2558 Background: The utility of interleukin-2 (IL-2) in treating RCC is limited by its significant toxicity, expense, and limited efficacy. Formulations that reduce post-injection peak concentration (Cmax) and support sustained therapeutic levels may improve efficacy and tolerability of IL-2 therapy. In preclinical studies, IL-2 formulated with Medusa (IL-2XL), a novel sustained drug delivery system, reduces Cmax and supports controlled release of IL-2 for up to 6 days.
METHODS
The open-label Phase I/II study was designed to accrue 12 patients (pts), with a goal of 10 evaluable pts. Pts aged 18-85 at high risk of recurrence after surgical resection of histologically confirmed RCC, and without CNS metastases, other malignancy, autoimmune disorders were eligible. Pts received one single subcutaneous (SC) injection of 10.6 MIU naked IL-2 (IL-2N) or IL-2XL. At least two weeks later, patients were crossed over to receive a single SC administration of 10.6 MIU of the other agent. Safety, PK, biological activity and immunological responses were assessed.
RESULTS
8 patients have accrued and results from 6 pts evaluable to date show a 4-fold reduction in Cmax following IL-2XL injection compared with IL-2N. IL-2 was detectable in serum 7 days after IL-2XL treatment, compared with 2 days for IL-2N. Relative bioavailability of IL-2XL was approximately 150% of IL-2N, and Tmax was appoximately 48 hrs compared with 2-4 hrs. T50 also was higher following IL-2XL administration compared with IL-2N (48 vs. 8 hrs). Soluble CD25 and neopterine, markers of IL-2 activity, had much higher Cmax (159 vs. 63 pg/ml and 14 vs. 6 pM for sCD25 and neopterin) and AUC (14,749 vs. 7,701 pg/ml/hrs and 1,569 vs. 665 pM/hrs for sCD25 and neopterin) following IL-2XL treatment compared with IL-2N. Compared to IL-2N immunoflowcytometry showed an increase in percentage and activation of lymphocytes (CD3+/CD45+; CD8+/CD25+ and CD4+/CD25+).
CONCLUSIONS
Weekly dosing of IL-2XL reduces Cmax, increases induction of IL-2 biomarkers and improves immunologic responses compared with IL-2N. Data support the development of IL-2-XL used on a weekly schedule for treating cancer and viral disease such as HIV. No significant financial relationships to disclose.