toxicities, more specifically nephrotoxicity. In the kidneys, BNP7787 is rapidly converted into mesna that can inactivate the toxic monohydrated species of cisplatin. In a phase I trial with escalating doses of BNP7787, pts with solid tumors received a fixed dose of cisplatin 75 mg/m2 as a 1-hour infusion and BNP7787 given as a 15-min infusion just before cisplatin. Pts had not been treated with cisplatin before and creatinine clearance was 60 ml/min. At present, the dose of BNP7787 has been escalated in 5 steps from 4.1 g/m2 up to 23 g/m2 in groups of 3 pts each. In 1 pt per dose level plasma concentrations of intact cisplatin, hydrated cisplatin, total platinum, unbound platinum, BNP7787 and mesna were monitored. Up to now, 13 pts have been enrolled into the study. Side-effects of BNP7787 alone consisted of irritation at the injection site which disappeared upon addition of NaHCO3 8.4% to the solution. Toxicity of BNP7787 + cisplatin in the first 2 cycles (11 pts) consisted of nausea grade 2 or 3 in 7 pts, vomiting grade 2 in 3 pts, leukopenia grade 1 or 2 in 2 pts, thrombocytopenia grade 1 in 3 pts. In 5 pts that received BNP7787 + cisplatin 5 cycles only one showed a decrease in creatinine clearance of 83 to 59 ml/min and another pt had neuropathy grade 1 (both received BNP7787 4.1 g/m2). Out of 11 pts with 2 cycles of cisplatin 2 had PR (31+ and 18+ weeks), 1 MR, 2 SD, and 6 PD. Pharmacokinetics have been completed up to the BNP7787 18.4 g/m2 level. BNP7787 did not influence Cmax and t1/2 of hydrated cisplatin, total platinum and unbound platinum, but at lower doses of BNP7787 the concentration of intact cisplatin appeared to be reduced. The mean normalized AUC-values of BNP7787 without or with cisplatin were 391.1 ± 131.3 and 374.7 ± 89.1 uM.h/g, respectively and for mesna these were 36.1 ± 16.1 and 28.6 ± 12.1 uM.h/g, respectively. In conclusion, 1) BNP7787 appears to be relatively non-toxic at dose levels up to 23 g/m2, 2) objective responses are being observed with BNP7787 + cisplatin, 3) BNP7787 at high doses does not interfere with the pharmacokinetics of cisplatin.
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