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|Ref Type||Journal Article|
|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|
|Title||Autophagy Inhibition to Augment mTOR Inhibition: a Phase I/II Trial of Everolimus and Hydroxychloroquine in Patients with Previously Treated Renal Cell Carcinoma.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2019 Apr 01|
|Abstract Text||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).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.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.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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|KDR||T771M||missense||unknown||KDR (VEGFR2) T771M lies within the transmembrane domain of the Kdr (Vegfr2) protein (UniProt.org). T771M has been identified in sequencing studies (PMID: 30239046, PMID: 30635337), but has not been biochemically characterized and therefore, its effect on Kdr (Vegfr2) protein function is unknown (PubMed, Jan 2021).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||clear cell renal cell carcinoma||not applicable||Everolimus + Hydroxychloroquine||Phase Ib/II||Actionable||In a Phase I/II trial, treatment with the combination of Afinitor (everolimus) and Plaquenil (hydroxychloroquine) was well-tolerated, and resulted in a median progression-free survival (PFS) of 6.3 months, PFS of 6 months or greater in 45% (15/33), and partial response (PR) or stable disease (SD) greater than 3 months in 66% (22/33; 2 PR and 20 SD) of clear cell renal cell carcinoma patients (PMID: 30635337).||30635337|