Autophagy Inhibition to Augment mTOR Inhibition: a Phase I/II Trial of Everolimus and Hydroxychloroquine in Patients with Previously Treated Renal Cell Carcinoma
| Autor: | Leonard Joseph Appleman, Angelique Onorati, Naomi B. Haas, Sabah Kadri, Phyllis A. Gimotty, Ravi K. Amaravadi, Taehyong Kim, Chao Jie Zhen, Xiaowei Xu, Mark N. Stein, Melissa Wilks, Jeremy P. Segal, Maryann Redlinger, Anusha Kalavacharla, Lisa E. Davis |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine Oncology Cancer Research medicine.medical_specialty Article 03 medical and health sciences 0302 clinical medicine Renal cell carcinoma Internal medicine Antineoplastic Combined Chemotherapy Protocols Autophagy Clinical endpoint Carcinoma Humans Medicine Everolimus Carcinoma Renal Cell Survival analysis Aged Aged 80 and over business.industry TOR Serine-Threonine Kinases Hydroxychloroquine Middle Aged Prognosis medicine.disease Survival Analysis Kidney Neoplasms Clinical trial Treatment Outcome 030104 developmental biology 030220 oncology & carcinogenesis Retreatment Toxicity Female business medicine.drug |
| Zdroj: | Clin Cancer Res |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-18-2204 |
| Popis: | Purpose: Everolimus inhibits the mTOR, activating cytoprotective 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 + 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. |
| Databáze: | OpenAIRE |
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