A multicentre phase I and pharmacokinetic study of BN80915 (diflomotecan) administered daily as a 20-min intravenous infusion for 5 days every 3 weeks to patients with advanced solid tumours

Authors: Scott, L; Soepenberg, O; Verweij, J; de Jonge, MJA; Th Planting, AS; McGovern, D; Principe, P; Obach, R; Twelves, C

Source: Annals of Oncology, Volume 18, Number 3, March 2007 , pp. 569-575(7)

Publisher: Oxford University Press

Key:
Free Content - Free Content
New Content - New Content
Subscribed Content - Subscribed Content
Free Trial Content - Free Trial Content

Abstract:

Background: BN80915 (diflomotecan) is an E-ring modified camptothecin analogue, which possesses greater lactone stability in plasma compared with other topoisomerase I inhibitors. This phase I study was carried out using a daily times five administration schedule (d×5) repeated three weekly. The primary objective was to determine the maximum tolerated dose (MTD) and recommended dose (RD) for phase II studies. Secondary objectives were to determine the safety and pharmacokinetic (PK) profile, and to make a preliminary assessment of antitumour activity.

Patients and methods: Diflomotecan was administered intravenously on days 1-5 every 3 weeks. Patients were treated in cohorts of three to six per dose level and the dose of diflomotecan was escalated according to modified Fibonacci schedule. Plasma concentrations of diflomotecan and its metabolite BN80942 were quantified.

Results: Thirty patients were assessable for toxicity. Dose levels explored were 0.05, 0.1, 0.125 and 0.15 mg/m2/day. The 0.15-mg/m2 dose level was determined to be the MTD. Toxicity was acceptable at the 0.125-mg/m2/day dose level. PK analysis showed the principal parameters were neither time nor dose dependent. There was a wide interpatient variability in PK at all dose levels. One patient with colorectal cancer, previously treated with irinotecan, had a partial response. A further eight patients had disease stabilisation.

Conclusions: The MTD and RD of diflomotecan administered according to a d×5 repeated three weekly are 0.15 and 0.125 mg/m2/day, respectively. In general, treatment was well tolerated; the principal toxicity was reversible myelosuppression. An objective response was seen in a patient previously treated with irinotecan.

Keywords: BN80915; clinical trial; diflomotecan; phase I

Document Type: Research article

DOI: 10.1093/annonc/mdl439

The full text electronic article is available for purchase. You will be able to download the full text electronic article after payment.

$40.19 plus tax      Refund Policy

 

OR

Back to top

Key:
Free Content - Free Content
New Content - New Content
Subscribed Content - Subscribed Content
Free Trial Content - Free Trial Content
Share this item with others: These icons link to social bookmarking sites where readers can share and discover new web pages.
Page Help Click here for Page Help
Shopping cart
Tools
Sign in






Need to register?
Sign up here
Text size: A | A | A | A