TY - JOUR
T1 - Autophagy inhibition to augment mTOR inhibition
T2 - A phase I/II trial of everolimus and hydroxychloroquine in patients with previously treated renal cell carcinoma
AU - Haas, Naomi B.
AU - Appleman, Leonard J.
AU - Stein, Mark
AU - Redlinger, Maryann
AU - Wilks, Melissa
AU - Xu, Xiaowei
AU - Onorati, Angelique
AU - Kalavacharla, Anusha
AU - Kim, Taehyong
AU - Zhen, Chao Jie
AU - Kadri, Sabah
AU - Segal, Jeremy P.
AU - Gimotty, Phyllis A.
AU - Davis, Lisa E.
AU - Amaravadi, Ravi K.
N1 - Funding Information:
N.B. Haas is a consultant/advisory board member for Merck and Exelixis. M. Stein reports receiving commercial research grants from Bristol-Myers Squibb, Merck Sharp & Dohme, Genocea Biosciences, Lilly, Nektar, Seattle Genetics, Harpoon, Advaxis, Janssen Oncology, Oncoceutics, and Mediva-tion/Astellas and is a consultant/advisory board member for Merck Sharp & Dohme and Exelixis. J.P. Segal reports receiving commercial research grants from Abbvie. R.K. Amaravadi reports receiving other commercial research support from Novartis, holds ownership interest (including patents) in Immunaccel and Pinpoint Therapeutics, and is a consultant/advisory board member for Sprint Biosciences. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
This work was supported by investigator-initiated study funded by Novartis.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-18-2204
DO - 10.1158/1078-0432.CCR-18-2204
M3 - Article
C2 - 30635337
AN - SCOPUS:85062225370
SN - 1078-0432
VL - 25
SP - 2080
EP - 2087
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -