Phase I and pharmacokinetic study of the novel chemoprotector BNP7787 in combination with cisplatin and attempt to eliminate the hydration schedule

Abstract

BNP7787 (disodium 2,20 -dithio-bis-ethane sulphonate; Tavoceptt) is a novel agent developed to protect against cisplatin (cisdiammine-dichloroplatinum(II))-associated chronic toxicities. In this study, we determined the recommended dose of BNP7787 when preceding a fixed dose of cisplatin, the pharmacokinetics (PKs) and the possible reduction of saline hydration. Patients with advanced solid tumours received BNP7787 in escalating doses of 4.1 -41 g m À2 as a 15-min intravenous (i.v.) infusion followed by cisplatin 75 mg m À2 as a 60-min i.v. infusion together with pre-and postcisplatin saline hydration in a volume of 2200 ml; cycles were repeated every 3 weeks. PK was carried out using BNP7787, cisplatin and the combination. Twenty-five patients were enrolled in stage I of the study to determine the recommended dose of BNP7787. No dose-limiting toxicity was reached. The highest dose level of 41 g m À2 resulted in a low incidence of grade 2 toxicities, being nausea and vomiting, dry mouth or bad taste and i.v. injection site discomfort. Doses of BNP7787 X18.4 g m À2 did not show a drug interaction between BNP7787 and cisplatin. In stage II of the study, patients received a fixed dose of BNP7787 of 18.4 g m À2 preceding cisplatin and were entered in prespecified reduced saline hydration steps. A total of 21 patients in cohorts of six to nine patients received reduced saline hydration of 1600 ml (step A), 1000 ml (step B) and 500 ml (step C). In step C, two out of six evaluable patients experienced grade 1 nephrotoxicity. Cisplatin acute toxicities in all 46 patients were as expected. Only five patients complained of paresthesias grade 1 and six developed slight audiometric changes. Partial tumour response was observed in four patients and stable disease in 15 patients. In conclusion, BNP7787 was tolerated well up to doses of 41 g m À2 . The recommended dose of 18.4 g m À2 enabled safe reduction of the saline hydration schedule for cisplatin to 1000 ml. Further studies will assess whether BNP7787 offers protection against platinum-related late side effects.

Phase I and pharmacologic study of BNP7787, a novel chemoprotector in patients with advanced non-small cell lung cancer

“…BNP7787 pharmacokinetics was similar to those reported in a previous human phase I study [3, 21]. After cessation of infusion, the BNP7787 curves showed single-exponential decay (Fig.…”

Analysis of BNP7787 thiol-disulfide exchange reactions in phosphate buffer and human plasma using microscale electrochemical high performance liquid chromatography

“…We postulate that the formation of these mesnadisulfide heteroconjugates and free mesna at specific locations in vivo may contribute to BNP7787-mediated cisplatin nephroprotection (Fig. 8) [1][2][3][4][5][6][7][8][9][10].…”

“…In clinical and preclinical studies, BNP7787 (disodium 2,2 -dithio-bis ethane sulfonate; Tavocept TM ), a water-soluble disulfide, has been shown to have potential for protecting against cisplatininduced nephrotoxicity without reducing anti-tumor activity [1][2][3][4][5][6][7][8][9][10]. We have proposed that BNP7787-mediated nephroprotection involves the non-enzymatic thiol transfer reactions of BNP7787 with physiological thiols, such as glutathione, cysteine, homocysteine, cysteinyl-glutamate, or cysteinyl-glycine, present in plasma and in cells to produce active mesna-disulfide heteroconjugates that may impart nephroprotection ( Fig.…”

BNP7787-Mediated Modulation of Paclitaxel- and Cisplatin-Induced Aberrant Microtubule Protein Polymerization In vitro

“…Further, in animal models, BNP7787 did not exhibit tumor protection when given with taxane and platinum agents and concurrently prevented lethal chemotherapy-induced toxicity from paclitaxel, cisplatin, carboplatin, and oxaliplatin (11,37,38,40,46). In phase I and III clinical trials, BNP7787 was not observed to interfere with the antitumor activity of cisplatin and paclitaxel (11,47). In an additional phase III clinical trial, treatment with BNP7787 seemed to significantly improve 1-year survival of patients with advanced primary adenocarcinoma of the lung who were being treated with cisplatin and paclitaxel regimens in the first-line setting (36).…”