A phase 0 exploratory study to assess the pharmacodynamic effects of single intratumoral dose of a novel bispecific targeting/immune-activating agent on the melanoma tumor microenvironment.

Abstract

TPS160 Background: IMCgp100 is a novel biologic comprising a soluble T cell receptor (TCR) fused to an antibody fragment (scFv) being developed for the treatment of metastatic melanoma. The TCR component binds to the melanoma associated antigen (Ag) gp100 which is overexpressed and presented by HLA A2 on melanoma cells. The scFv component activates T cells in physical contact with the target via CD3. Thus, IMCgp100 is expected to bind melanoma cells and stimulate the immune system to attack the target tissue via cytotoxic lymphocyte killing and via stimulation of accessory immune mechanisms.The purpose of this trial is to assess the pharmacodynamic effects of a single intratumoral dose of IMCgp100 on the tumour microenvironment and to establish what local concentration of drug is required for optimal effect. Such data will aid in future trial design and facilitate clinical development. Methods: This 2 stage exploratory study will assess the effects of 2 different doses of IMCgp100 in subjects with advanced unresectable melanoma not currently requiring systemic treatment and/or in a window between treatments. Eligible subjects must have completed other cancer therapies 14 days prior to injection, ECOG PS ≤ 2, no active, uncontrolled infection, no steroids within 2 weeks of injection. In the first stage, subjects will receive a single intratumoral injection of 0.00017mg of IMCgp100 into a target cutaneous or subcutaneous metastasis, 7-15mm in size. This should generate a local concentration of 1nM; shown to induce maximal tumour cell killing in vitro. One week later, biopsies of the target lesion and a designated reference lesion will be performed. Primary endpoints include: assessment of tumor and reference tissue for lymphocyte infiltration and Ag expression by IHC; molecular analysis of immune cell infiltration and activation status using Q-RT-PCR, flow cytometry, Luminex analysis. Secondary endpoints will measure markers of systemic immune activity and safety. The second stage will assess a 10 fold higher dose. Enrollment for the trial is now open. Up to 20 subjects may be enrolled to yield 6 evaluable, HLA 2+ subjects.