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)

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Abstract

A single-agent dose-escalating phase I study on the novel sulfonamide E7070 was performed to determine the toxicity profile and the recommended dose for phase II studies. The pharmacokinetic profile of E7070 was also determined. E7070 was administered as a continuous infusion over 5 days repeated every 3 weeks. 27 patients were treated at doses ranging from 6 to 200 mg/m2/day. As with other administration schedules, the dose-limiting toxicities were dose-dependent, reversible neutropenia and thrombocytopenia. Although no objective responses were observed, seven patients had stable disease. E7070 displayed a non-linear pharmacokinetic profile, especially at dose-levels greater than 24 mg/m2/day, with a reduction in clearance and an increase in the half-life at the higher dose levels. The risk of myelosuppression became significant with an AUC greater than 4000 μg h/ml. The recommended dose of E7070 for further studies is 96 mg/m2/day when administered on a 5-day continuous infusion schedule every 3 weeks.

Introduction

E7070 or N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide 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 and cyclin E, which are involved in the transition of the G1 to S phase in the cell cycle [3].

E7070 shows similarities with chloroquinoxaline sulfonamide (CQS) which is known to cause cardiac tachy-arrhythmias and hypoglycaemia [4]. E7070 produced a slight prolongation of the QTc interval and some fluctuations of blood glucose at the maximum tolerated dose (MTD) in rat and beagle dogs, respectively. Despite their similarities, E7070 displayed antiproliferative effects that were approximately 10 times more potent than that of CQS in human colon and non-small cell lung cancer models.

The purpose of the current study was to determine the MTD of E7070 when administered as a 5-day continuous 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 and finally to detect any antitumour activity of the drug.

Section snippets

Eligibility

Patients with a histologically- or cytologically-confirmed solid tumour not amenable to established forms of treatment were eligible for this study. Other eligibility criteria included: age ⩾18 years; a World Health Organization (WHO) performance status (PS) ⩽2; life expectancy of at least 3 months; no prior anticancer therapy within 4 weeks prior to entry in the study (6 weeks for nitrosoureas, and extensive radiotherapy); absolute neutrophil count [ANC] ⩾1.5×109 cells/l, platelets ⩾100×109

Population characteristics

The characteristics of the 29 patients (19 women, 10 men) treated with E7070 are listed in Table 1. All patients were evaluated for toxicity and antitumour activity. The median age was 49 years and PS was 0 or 1 in 26 patients. All patients had received prior treatment for their cancer. The most common tumour types were ovarian, colorectal, renal and breast cancer.

27 patients received 70 courses of E7070 at 10 different dose levels (Table 2). The median number of courses administered per

Discussion

In this study, testing a 5-day continuous infusion schedule, the MTD of E7070 was 130 mg/m2/day. When compared with the other schedules of administration tested, this MTD was the lowest dose obtained (800 mg/m2 3-weekly to 1000 mg/m2 3-weekly) 7, 8, 9. This may reflect an increased toxicity of E7070 when administered as a continuous infusion. As with other administration schedules, the DLTs in this phase I study were principally haematological. In all cases, these haematological toxicities were

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