First-in-human study of RAG-01: A novel small activating RNA therapeutic in BCG failure non-muscle invasive bladder cancer (NMIBC) patients.

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e16587 Background: Targeting the p21 WAF1/CIP1 (p21) gene represents a promising yet challenging therapeutic strategy in cancer treatment. p21, a critical cell cycle inhibitor with significant tumor suppressive potential, has remained largely "undruggable" for conventional modalities. RAG-01 introduces a novel approach using small activating RNA (saRNA) technology to directly upregulate p21 gene expression at the transcriptional level via the RNAa mechanism. This study (NCT06351904) represents the first-in-human clinical trial of a saRNA targeting p21, in patients with NMIBC to establish a potential novel therapeutic paradigm in the treatment of cancer by activating tumor suppressor genes. Methods: This open-label, multi-center, phase I study uses a 3+3 dose-escalation design to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of intravesical RAG-01 in patients with Bacillus Calmette Guérin (BCG) unresponsive NMIBC. Patients receive RAG-01 at escalating doses (30 mg, 100 mg, 300mg, and 600 mg). Two doses will be selected for the expansion phase. Treatment consists of a 6-week induction course (weekly instillations) followed by maintenance of 3 weekly instillations every 12 weeks (weeks 12, 24, 36, 48, and 72). Patients with persistent carcinoma in situ (CIS) or high-grade Ta at 12 weeks may receive a six-week re-induction. Results: As of December 15, 2024, 9 patients were enrolled across 3 dose-escalation cohorts (30-300 mg). Dose escalation is ongoing, and no dose-limiting toxicities (DLTs) have occurred. Adverse events (AEs), all grade ≤2, were reported in 8 patients (88.9%, 8/9). The most frequently reported AEs included urinary urgency (11.1%, 1/9), increased urinary frequency (11.1%), urinary tract infection (11.1%), dyspnea (11.1%), lethargy (11.1%), nausea (11.1%), and decreased appetite (11.1%). RAG-01 showed minimal systemic exposure with a dose-dependent maximum urine concentration (83.3-1,820 µg/ml at 2 hours) and urine AUC 0-24h . A dose-dependent increase in p21-positive urothelial cells was observed. Preliminary efficacy analysis revealed a 66.7% (2/3) complete response rate for CIS at any time and a 66.7% (2/3) disease-free survival rate for papillary tumors at 3 months. Conclusions: Intravesical RAG-01 demonstrated a favorable safety profile across three escalating dose levels (30, 100, and 300 mg). Dose-dependent p21 protein induction in urothelial cells confirmed target engagement. Preliminary anti-tumor efficacy supports further clinical investigation of this saRNA as a novel therapeutic approach for NMIBC. Clinical trial information: NCT06351904 .

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