Phase 1b/2, open-label, multicenter, dose escalation and expansion trial of intratumoral SD 101 in combination with pembrolizumab in patients with metastatic melanoma

Abstract

Background: SD-101 is a synthetic Class C CpG-ODN that stimulates plasmacytoid dendritic cells to release interferon-alpha and mature into efficient antigen presenting cells. SD-101 in combination with low dose radiation has demonstrated abscopal activity in indolent B-cell lymphoma (Levy et al AACR 2016). Pre-clinically, in a CT26 mouse model, SD-101 in combination with an anti-PD-1 induced T cell infiltration and durable complete responses in all treated animals (Campos et al, AACR 2016). Pembrolizumab is a PD-1 inhibitor that has been approved for the treatment of metastatic melanoma. Methods: The MEL-01 trial (NCT02521870) is assessing the safety and preliminary efficacy of SD-101 + pembrolizumab in unresectable stage IIIC-IV melanoma. Phase 1b is a modified 3 + 3 design of 3 dose levels of SD-101 (2, 4, and 8 mg) followed by a phase 2 dose expansion (n = 85). SD-101 is injected into a tumor lesion weekly X 4 followed by q 3 weekly X 3. Pembrolizumab dose is 200 mg IV q 3 weeks. Biopsies of the injected tumor are taken pretreatment and on treatment. Tumor responses are assessed using RECIST v1.1. Results: In the phase 1b study, 5 patients were enrolled in the 2 mg group and 5 in the 4 mg group. Treatment was well tolerated; there were no DLTs. Adverse events associated with SD-101 were flu-like symptoms the evening following an injection that were treated with over-the-counter medications. No increased toxicity of the combination of drugs has been observed. At 12 weeks, in the 2 mg group, there were 2 PRs, 1 SD, 1 PD (at day 22) and 1 not yet available. One of the patients with a PR had a tumor biopsy that was negative for melanoma. Five patients were enrolled in late April 2016 in the 4 mg cohort; response data will be available by October. Additionally, mechanistic insight into therapeutic activity obtained through examination of tumor biopsies by IHC, PD-L1 expression, and NanoString RNA expression profiling will be presented. Conclusions: Preliminary results suggest that the combination of SD-101 + pembrolizumab shows activity in metastatic melanoma.