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Lookup NU author(s): Professor Alan Calvert
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Purpose: E7070 is a sulfonamide that induces arrest at the G(1)-S boundary with subsequent dose and exposure-dependent apoptosis. The objectives of this study were (a) to determine the maximum-tolerated dose (MTD) and recommended safe dose (RD) of E7070 for additional evaluation, (b) to define the dose limiting toxicity(ies) [DLT(s)], (c) to study the pharmacokinetics of E7070, and (d) to seek preliminary evidence of antitumor activity. Experimental Design: Patients with solid tumors who had either failed or were not amenable to established forms of treatment were eligible for the study. E7070 was administered i.v. at weekly intervals for 4 consecutive weeks to cohorts of 3-6 patients at each dose level. Treatment was repeated six weekly in the absence of tumor progression. A Fibonacci-like scheme was used for dose escalation. The MTD was determined in a stepwise procedure for two cohorts of patients; the "initial patient cohort" who met the original inclusion criteria (group A) and the "better prognosis cohort" (group B) who had adequate hepatic function, less extensive tumor involvement of the liver, and no more than three previous lines of chemotherapy. The RD was defined as the highest dose at which the incidence of definitely drug-related DLTs was <33%. The pharmacokinetic profile of E7070 was determined. Results: Overall, 46 patients entered the study; information from 36 of the 37 patients forming group A was used to determine the overall MTD. An additional 9 patients plus 9 patients from group A who met the more restrictive inclusion criteria made up group B. The MTD was 500 mg/m(2)/week for both groups. Reversible neutropenia and thrombocytopenia were the most common DLTs. Other DLTs included stomatitis, hyperglycemia, sepsis, fever, hemorrhage, diarrhea, nausea, and fatigue. The pharmacokinetics of E7070 were nonlinear over the dose range 160500 mg/m(2). One partial response was observed in a patient with an endometrial adenocarcinoma who had previously been treated with radiotherapy. Twelve other patients had stable disease as their best response (27%); among them. 1 patient with metastatic melanoma who received 21 cycles of therapy. Conclusions: The RD for further study of E7070 using this administration schedule is 400 mg/m(2)/week. Using this schedule, the predominant toxicity of E7070 is myelosuppression. E7070 has anticancer activity in pretreated patients.
Author(s): Dittrich, C., Dumez, H., Calvert, A. H., Hanauske, A., Faber, M., Wanders, J., Yule, M., Ravic, M., Fumoleau, P.
Publication type: Article
Publication status: Published
Journal: Clinical Cancer Research
Year: 2003
Volume: 9
Issue: 14
Pages: 5195-5204
ISSN (print): 1078-0432
ISSN (electronic): 1557-3265
URL: http://clincancerres.aacrjournals.org/cgi/content/abstract/9/14/5195
