Phase II study of E7070 in patients with metastatic melanoma
J. F. Smyth1,*,
S. Aamdal2,
A. Awada3,
C. Dittrich4,
F. Caponigro5,
P. Schöffski6,
M. Gore7,
T. Lesimple8,
N. Djurasinovic9,
B. Baron9,
M. Ravic10,
P. Fumoleau11 and
C. J. A. Punt12 On behalf of the EORTC New Drug Development and Melanoma Groups
1 University of Edinburgh, Cancer Research Centre, Western General Hospital, Edinburgh, UK; 2 The Norwegian Radium Hospital, 0310 Oslo 3, Norway; 3 Department of Medical Oncology, Institut Jules Bordet, Brussels, Belgium; 4 LBI Applied Cancer Research, Kaiser Franz Josef Spital, Vienna, Austria; 5 Div. Oncologia Medica A, Instituto Nazionale Per lo Studio e la Cura dei Tumori, Italy; 6 Medizinische Hochschule Hannover, Abt. Haematologie und Onkologie, Hannover, Germany; 7 Royal Marsden Hospital, London, UK; 8 Centre Eugene Marquis, Renes, France; 9 EORTC, Avenue Mounier 83, Brussels, Belgium; 10 Centre Rene Gauducheau, Nantes, St-Herblain, Cedex, France; 11 Centre Rene Gauducheau, Boulevard Jacques Monod, F-44805 Nantes, St. Herblain, Cedex, France; 12 University Medical Centre Nijmegen, Department of Medical Oncology, The Netherlands
* Correspondence to: Professor J. Smyth, University of Edinburgh, Cancer Research Centre, Crewe Road South, Edinburgh EH4 2XR, UK. Tel: +44-131-777-3512; Fax: +44-131-777-3520; Email: john.smyth{at}cancer.org.uk
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Abstract
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E7070 is a synthetic chloro-indolyl sulphonamide that is being developed as an anti cancer agent. In this phase II study, 28 patients with metastatic melanoma received 700 mg/m2 of E7070 as a 60-min infusion repeated every 3 weeks. Although therapy was well tolerated, with one patient receiving 14 courses of treatment, there were only minor responses on independent radiological review. E7070 does not warrant further development as a single agent for the treatment of metastatic melanoma.
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Introduction
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Malignant melanoma accounts for 2% of all cancers in the USA and Europe [1
]. Wide local excision is the treatment of choice for primary tumours and for locoregional recurrence. Metastatic disease is incurable with a median survival of approximately 7 months from diagnosis. Dacarbazine is the current standard therapy for metastatic melanoma with a response rate of
15%. Responses to dacarbazine are generally incomplete and last only a few months. The use of combination chemotherapy produces higher response rates, but at a cost of increased toxicity with no increase in response duration or survival [2
].
E7070 is a synthetic chloro-indolyl sulfonamide derivative with a wide range of activity in human tumour cell lines [3
]. In the A549 non-small-cell lung cancer cell line, treatment with E7070 produced a profound arrest at the G1/S boundary accompanied by hypophosphorylation of the retinoblastoma protein and a reduction in the expression of cyclins A, B1 and the cyclin-dependent kinase 2. At higher concentrations, E7070 was associated with upregulation of p53 and p21 and subsequent apoptosis [4
]. Although the precise mechanism of action remains to be defined, recent studies have indicated that E7070 inhibits cytosolic malate dehydrogenase by preventing the binding of its cofactor nicotinamide adenine diphosphate, although the relationship between this event and the drug's biological activity remains poorly defined [5
]. Dose finding studies in man using a variety of schedules have been completed and show that the drug's dose limiting toxicities are reversible neutropenia and thrombocytopenia. Other toxicities included mucositis and fatigue [6
9]. There was no clear difference in efficacy between administration schedules and a single dose of 700 mg/m2 repeated three weekly was selected for further development, largely on the basis of convenience. Seven patients with pretreated metastatic melanoma were entered into the E7070 phase I program. One patient experienced a minor response and remains well more than 3 years since starting treatment. A further three patients reported a best response of stable disease for three, six and eight courses of E7070, respectively. In view of the limitations of existing therapies, this level of activity was sufficient to support a phase II study of E7070 in metastatic melanoma.
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Patients and methods
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This study was a multi-centre phase II study of E7070 conducted by the EORTC New Drug Development Group and Melanoma Cooperative Group between May and November 2001. The principal objective of the trial was to assess the therapeutic activity of E7070 in patients with metastatic melanoma who had not received prior chemotherapy in the metastatic setting. A secondary objective was to further define the acute side-effects of E7070 in this patient population.
Patient selection
Patients were considered eligible for the study if the following criteria were met. Histologically proven diagnosis of melanoma with distant metastases (stage IV), with at least one bidimensionally measurable lesion according to WHO criteria, Eastern Cooperative Oncology Group (ECOG) performance status
2. Patients could not have received prior chemotherapy or immunotherapy for metastatic disease. Neo-adjuvant therapy and experimental vaccine treatment were allowed. Patients had adequate haematological function, (haemoglobin >10 g/dl, neutrophils >1.5 x 109/l and platelets >100 x 109/l), adequate renal function [serum creatinine <1.5x upper limit of normal (ULN) or creatinine clearance
60 ml/min] and adequate hepatic function [serum bilirubin <25 µmol/l (1.5 mg/dl), alanine transaminase or aspartate transaminase <2.5x ULN (unless related to liver metastases in which case
5x ULN was acceptable)]. Patients with central nervous system (CNS) metastasis, diabetes mellitus, prior or concurrent malignancy, uncontrolled infection, or cardiac dysfunction were excluded. Patients were also excluded if they were pregnant, breast feeding (men and women of child-bearing potential were required to use a reliable method of contraception) or suffered from an existing condition which was incompatible with adherence to the protocol. The protocol was approved by appropriate central and local ethics committees and all patients were required to give written informed consent.
Study design and endpoints
The primary objective of this study was to measure the objective response rate. Secondary objectives were duration of response, progression-free survival, median survival and the safety and tolerability of E7070. A target response rate of 15% was identified for the study. Accepting the possibility of rejecting a drug with a 15% response rate as 0.05 provided a two-stage Gehan design with 19 patients being recruited into the first stage. Provided at least one objective response was identified in the first stage, a total of 24 patients were to be treated. If no responses were seen recruitment was to be halted after the first 19 patients. In the absence of any safety concerns recruitment was to be continuous between stages.
Treatment plan
Patients were registered centrally and screened within 14 days prior to starting E7070. Treatment was continued until disease progression or unacceptable toxicity occurred. E7070 at a dose of 700 mg/m2 was administered intravenously via a peripheral line over 60 min. Treatment was repeated every 3 weeks. E7070 was delayed if the neutrophil count was <1 x 109/l, the platelet count was <100 x 109/l or treatment emergent toxicities had not returned to baseline or recovered to a maximum of Grade 2 in severity. A maximum delay of up to 2 weeks was permitted. Toxicity was assessed using the National Cancer Institute Common Toxicity Criteria (NCI CTC version 2). Routine biochemical screens and haematology was performed weekly or more frequently if clinically indicated. Objective tumour response was measured according to WHO criteria; thus a complete response required complete disappearance of all disease, determined by two observations not less than 4 weeks apart, and a partial response required a 50% or more decrease in the total tumour volume (when compared to the initial tumour volume) established on two observations not less than 4 weeks apart. In addition, there was to be no appearance of any new lesion or progression of any lesion. Progression was defined as an increase of 25% in the total tumour volume. Stable disease was defined as neither an objective response nor progressive disease, demonstrated at least two cycles after the start of treatment. Tumour assessments were made on computed tomography or magnetic resonance imaging scans following every two cycles of E7070. All radiological responses were assessed by two independent reviewers.
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Results
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Twenty-eight patients were treated with E7070 in eight institutions. Demographic data and previous therapy are presented in Table 1. Four patients were considered ineligible for the study during EORTC review: one patient was anaemic at study entry, two patients had unstable diabetes mellitus and the fourth patient had an ocular primary. An additional patient was noted to have CNS metastases at screening at the time of independent radiological review. These were not detected at the site and the patient was included in the eligible population. A total of 71 cycles of E7070 were administered (median two, range one to 14). Only two patients did not get at least 95% of the planned dose intensity. Temporary interruption of drug administration occurred at least once in one-quarter of the patients as a consequence of infusion reactions.
Response
The best overall response for the eligible population is summarised in Table 2. According to independent review there were no objective responses [response rate 0%, 95% confidence interval (CI), 0%16%; eligible population, n=24]. Although there were no objective responses in the first 14 patients, recruitment continued to completion on the basis of continuing shrinkage of liver metastases in one patient. Four patients had a best response of stable disease. One of these patients received 14 cycles of E7070. Although she achieved a 60% reduction in the volume of her hepatic metastases she was noted to have developed a new soft tissue lesion following four cycles and thus was considered to have a best response of stable disease following two cycles. A second patient achieved a 36% reduction in the volume of measurable disease following two cycles of E7070 but was withdrawn from the study at that time. The median progression-free survival was 42 days (95% CI, 4044 days). The median survival was 7.1 months (95% CI, 110329 days).
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Toxicity
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Three patients died within 30 days of receiving E7070. In two of these cases death was clearly related to progressive melanoma. The third patient died suddenly at home 6 days after receiving her initial dose of E7070. The cause of death was not established, pulmonary embolus was suspected and the investigator classified the event as being possibly related to treatment with E7070. Otherwise treatment was generally well tolerated. Haematological toxicity was predominantly grade 1 or 2 in severity (Table 3). There were no episodes of febrile neutropenia. Grade 3 and 4 adverse events considered to be either possibly or probably related to E7070 are presented in Figure 1.
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Discussion
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Patients with metastatic melanoma continue to have a dismal prognosis and current chemotherapies are administered with palliative intent. There is an urgent need to improve on existing therapies. Although minor responses were seen in two patients, no objective responses were seen in this study. Overall the results are disappointing and do not support the findings of the phase I program, where a high incidence of disease stabilisation was seen with both the three-weekly and weekly schedule of administration [6
, 8
]. In view of the relatively small numbers of patients involved it is likely that this difference results from patient selection. With regard to the patient population in this study, although more than three-quarters of the patients had visceral metastases at screening only 29% had hepatic metastases. Eighty-two percent of patients had an elevated serum lactate dehydrogenase at screening (Table 1). The size of the study makes it impossible to make meaningful comparisons between this study population and those in other phase II/III populations.
The toxicity profile of E7070 differed in this study from that reported previously. Unlike all other phase II studies with the drug there were no grade 4 haematological toxicities or episodes of neutropenic fever. Indeed the incidence of severe toxicity in this study is considerably less than that expected on the basis of the dose finding studies [6
8
]. The most likely explanation for this observation is that the frequency of E7070-induced haematological toxicity is strongly correlated to the extent of prior cytotoxic therapy. Indeed, this was found to be the case during the phase I study where a dose of 800 mg/m2 was safe in patients who had received no more than three previous lines of chemotherapy. It seems likely that a higher dose of E7070 may have been more appropriate in this patient population in view of the absence of prior chemotherapy although it is unclear as to whether a higher dose would have proven any more efficacious. In contrast to the mild haematological toxicity, a higher incidence of rash, fatigue and injection site events was reported.
The absence of objective responses in this study does not support further single agent studies of E7070 in melanoma.
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Acknowledgements
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The authors thank B. Marchal, who managed the data for the trial.
Received for publication June 16, 2004.
Accepted for publication August 23, 2004.
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