Abstract CT106: A phase I/IIa study of IMCgp100: Partial and complete durable responses with a novel first-in-class immunotherapy for advanced melanoma
Authors: Middleton Mark R. , Corrie Pippa , Sznol Mario , Infante Jeffrey , Mulatero Clive , Evans Jeff , Steven Neil , Krige David , Shingler William H. , McGrath Yvonne , Hassan Namir J. , Jakobsen Bent K. 
Published: August 2015

Abstract
Background: IMCgp100 is an affinity-enhanced T cell receptor (TCR) specific for the HLA-A2 restricted melanoma gp100 peptide (YLEPGPVTA) fused to an anti-CD3 antibody fragment. Binding of IMCgp100 to melanoma cells redirects T cell cytotoxicity even in the presence of significant levels of PD-1 and PD-L1. Due to its high affinity, IMCgp100 enables T cells to kill HLA down-regulated melanoma cells otherwise invisible to natural T cell recognition. During phase I dose escalation of a weekly schedule, the Maximum Tolerated Dose (MTD) was 600ng/kg or 50mcg absolute dose. An expanded cohort is accruing at the MTD, and a second dose escalation was initiated to determine the MTD, toxicity and potential activity of a daily x 4 q3w schedule.
Methods: Patients enrolled are HLA A2 positive, stage IV or unresectable stage III melanoma, with an ECOG Performance Status (PS) ≤1 and a lymphocyte count of ≥0.5×109/L. The phase II expansion of weekly dosing has a target of 10 patients; accrual will continue until a trio of evaluable biopsies are available from at least six patients. Dose escalation for the daily x 4 q3w regimen began at 10mcg/daily. One cycle is 6 weeks.
Results: 16 patients have been treated weekly at MTD (600ng/kg or 50mcg). 63% were male, median age 58 yrs, ECOG PS 0 in 56%. All but one patient had stage IV disease. 63% of patients received ≥2 prior systemic therapies; some patients had prior ipilimumab (56%), RAFi (31%) and anti-PD1 or other immunotherapies (13%). Two patients were subsequently shown to be gp100 negative by IHC. Common toxicities included transient grade 3 pruritic rash and grade 2 pyrexia/edema. Lymphocytes migrated to skin and tumor as evidenced by biopsy analysis, accompanied by chemokine/cytokine release. Three partial responses (PR) and one complete response (CR) were observed and are still ongoing. Two PRs continue after &gt;12 months, one, in an ipilimumab refractory patient continues after &gt;3 months and a CR continues after &gt;4 months; these include responses in the two ocular melanoma patients enrolled (long term PR and CR). Sites of response include lung, liver, lymphatic system and various soft tissues. For the daily x 4 regimen, the 20mcg daily dose is complete, toxicities are tolerable and escalation continues.
Conclusions: Toxicities of IMCgp100 were consistent with the mode of action of the drug i.e. IMCgp100 mediated T cell mobilisation, activation and tumor killing. Objective durable responses were observed including in ocular melanoma patients. Additional patients are being accrued at 50mcg weekly. For the daily x 4 regimen, the 20mcg dose was completed, which equates to 80mcg every 3 weeks, or just over half the dose achievable in this period with weekly dosing. Dose escalation in the d x 4 regimen continues.
Citation Format: Mark R. Middleton, Pippa Corrie, Mario Sznol, Jeffrey Infante, Clive Mulatero, Jeff Evans, Neil Steven, David Krige, William H. Shingler, Yvonne McGrath, Namir J. Hassan, Bent K. Jakobsen. A phase I/IIa study of IMCgp100: Partial and complete durable responses with a novel first-in-class immunotherapy for advanced melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT106. doi:10.1158/1538-7445.AM2015-CT106