Background: Aldesleukin (recombinant human interleukin-2, IL-2) has been an FDA-approved treatment for mRCC since 1992 with a 5-10% rate of durable complete response. Hydroxychloroquine (HCQ) inhibits cellular autophagy, a protective mechanism that enables cells to survive metabolic stress. In murine models, the combination of IL-2 and HCQ was associated with diminished toxicity and increased efficacy. We hypothesized that this combination would be tolerable and active in patients with metastatic renal cell carcinoma (mRCC). Methods: The Cytokine Working Group studied high-dose IL-2 in combination with oral HCQ for patients with mRCC. Subjects received IL-2, 600,000 International Units/kg, every 8 hours up to 14 doses/cycle. HCQ was administered daily by mouth, starting 2 weeks prior to the first dose of IL-2 and continued up to one year. The initial HCQ dose was 600 mg daily, with a planned dose escalation to 1200 mg daily. Subjects were monitored for safety and tolerability as well as response per RECIST 1.1. Results: 30 patients (9F, 22M) received study treatment, and 29 were evaluable for response. MSKCC prognostic group: good- 38%; intermediate- 55%; poor- 11%. Five subjects were treated at 600 mg daily HCQ with no unexpected toxicity. Thirteen subjects were then treated at HCQ 1200 mg. Of these, 2 experienced hypotension and tachycardia, and 1 patient died from pulmonary emboli. The cardiac events, consistent with IL-2 toxicity, were observed earlier in the course of treatment than anticipated. HCQ dose was therefore de-escalated to 600 mg daily, and 12 additional subjects were enrolled with no unexpected toxicity. There were 3 confirmed complete responses and 3 partial responses (1 confirmed); the median overall survival has not been reached. Surprisingly, median progression-free survival was 5 months for the 1200 mg cohort and > 17 months for the 600 mg group, 3-4x the historical duration. High baseline levels of serum hepatocyte growth factor > median predicted for inferior overall survival. Soluble LAG-3 levels increased with IL-2 therapy. Conclusions: IL-2 plus HCQ was well tolerated and clinically active with encouraging PFS of 17 months at the 600 mg HCQ dose. NCT01550367Clinical trial information: NCT01550367