A phase 1, first-in-human, dose-escalation, expansion trial of cytokine encoding synthetic mRNA-mixture alone or with cemiplimab in advanced solid tumors.

Abstract

Purpose: We investigated SAR441000 (mixture of four mRNAs encoding interleukin [IL]-12, single chain interferon [IF]-α-2b, granulocyte-macrophage colony-stimulating factor, and IL-15 sushi domain) alone or in combination with cemiplimab in patients with advanced solid tumors.

Patients and methods: SAR441000 was intratumorally administered weekly in a 4-week cycle in monotherapy and in a 3-week cycle at a pre-defined dose level (DL) with 350 mg cemiplimab (intravenously) every 3 weeks in combination therapy. The primary objective was to determine maximum tolerated or maximum administered dose (MAD), overall safety, tolerability, and objective response rate of SAR441000.

Results: We enrolled 77 patients previously treated with anti-cancer therapies (escalation monotherapy: N=21; escalation combination: N=15; and expansion combination [PD-1 refractory melanoma]: N=41). MAD at DL8 was 4000 µg. The most common Grade ≥3 treatment-related adverse event was fatigue in escalation phase (monotherapy: 28.6%; combination therapy: 66.7%) and injection-site pain (31.7%) in expansion phase. In combination therapy, one patient in escalation and two in expansion phase achieved partial responses. At 4000 μg (highest dose) across all cohorts, the maximum fold change in plasma cytokine concentration was the highest and lowest for IFN-α-2 (74.9-folds) and IL-15 (1.96-folds), respectively. Increased blood IFN-γ and IP-10 levels were observed for most patients.

Conclusions: Intratumoral administration of SAR441000 in combination with cemiplimab, was generally well tolerated with anti-tumor activity in loco-regional disease setting. Anecdotal evidence of pharmacodynamic immune-modulatory effect and distant non-injected lesion anti-tumor response was observed, without significant effect in patients with advanced solid tumors previously treated with anti-PD1 therapies.