Autophagy inhibition to augment mTOR inhibition: A phase I/II trial of everolimus and hydroxychloroquine in patients with previously treated renal cell carcinoma.

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Autophagy inhibition to augment mTOR inhibition: A phase I/II trial of everolimus and hydroxychloroquine in patients with previously treated renal cell carcinoma.

Clin Cancer Res. 2019 Jan 11;:

Authors: Haas NB, Appleman LJ, Stein M, Redlinger M, Wilks M, Xu X, Onorati A, Kalavacharla A, Kim T, Zhen CJ, Kadri S, Segal JP, Gimotty PA, Davis LE, Amaravadi RK

Abstract
Purpose Everolimus inhibits the mechanistic target of rapamycin (mTOR), activating cytoprotective autophagy. Hydroxychloroquine (HCQ) inhibits autophagy. Based on preclinical data demonstrating synergistic cytotoxicity when mTOR inhibitors are combined with an autophagy inhibitor, we launched a clinical trial of combined everolimus and HCQ, to determine its safety and activity in patients with clear cell renal carcinoma (ccRCC). Experimental Design Three centers conducted a phase I/II trial of everolimus 10 mg daily and HCQ in patients with advanced ccRCC. The objectives were to determine the maximum tolerated dose of HCQ with daily everolimus, and to estimate the rate of 6 month progression-free survival (PFS) in ccRCC patients receiving everolimus/HCQ after 1-3 prior treatment regimens. Correlative studies to identify patient subpopulations that achieved the most benefit included population pharmacokinetics, measurement of autophagosomes by electron microscopy and next generation tumor sequencing. Results No DLT was observed in the phase I trial. The recommended phase II dose of HCQ 600 mg bid with everolimus was identified. Disease control (Stable disease (SD) + partial response (PR)) occurred in 22/33 (67%) evaluable patients. Partial response was observed in 2/33 patients (6%). PFS ≥6 months was achieved in 15/33 (45%) of patients who achieved disease control. Conclusion Combined HCQ 600mg twice daily with 10 mg daily everolimus was tolerable. The primary endpoint of >40% 6 month PFS rate was met. HCQ is a tolerable autophagy inhibitor in future RCC or other trials.

PMID: 30635337 [PubMed - as supplied by publisher]

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