Abstract 5881: PERIO-01: Initial safety experience and immunologic effects of a Class C TLR9 agonist using pressure- enabled drug delivery in a phase 1 trial of hepatic arterial infusion of SD-101 +/- checkpoint inhibition in metastatic uveal melanoma
Authors: Patel Sapna P. , Haymaker Cara , Sheth Rahul A. , Kuban Joshua D. , Weintraub Joshua , Wehrenberg-Klee Eric , Novelli Paula , Gonsalves Carin , Adamo Robert , Honaker Virgina , Timciuc Laura , Hennegan Tarin , Molina Juan C. Amador , Duose Dzifa , Cuenta Edwin R. Parras , Lucci Anthony , Meas Salyna , Sarli Vanessa , Prieto Victor G. , LaPorte Jason , Hulstine Ann-Marie , Moody Ashley , Cox Bryan , Geller David , Davar Diwakar , Montazeri Kamaneh , Orloff Marlana , Katz Steven C. , Carvajal Richard 
Published: April 2023

Immune checkpoint inhibitors (ICI) have demonstrated limited success in patients with metastatic uveal melanoma (MUM) with liver involvement due to an immunosuppressive tumor microenvironment (TME) driven in part by myeloid-derived suppressor cells (MDSCs). Toll-like receptor-9 agonists (TLR-9A) have improved ICI response rates in cutaneous melanoma, but delivery challenges have limited their application for MUM. Hepatic arterial infusion (HAI) of TLR-9A using a pressure-enabled drug deliveryTM (PEDDTM) device has the potential to enhance responsiveness to ICI by optimizing delivery to intrahepatic tumors and reprogramming the TME, including elimination of MDSCs.PERIO-01 is an open-label first-in-human Phase 1 trial of SD-101 given by HAI using a PEDDTM in MUM (NCT04935229). The study consists of dose-escalation cohorts of single agent SD-101 alone and with ICI. SD-101 is delivered over 2 cycles, with 3 weekly doses per cycle. Research blood, tumor and normal liver biopsies are collected serially for correlative studies. At data cutoff, a total of 20 patients were enrolled, with 13 in the single agent dose escalation cohort (2, 4, and 8 mg) and 7 patients with SD-101 (2 mg) + nivolumab. The median age was 65.5 years with an equal gender distribution. Only 2 patients were treatment-naïve and the median number of liver metastases was 5.1. The average number of SD-101 infusions was 5.2. One patient in the combination cohort experienced a serious adverse event related to treatment - asymptomatic Grade 3 increase in liver enzymes. PEDDTM resulted in high drug levels in the liver (up to 2,340 ng/ml at 8mg) with only transient exposure in the periphery (&lt;4 hours) with one Grade 2 cytokine related syndrome adverse event. Dose-dependent increases in canonical TLR9-associated cytokines (IL-18, IFNγ, IP-10, and soluble CD25) was observed across the 2mg, 4mg, and 8mg single-agent dose levels. Concordant with predicted mechanism of action, PEDDTM HAI administered SD-101 resulted in decreases in liver monocytic MDSCs in 4 of 4 patients with available multiplex immunofluorescence data. NanoString analysis from three patients revealed increases in ISG15, IL-9, IFNα, and IL-2 transcripts and decreases in ARG1 and IDO transcripts, with increased scores for macrophages, activated CD8 T cells, Th1 cells, and Th1 activation. For patients who received 2mg SD-101 + ICI with available liquid biopsy data, 4 of 7 demonstrated decreases in circulating tumor cells and 3 of 5 showing ctDNA decreases after the first cycle. In this first-in-human experience, HAI of SD-101 via PEDDTM was well tolerated and associated with encouraging immunologic activity. Evidence of biologic activity with 2 mg of SD-101 with nivolumab is encouraging and patients are currently enrolling at higher SD-101 dose levels + ICI.

Citation Format: Sapna P. Patel, Cara Haymaker, Rahul A. Sheth, Joshua D. Kuban, Joshua Weintraub, Eric Wehrenberg-Klee, Paula Novelli, Carin Gonsalves, Robert Adamo, Virgina Honaker, Laura Timciuc, Tarin Hennegan, Juan C. Amador Molina, Dzifa Duose, Edwin R. Parras Cuenta, Anthony Lucci, Salyna Meas, Vanessa Sarli, Victor G. Prieto, Jason LaPorte, Ann-Marie Hulstine, Ashley Moody, Bryan Cox, David Geller, Diwakar Davar, Kamaneh Montazeri, Marlana Orloff, Steven C. Katz, Richard Carvajal. PERIO-01: Initial safety experience and immunologic effects of a Class C TLR9 agonist using pressure- enabled drug delivery in a phase 1 trial of hepatic arterial infusion of SD-101 +/- checkpoint inhibition in metastatic uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5881.