Phase I clinical and pharmacokinetic study of E7070, a novel sulfonamide given as a 5-day continuous infusion repeated every 3 weeks in patients with solid tumours. A study by the EORTC Early Clinical Study Group (ECSG) C. Terret a, *,S.Zanetta b ,H.Roche´ a , J.H.M. Schellens c , M.N. Faber d , J. Wanders d , M. Ravic e ,J.P.Droz b a Department of Medical Oncology, Institut Claudius Regaud, Toulouse, France b Department of Medical Oncology, Centre Le ´on Be ´rard, 28 rue Lae ¨nnec, F-69373 Lyon Cedex 08, France c Department of Internal Medicine/Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands d NDDO Oncology, Amsterdam, The Netherlands e Eisai Limited, London, UK Received 9 December 2002; accepted 18 December 2002 Abstract Asingle-agentdose-escalatingphaseIstudyonthenovelsulfonamideE7070wasperformedtodeterminethetoxicityprofileand therecommendeddoseforphaseIIstudies.ThepharmacokineticprofileofE7070wasalsodetermined.E7070wasadministeredas a continuous infusion over 5 days repeated every 3 weeks. 27 patients were treated at doses ranging from 6 to 200 mg/m 2 /day. As with other administration schedules, the dose-limiting toxicities were dose-dependent, reversible neutropenia and thrombocytope- nia. Although no objective responses were observed, seven patients had stable disease. E7070 displayed a non-linear pharmacoki- neticprofile,especiallyatdose-levelsgreaterthan24mg/m 2 /day,withareductioninclearanceandanincreaseinthehalf-lifeatthe higher dose levels. The risk of myelosuppression became significant with an AUC greater than 4000 mg h/ml. The recommended doseofE7070forfurtherstudiesis96mg/m 2 /day when administered on a 5-day continuous infusion schedule every 3 weeks. # 2003 Elsevier Science Ltd. All rights reserved. Keywords: E7070; Pharmacokinetics; Phase I trial; Sulfonamide 1. Introduction E7070 or N-(3-chloro-7-indolyl)-1,4-benzenedisulfo- namide is a novel sulfonamide [1] with a wide range of activity in human tumour cell lines [2]. E7070 acts by inhibiting the activation of cyclin-dependent kinase 2 andcyclinE,whichareinvolvedinthetransitionofthe G1toSphaseinthecellcycle [3]. E7070 shows similarities with chloroquinoxaline sulfo- namide (CQS) which is known to cause cardiac tachy- arrhythmias and hypoglycaemia [4]. E7070 produced a slight prolongation of the QTc interval and some fluctua- tions of blood glucose at the maximum tolerated dose (MTD)inratandbeagledogs,respectively. Despite their similarities, E7070 displayed antiproliferative effects that wereapproximately10timesmorepotentthanthatofCQS inhumancolonandnon-smallcelllungcancermodels. Thepurposeofthecurrentstudywastodeterminethe MTDofE7070whenadministeredasa5-daycontinuous infusion repeated every 3 weeks in patients with solid tumours. Other objectives were to determine the toxicity profile of E7070, to propose a recommended dose for phase II evaluation, to study E7070 pharmacokinetics andfinallytodetectanyantitumouractivityofthedrug. 2. Patients and methods 2.1. Eligibility Patients with a histologically- or cytologically-con- firmed solid tumour not amenable to established forms 0959-8049/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0959-8049(03)00128-X European Journal of Cancer 39 (2003) 1097–1104 www.ejconline.com * Corresponding author. Tel.: +33-4-7878-2757; fax: +33-4-7878- 2716. E-mail address: terret@lyon.fnclcc.fr (C. Terret).