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Autophagy. 2014 Aug;10(8):1391-402. doi: 10.4161/auto.29119. Epub 2014 May 20.

Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma.

Author information

1
Department of Medicine and the Abramson Cancer Center; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
2
Department of Radiology Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
3
Center for Biostatistics and Epidemiology; University of Pennsylvania; Philadelphia, PA USA.
4
Department of Pharmacy Practice and Pharmacy Administration; Philadelphia College of Pharmacy; University of the Sciences; Philadelphia, PA USA.
5
Department of Mathematics, Physics, and Statistics; University of the Sciences; Philadelphia, PA USA.
6
Department of Medicine and the Abramson Cancer Center; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA; Department of Pharmacy Practice and Pharmacy Administration; Philadelphia College of Pharmacy; University of the Sciences; Philadelphia, PA USA.

Abstract

The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted.

KEYWORDS:

MTOR; autophagy; clinical trial; hydroxychloroquine; melanoma

PMID:
24991838
PMCID:
PMC4203516
DOI:
10.4161/auto.29119
[Indexed for MEDLINE]
Free PMC Article

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