A phase 1, first-in-human, drug dose-escalation study of RM-1995 photoimmunotherapy, as monotherapy or combined with pembrolizumab, in patients with advanced cutaneous squamous cell carcinoma or with head and neck squamous cell carcinoma.

Abstract

TPS6103 Background: RM-1995 comprises an antibody against CD25, conjugated with a light-activatable dye (IRDye 700DX), which can subsequently be activated by illumination with 690 nm non-thermal red light for precise, targeted cell killing. Administration of the antibody-dye conjugate followed by local illumination results in target cell membrane disruption, while limiting damage to surrounding tissue. CD25 (lL-2Rα) is highly expressed by regulatory T cells (Tregs), thereby providing an opportunity to specifically target intratumoral Tregs for depletion via photoimmunotherapy. Tregs are critical in promoting immune homeostasis; however, in the context of solid tumors, Treg-mediated suppression detrimentally constrains anticancer T-cell responses, and a low ratio of CD8+ T cells:Tregs in the tumor is negatively correlated with clinical outcomes. Preclinical data suggest that RM-1995 photoimmunotherapy treatment alleviates local Treg-mediated restraint within the tumor microenvironment. Anticancer responses were further improved when combined with anti-PD-1 checkpoint inhibition. Methods: A phase 1 first-in-human dose-escalation study of RM-1995 photoimmunotherapy as monotherapy, or in combination with pembrolizumab, in patients with advanced cutaneous squamous cell carcinoma (cuSCC) and head and neck squamous cell carcinoma (HNSCC) is now enrolling (NCT05220748). The phase 1a portion will evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent RM-1995 photoimmunotherapy and determine the maximum tolerated dose or maximum administered dose of RM-1995 with a fixed light dose for tumor illumination. The phase 1b portion will include combination therapy with pembrolizumab. Enrolled patients will receive RM-1995 IV, followed 24±4 hours later by local tumor illumination. Pembrolizumab (200 mg) will be administered 5–7 days prior to RM-1995 infusion, then again 3 weeks later. Patients may be eligible to receive repeated photoimmunotherapy cycles for up to 12 months. Primary outcomes include safety and tolerability, and dose finding. The study will include cuSCC or HNSCC patients with locally advanced or locoregional disease with or without metastases that has recurred or progressed on or after platinum-based chemotherapy, and who are not eligible for further locoregional treatment. Other criteria include ECOG 0–2 and having ≥1 tumor accessible for illumination. Key exclusion criteria are: tumor sites located in sensitive or vital anatomic structures or invading a major blood vessel (unless treated to prevent hemorrhage); and other clinically significant or uncontrolled disease processes. An estimated 18 patients will be enrolled into each portion of the study. Clinical trial information: NCT05220748.