Background: IMCgp100 comprises 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. Importantly, IMCgp100 enables T cells to kill HLA down-regulated melanoma cells otherwise invisible to cancer specific T cells. A Phase I study was conducted to determine the Maximum Tolerated Dose (MTD) and toxicity of IMCgp100 in patients with metastatic melanoma.

Methods: HLA A2 positive patients with Stage IV or unresectable Stage III melanoma, with an ECOG Performance Status (PS) ≤1 and a lymphocyte count of ≥0.5x109/L were enrolled. Those with symptomatic, unstable brain metastases requiring steroids and those who might benefit from immediate vemurafenib treatment were excluded. IMCgp100 was administered on day 1 and patients followed to day 30. Those who tolerated the first dose received repeated cycles of six weekly doses. The dose of IMCgp100 was escalated in cohorts of 3 (+3) patients until criteria for MTD were met. MTD was defined as the highest dose level with an observed incidence of Dose Limiting Toxicity (DLT) in fewer than 33% of patients enrolled at that level. Transient Grade 3 lymphopenia and Grade 3 skin toxicity were excluded from the definition of a DLT.

Results: 31 patients were enrolled in 8 cohorts (doses from 5 to 900ng/Kg). 58% were male, median age was 61, ECOG PS 0 in 52% and 1 in 48%. All but 1 patient had stage IV disease. 60% of patients had received systemic treatment with DTIC (29%), ipilimumab (6%), vemurafenib (3%) or one or more experimental therapies (22%) prior to enrolment. At dose 900ng/Kg, 2/4 patients developed Grade 3 hypotension, therefore the MTD was defined at 600ng/Kg. Common toxicities included transient grade 3 pruritic rash and grade 2 pyrexia. Patients experienced profound lymphocyte trafficking to skin as evidenced by immunohistochemical analysis of skin biopsies, accompanied by chemokine/cytokine release. Rash was initially observed at dose level 45ng/Kg. Tumor flare was observed in patients with cutaneous or subcutaneous disease. Four partial responses (PR) and multiple lesser responses (not meeting RECIST PR) have been documented to date. One PR was achieved after a single dose. Two PRs continue after >9 months of continued treatment. One patient continues with stable disease for >10 months. Sites of response included the lung, the liver, the lymphatic system and various soft tissues.

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. The study has been expanded to accrue additional patients at 600ng/Kg and to explore potentially superior dosing regimens.

Citation Format: Mark Middleton, Jeff Evans, Neil Steven, Pippa Corrie, Clive Mulatero, Mario Sznol, William H. Shingler, Dominic Smethurst, Namir Hassan, Yvonne McGrath, Bent Jakobsen. A Phase I study of IMCgp100: durable responses with a novel first-in-class immunotherapy for advanced melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT329. doi:10.1158/1538-7445.AM2014-CT329