A two stage multicentre phase II study of Imatinib in the treatment of patients with c-kit positive metastatic uvEal Melanoma (ITEM)


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Ernie Marshall1, Carlos Escriu1, Paul Nathan4, S Danson5, M Marples6, Sarah E Coupland2, Catrin Tudur Smith3, Susanna Dodd3, Matthew Bickerstaff3, Bertil Damato2

1Clatterbridge Centre for Oncology, Merseyside, UK, 2Royal Liverpool University Hospital, UK, 3Liverpool Clinical Trials Unit, UK, 4Mount Vernon Hospital, Middlesex, UK, 5Weston Park Hospital, Sheffield, UK, 6St James University Hospital, Leeds, UK

Abstract

Background
Uveal melanomas differ from their cutaneous counterparts with respect to biological behaviour and molecular pathogenesis. Almost 50% of patients with uveal melanoma develop metastatic disease, which has a median survival of only 2 to 6 months, a median progression free survival (PFS) of up to 3 months and a mortality of 85%. There is no systemic chemotherapy that significantly prolongs survival. In vitro assays and short case series reports suggest that there should be a clinical benefit from Imatinib mesylate, a highly selective inhibitor of c-kit. A previous phase II study found no significant increase in six-month PFS in 25 patients with metastatic disease, however only 10 patients had at least moderate c-kit expression on retrospective analysis. The effectiveness of Imatinib in c-kit positive patients remains unknown. The objective of this trial was to explore the clinical benefit of Imatinib in patients with prospectively tested c-kit positive (centralized testing of at least 25% expression by immuno-histochemistry) metastatic uveal melanoma, PS 0-2 and measurable disease.

Method
This was a UK-wide multicentre two stage Gehan Phase II design. The initial stage included 14 patients with a maximum sample size of 25 patients. The primary outcome measure was PFS rate at 3 months. Secondary objectives were safety and toxicity assessment, overall survival, overall progression free survival and disease response. A biomarker screening study was included in the trial design.

Results
24 of the 26 patients (92%) screened had a c-kit positive tumour. 14 patients (3 female) with PS 0-1 have been recruited so far. 7 patients had high LDH levels (>460IU/L). The median time from diagnosis of metastatic disease to trial registration was of 11.4 months. 4 patients had previous chemotherapy treatment and only 1 patient did not have liver involvement by metastasis.

Conclusion
A multicentre clinical trial of Imatinib in patients with metastatic uveal melanoma is currently ongoing in its second stage. C-kit positivity rates have been excellent so far, although they might be biased by local testing before referral to ITEM. We expect to complete recruitment in October, when we will commence a UK-wide randomised phase II clinical trial of Sunitinib in similar patients.

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