Phase I and pharmacokinetic study of Yondelis™ (Ecteinascidin-743; ET-743) administered as an infusion over 1 h or 3 h every 21 days in patients with solid tumours
Introduction
Yondelis™ (Ecteinascidin-743 or ET-743), a novel antitumour agent isolated from the marine ascidian Ecteinascidia turbinata, has considerable antitumour activity in murine and human tumours in vitro1, 2. Potent antitumour activity has been demonstrated in a broad range of in vivo tumour models, including human tumour xenografts in nude mice 3, 4, 5.
ET-743 acts by a novel, complex mechanism predominantly at the level of gene transcription. ET-743 binds to guanine–cytosine rich sequences in the minor groove of DNA and alkylates guanine residues at the N2 position [6]. Cell cycle studies have demonstrated that ET-743 decreases the rate of progression of tumour cells through S-phase and causes prolonged p53-independent blockade in G2/M, giving rise to a strong apoptotic response [7]. Cells in G1 are more sensitive to the cytotoxic effects of ET-743 than cells in S-phase or G2/M [8]. These effects appear to be mediated by multiple mechanisms. ET-743 inhibits activation of the transcription of certain genes relevant to the process of the mdr-1 resistant pathway and nucleotide excision repair mechanism 8, 9, 10, 11.
Toxicological evaluations of ET-743 as a single or a fractionated dose by the intravenous (i.v.) route in mice, rats, and dogs have consistently shown the potential of ET-743 to induce reversible haematological and hepatic toxicity. Hepatotoxicity was evident from transient increases in serum levels of liver enzymes, bilirubin and bile acids, and from histopathological changes in the liver. Further toxicity included lesions at the site of injection, spleen and thymus lesions, bile duct hyperplasia and decreased testicular and ovarian weights. Studies in dogs showed vomiting and diarrhoea following the administration of ET-743. A study in cynomolgus monkeys confirmed the potential of single doses of ET-743 to induce hepatic and haematological toxicity, emesis and diarrhoea. However, fractionated dosing induced only minor toxicity in dogs [12].
An in vitro bone marrow assay using human, murine and canine progenitor cells, showed equal sensitivity of erythropoietic and myeloid cells to ET-743. Prolonged or repeated exposure to the drug proved more toxic to haematopoietic progenitors than a single 1-h exposure [13]. The therapeutic index of ET-743 was more favourable with a prolonged exposure.
A clinical development programme of ET-743 in cancer patients was started with phase I studies investigating 1-, 3-, 24- and 72-h i.v. infusion schedules and a daily ×5 (d×5) schedule. Results of the 3-, 24- and 72-h and d×5 studies have been reported recently 14, 15, 16, 17, 18, 19. Here, we report the phase I study investigating the 1-h schedule repeated every 3 weeks. The study was amended to continue with a 3-h infusion duration when the maximum tolerated dose (MTD) for the 1-h infusion had been reached.
Section snippets
Patients and methods
ET-743 was first administered as a single 1-h i.v. infusion every 21 days in a conventional open-label, non-randomised phase I dose escalation study. The primary aim was to determine the MTD of this dose schedule, defined as that producing dose-limiting toxicity (DLT) in ⩾2/6 patients in the first cycle. DLT was defined as:
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Grade 4 neutropenia that lasted more than 5 days, was complicated or associated with fever.
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Grade 3 or 4 elevation of transaminases, bilirubin or alkaline phosphatase, which
Patients' characteristics and treatments administered
72 patients were enrolled in the two parts of the study between June 1996 and June 2000. The patient population is summarised in Table 1. Tumours of the gastrointestinal tract were the most common and almost all patients had received prior chemotherapy (85%) or radiotherapy (29%).
Cohorts of 3–6 patients were entered at doses escalating from 50 to 1100 μg/m2 using the 1-h infusion (Table 2). Since 1100 μg/m2 appeared to be the MTD (see below), 8 further patients were entered at a dose of 1000
Discussion
This phase I trial shows that ET-743 can be administered safely by 1- and 3-h i.v. infusions to patients with solid tumours. The MTD and the recommended phase II dose of the drug could be increased markedly from 1100 and 1000 μg/m2 to 1800 and 1650 μg/m2, respectively, by prolonging the duration of the infusion from 1 to 3 h, without affecting the toxicity profile. The MTD for the 3-h infusion in this study was identical to the MTD found in another phase I study investigating ET-743 using a
Acknowledgements
The authors gratefully acknowledge the contributions to this study by Helen Gall (Research Nurse, University Hospital Vrije Universiteit, Amsterdam), Tia van Houten (Data Manager, NDDO Oncology, Amsterdam) and Antonio Nieto (Statistician, PharmaMar, Tres Cantos).
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Current address: University Hospital, Antwerp, Belgium.