ORIGINAL ARTICLE Phase I study of high-dose topotecan with haematopoietic stem cell support in the treatment of ovarian carcinomas: the ITOV 01 protocol J-P Lotz 1 , P Pautier 2 , F Selle 1 , P Viens 3 , M Fabbro 4 , F Lokiec 5 , F Viret 3 , J Gligorov 1 , B Gosse 6 , S Provent 1 , V Ribrag 2 , J-M Micle´a 7 , C Dosquet 7 , A Goetschel 8 , C Cailliot 9 , G Lefe`vre 1 , J Gene`ve 10 and C Lhomme´ 2 , on behalf of the Groupe d’Intensification des traitements des Tumeurs Ovariennes (ITOV Group) 11 1 Department of Medical Oncology, Hoˆpital Tenon, Assistance Publique – Hoˆpitaux de Paris, Universite´Pierre et Marie Curie, Paris, France; 2 Department of Medical Oncology, Institut Gustave-Roussy, Villejuif, France; 3 Department of Medical Oncology, Institut Paoli-Calmette, Marseille, France; 4 Department of Medical Oncology, Centre Val d’Aurelle, Montpellier, France; 5 Department of Pharmacology, Centre Rene´Huguenin, St-Cloud, France; 6 Department of Pharmacology, Le Cannet, France; 7 Department of Haematology and Apheresis Units, Hoˆpital St-Louis, Paris, France; 8 Laboratories Glaxo-SmithKline, Marly Le Roi, France; 9 Laboratoires Amgen, Neuilly sur Seine, France and 10 Fe´de´ration Nationale des Centres de Lutte Contre Le Cancer, Paris, France Topotecan has demonstrated activity in ovarian carcino- mas. In order to increase the tumour response rate and to define the maximum tolerated dose (MTD) of topotecan, we decided to develop a high-dose phase I regimen supported by stem cell support. High-doses schedules using a 1-day single administration have MTDs of 10.5 (24 h continuous infusion (CI)) or 22.5 mg/m 2 (30 min infusion). Five-day CI induces grade IV mucositis at high doses (MTDo12 mg/m 2 ). We chose to administer topo- tecan in a 5-day schedule with a 30 min daily infusion. Patients were scheduled to receive one cycle of therapy. The first dose level was 4.0 mg/m 2 /day  5 days. Limiting toxicities were defined as toxic death, grade IV non- haematopoietic or haematopoietic toxicity 46 weeks. From August 1998 to April 2002, 49 patients were included. Forty-three patients have completed one course and 15 have received two cycles. One patient treated at level 7 mg/m 2 /day died of sepsis. Median duration of grade IV neutropenia was 9 days. Two episodes of grade IV diarrhoea were observed at level 9.5 mg/m 2 /day. Pharmacokinetic data were linear within the dose range of 4–9.0 mg/m 2 /day. The MTD was reached at 9 mg/m 2 / day  5 days. Bone Marrow Transplantation (2006) 37, 669–675. doi:10.1038/sj.bmt.1705310; published online 27 February 2006 Keywords: ovarian carcinoma; topotecan; high-dose chemo- therapy Introduction The prognosis of ovarian cancers (OC) remains poor. Despite the progress achieved in the 1990s, enabling the achievement of clinical complete response (CR) rates of 50% and histological CR rates of 25%, the majority of patients will relapse and die. 1,2 The outlook is particularly poor in patients presenting with residual macroscopic disease after initial chemotherapy (CT), or whose disease progresses during CT or relapses after a short treatment- free interval following platin-based therapy, or whose initial disease is stage IV. 3 For patients whose disease is resistant to platinum salts, the efficacy of new drugs that are non-cross-resistant with those previously used should be tested. Treatment intensification followed by autologous haematopoietic stem cell transplantation (AHSCT) has been an experimental approach to optimize the induction and/or consolidation treatments. Topotecan (topotecan hydrochloride, Hycamtin s , Laboratoire GlaxoSmithKline, Marly le Roi, France), which has demonstrated activity in second-line treatment of OC, is associated mainly with haematopoietic toxicity and seems to be a good candidate for dose-intensification studies. 4,5 Its key pharmacokinetic characteristics may support its use: linear relationship between AUC and dose, no evidence of accumulation when the drug is administered as a 30 min infusion on 5 consecutive days, elimination half-life of the order of 3 h even at high doses, necessity for dose adjustment according to renal function, but less according to hepatic function. 6–8 In view of these data, we decided to develop a phase I protocol of high-dose chemotherapy (HDCT) using single agent topotecan at increasing doses, supported by AHSCT and granulocyte colony-stimulating factor (G-CSF) in poor-prognosis OC patients. The aim was to define its maximum tolerated dose (MTD) as a single agent, administered as a 30 min bolus infusion for 5 days. We herein report the definitive results of this phase I study, the so-called ITOV 01 protocol. Received 30 September 2005; revised 13 January 2006; accepted 15 January 2006; published online 27 February 2006 Correspondence: Professor J-P Lotz, Hoˆptal Tenon, CancerEst, Assistance Publique – Hoˆpitaux de Paris, 4 rue de Chine, 75970 Paris cedex 20, France. E-mail: jean-pierre.lotz@tnn.ap-hop-paris.fr 11 Fe´de´ration Nationale des Centres de Lutte Contre le Cancer, 101 rue de Tolbiac, Paris, France. Bone Marrow Transplantation (2006) 37, 669–675 & 2006 Nature Publishing Group All rights reserved 0268-3369/06 $30.00 www.nature.com/bmt