[2000]-[BNP7787]-[Phase I dose-finding and pharmacokinetics (PK) study of BNP7787 (dimesna) as a possible protector of cisplatin-induced side-effects]
Abstract number: 657P
Citation: Annals of Oncology, Vol 11, Suppl.4 October 2000, page 143
Phase I dose-finding and pharmacokinetics (PK) study of BNP7787 (dimesna) as a possible protector of cisplatin-induced side-effects.
Epie Boven1, Miranda Verschraagen1, Ivon Zegers1, Frederick H. Hausheer2, Herbert M. Pinedo1, Wim J.F. Van der Vijgh1
1Medical Oncology, Vrije Universiteit Medical Centre, Amsterdam, Netherlands; 2Bionumerik Pharmaceuticals, Inc., San Antonio, TX, USA
BNP7787 shows protection against nephrotoxicity from cisplatin in preclinical tumor models while the antitumor activity is retained. At the site of the kidneys BNP7787 will be rapidly converted into mesna, where the toxic monohydrated species of cisplatin can be inactivated. BNP7787 was studied in pts with advanced solid tumors in 7 dosing steps from 4.1 g/m2 - 41 g/m2 (cohorts of 3 pts, highest dose 6 pts) as a 15-min infusion preceding cisplatin in a fixed dose of 75 mg/m2 as a 1-h infusion every 3 weeks. Pts had not been treated with cisplatin before and creatinine clearance was > 60 ml/min. Side-effects from BNP7787 consisting of irritation at the site of injection were less severe upon addition of NaHCO3 to the solution. Only at the 41 g/m2 dose pts complained of a warm feeling and dizziness during the 15-min infusion period. In 9 pts treated with > 5 cycles one pt showed a decrease in creatinine clearance of 91 to 57 ml/min and 3 pts had neuropathy grade 1 (all in the lower dose range of BNP7787). Of 25 pts PR was observed in 3 pts and SD in 10 pts. PK revealed that BNP7787 in the high dose range did not influence Cmax and t1/2 of hydrated cisplatin, total platinum and unbound platinum. The mean normalized AUC-values of BNP7787 without or with cisplatin were 200(±48) 10-3.h*m2/l and 217(±38) 10-3.h*m2/l, and for mesna these values were 16.3(±7.3) 10-3.h*m2/l and 15.6(±6.8) 10-3.h*m2/l, respectively. In conclusion, 1) BNP7787 appears to be relatively non-toxic at dose levels up to 41 g/m2; 2) objective responses are observed with cisplatin preceded by BNP7787; 3) BNP7787 at high doses does not interfere with the PK of cisplatin; 4) cisplatin does not interfere with the PK of (di)mesna.
BNP7787
Cisplatin
Mesna
Nephroprotection
Pharmacokinetics
Phase I study
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