Phase I and pharmacologic study of BNP7787, a novel chemoprotector in patients with advanced non-small cell lung cancer.
OBJECTIVE
We conducted a phase I trial of BNP7787 (disodium 2,2'-dithio-bis-ethane sulfonate, Tavocept™), a novel chemoprotective and antitumor enhancing agent administered in combination with paclitaxel and cisplatin. The primary aim was to determine a safe and potentially efficacious BNP7787 dose for preventing and mitigating paclitaxel- and cisplatin-induced toxicities and to evaluate for preliminary evidence of efficacy of treatment.


METHODS
Twenty-two patients with stage IIIB/IV non-small cell lung cancer (NSCLC) received BNP7787 alone 1 week before co-administration of BNP7787 with paclitaxel followed by cisplatin. Twenty-one patients were treated with BNP7787 in escalating doses of 4.1-41.0 g/m² concurrently with paclitaxel 175 mg/m² and cisplatin 75 mg/m² every 3 weeks.


RESULTS
The appropriate dose was determined to be 18.4 g/m² of BNP7787 although no dose-limiting toxicity was observed up to 41.0 g/m². Mild intravenous site discomfort, thirst, and nausea were the most common toxicities. One patient developed grade 2 skin rash, which was severe enough to preclude further study treatment. The AUC(0-inf) of the metabolite mesna was approximately 6.3% of the AUC(0-inf) of BNP7787. Co-administration of paclitaxel and cisplatin did not appear to influence the pharmacokinetics of BNP7787 and mesna. The overall response rate was encouraging; 43% including 11 patients with prior chemotherapy.


CONCLUSIONS
The recommended dose for phase II/III studies is 18.4 mg/m² of BNP7787 in combination with paclitaxel and cisplatin. Further studies are warranted to assess whether BNP7787 prevents and mitigates common and serious paclitaxel- and cisplatin-related side effects and enhances the efficacy of paclitaxel and cisplatin in advanced NSCLC patients.
Masuda
Noriyuki
N
Department of Respiratory Medicine, Kitasato University School of Medicine, Minami-ku, Kitasato, Sagamihara, Japan. masuda@med.kitasato-u.ac.jp
Negoro
Shunichi
S
Hausheer
Frederick
F
Nakagawa
Kazuhiko
K
Matsui
Kaoru
K
Kudoh
Shinzoh
S
Takeda
Koji
K
Yamamoto
Nobuyuki
N
Yoshimura
Naruo
N
Ohashi
Yasuo
Y
Fukuoka
Masahiro
M
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D015080:Mesna / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D016896:Treatment Outcome
C027032:2,2'-dithiodiethanesulfonic acid; D015080:Mesna; D017239:Paclitaxel; D002945:Cisplatin
Cancer. 1981 Jan 1;47(1):207-14
7459811
Cancer Chemother Pharmacol. 2001 Dec;48(6):499-503
11800032
J Clin Oncol. 1998 Jun;16(6):2133-41
9626213
Chest. 1997 Jun;111(6):1710-7
9187198
J Clin Oncol. 2000 Feb;18(3):623-31
10653877
Clin Pharmacol Ther. 2003 Aug;74(2):157-69
12891226
J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Apr 1;877(10):857-66
19278906
Cancer Chemother Pharmacol. 2003 Jul;52 Suppl 1:S3-15
12819940
Eur J Cancer. 2002 May;38(8):1148-56
12008205
J Clin Oncol. 2004 Jan 15;22(2):330-53
14691125
Br J Cancer. 2005 May 9;92(9):1636-43
15841080
N Engl J Med. 2002 Jan 10;346(2):92-8
11784875
Cancer Chemother Pharmacol. 2003 Jun;51(6):499-504
12715205
Semin Oncol. 1998 Oct;25(5):584-99
9783598
Eur J Cancer. 1991;27(10):1243-7
1835593
J Clin Oncol. 2003 Aug 15;21(16):3016-24
12837811
Cancer Chemother Pharmacol. 2010 Apr;65(5):941-51
19714332
Semin Oncol. 2006 Feb;33(1):15-49
16473643
Eur J Cancer. 2008 Jul;44(11):1507-15
18571399
Ann Oncol. 2002 Oct;13(10):1539-49
12377641