title: Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma.
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.
authors.affiliation: Department of Medicine and the Abramson Cancer Center; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Reshma
authors.initials: R
authors.lastname: Rangwala
authors.affiliation: Department of Medicine and the Abramson Cancer Center; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Yunyoung C
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Department of Medicine and the Abramson Cancer Center; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Medicine and the Abramson Cancer Center; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Algazy
authors.affiliation: Department of Medicine and the Abramson Cancer Center; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Evans
authors.affiliation: Department of Medicine and the Abramson Cancer Center; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Fecher
authors.affiliation: Department of Medicine and the Abramson Cancer Center; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Schuchter
authors.affiliation: Department of Radiology Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Drew A
authors.initials: DA
authors.lastname: Torigian
authors.affiliation: Department of Radiology Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Panosian
authors.affiliation: Center for Biostatistics and Epidemiology; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Troxel
authors.affiliation: Center for Biostatistics and Epidemiology; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Kay-See
authors.initials: KS
authors.lastname: Tan
authors.affiliation: Center for Biostatistics and Epidemiology; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Heitjan
authors.affiliation: Department of Medicine and the Abramson Cancer Center; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: DeMichele
authors.affiliation: Department of Medicine and the Abramson Cancer Center; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Vaughn
authors.affiliation: Department of Medicine and the Abramson Cancer Center; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Maryann
authors.initials: M
authors.lastname: Redlinger
authors.affiliation: Department of Radiology Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Abass
authors.initials: A
authors.lastname: Alavi
authors.affiliation: Department of Pharmacy Practice and Pharmacy Administration; Philadelphia College of Pharmacy; University of the Sciences; Philadelphia, PA USA.
authors.forename: Jonathon
authors.initials: J
authors.lastname: Kaiser
authors.affiliation: Department of Mathematics, Physics, and Statistics; University of the Sciences; Philadelphia, PA USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Pontiggia
authors.affiliation: 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.
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Davis
authors.affiliation: Department of Medicine and the Abramson Cancer Center; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
authors.affiliation: Department of Medicine and the Abramson Cancer Center; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Amaravadi
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D006886:Hydroxychloroquine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D014617:Vacuoles / Q000187:drug effects / Q000648:ultrastructure
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D019788:Fluorodeoxyglucose F18; D006886:Hydroxychloroquine; C401859:temsirolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: MTOR; autophagy; clinical trial; hydroxychloroquine; melanoma