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

Naomi B. Haas*, Leonard J. Appleman, Mark Stein, Maryann Redlinger, Melissa Wilks, Xiaowei Xu, Angelique Onorati, Anusha Kalavacharla, Taehyong Kim, Chao Jie Zhen, Sabah Kadri, Jeremy P. Segal, Phyllis A. Gimotty, Lisa E. Davis, Ravi K. Amaravadi

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Purpose: Everolimus inhibits the mTOR, activating cyto-protective autophagy. Hydroxychloroquine inhibits autophagy. On the basis of preclinical data demonstrating synergistic cytotoxicity when mTOR inhibitors are combined with an autophagy inhibitor, we launched a clinical trial of combined everolimus and hydroxychloroquine, to determine its safety and activity in patients with clear-cell renal cell carcinoma (ccRCC). Patients and Methods: Three centers conducted a phase I/II trial of everolimus 10 mg daily and hydroxychloroquine in patients with advanced ccRCC. The objectives were to determine the MTD of hydroxychloroquine with daily everolimus, and to estimate the rate of 6-month progression-free survival (PFS) in patients with ccRCC receiving everolimus/hydroxychloroquine 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 dose-limiting toxicity was observed in the phase I trial. The recommended phase II dose of hydroxychloroquine 600 mg twice daily with everolimus was identified. Disease control [stable disease þ partial response (PR)] occurred in 22 of 33 (67%) evaluable patients. PR was observed in 2 of 33 patients (6%). PFS 6 months was achieved in 15 of 33 (45%) of patients who achieved disease control. Conclusions: Combined hydroxychloroquine 600 mg twice daily with 10 mg daily everolimus was tolerable. The primary endpoint of >40% 6-month PFS rate was met. Hydroxychloroquine is a tolerable autophagy inhibitor in future RCC or other trials.

Original languageEnglish (US)
Pages (from-to)2080-2087
Number of pages8
JournalClinical Cancer Research
Volume25
Issue number7
DOIs
StatePublished - Apr 1 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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