EphA2 siRNA in DOPC nanoliposomes (EPHARNA): A phase I clinical trial in patients with solid tumors.

3086 Background: EphA2 overexpression is common in human cancers and has an important role in promoting tumor growth and metastasis. Further, EphA2 has kinase-dependent and independent functions, making it ideal for RNAi-based targeting. EphA2 siRNA incorporated in DOPC nanoliposomes (EPHARNA) was effective in reducing EphA2 protein levels and reducing tumor growth in preclinical studies. This is a first-in-human phase I clinical trial of EPHARNA in patients with solid tumors. Methods: Adult patients with advanced solid tumors received escalating doses of intravenous EPHARNA twice weekly in 3-week cycles. A total of 8 dose levels were explored under a BOIN design (Table 1). Study objectives included evaluation of safety, tolerability, maximal tolerated dose, and efficacy. Adverse events were assessed per NCI CTCAE Version 4.03 and efficacy per RECIST v1.1. Patients were evaluable for response if they completed at least 2 cycles. Clinical benefit was defined as objective response or stable disease for 4 or more cycles. Results: A total of 48 patients were treated. Most common diagnoses were colorectal (29.2%) and ovarian cancer (12.5%). 20.8% of treated patients were Black and 8.3% were Hispanic. Median age was 60.3 years (range 24.5-78.8). Median number of prior therapies was 4 (range 0-12). Among treated patients, 36 (75%) experienced an AE. Most common AEs (≥20%) were fever (33.3%), infusion-related reaction (25%), and chills (20.8%). 5 (10.4%) treated patients experienced Grade 3 AEs that were dose-limiting toxicities including chills (2.1%), dyspnea (2.1%), hypertension (2.1%), infusion-related reaction (2.1%), and nausea/vomiting (2.1%). No Grade 4 AEs were noted. Of the 25 patients evaluable for response, disease control rate was 44% (95% CI: 24.5-63.5%) with 11 patients demonstrating stable disease for at least 2 cycles. No patients demonstrated partial or complete response. Clinical benefit was observed in 4 (16%, 95% CI: 1.6-30.4%) patients who demonstrated stable disease for at least 4 cycles. One patient received 16 cycles with stable disease before withdrawing consent and discontinuing the trial due to desire for a treatment break. The study was closed to enrollment prior to confirmation of the MTD due to unavailability of the drug. Conclusions: EPHARNA demonstrated an acceptable safety profile with manageable adverse events in patients with advanced solid tumors. Further investigation of this novel therapeutic approach is warranted to fully elucidate efficacy and optimal dosing strategy. Clinical trial information: NCT01591356 . Dose levels, patients treated, and DLTs. DoseLevel EphA2 siRNA-DOPC Dose (μg/m 2 ) Number of Patients Treated Number of Patients Experiencing DLTs DLTs 1 450 14 2 G3 chillsG3 nauseaG3 vomiting 2 675 6 1 G3 hypertension 3 1012.5 5 0 N/A 4 1518.75 5 0 N/A 5 2278.13 7 0 N/A 6 3417.2 2 2 G3 infusion-related reactionG3 dyspnea 7 3600 3 0 N/A 8 7200 6 0 N/A