title: Combined autophagy and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors.
abstract: We previously reported that inhibition of autophagy significantly augmented the anticancer activity of the histone deacetylase (HDAC) inhibitor vorinostat (VOR) through a cathepsin D-mediated mechanism. We thus conducted a first-in-human study to investigate the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of the combination of the autophagy inhibitor hydroxychloroquine (HCQ) and VOR in patients with advanced solid tumors. Of 27 patients treated in the study, 24 were considered fully evaluable for study assessments and toxicity. Patients were treated orally with escalating doses of HCQ daily (QD) (d 2 to 21 of a 21-d cycle) in combination with 400 mg VOR QD (d one to 21). Treatment-related adverse events (AE) included grade 1 to 2 nausea, diarrhea, fatigue, weight loss, anemia, and elevated creatinine. Grade 3 fatigue and/or myelosuppression were observed in a minority of patients. Fatigue and gastrointestinal AE were dose-limiting toxicities. Six-hundred milligrams HCQ and 400 mg VOR was established as the maximum tolerated dose and recommended phase II regimen. One patient with renal cell carcinoma had a confirmed durable partial response and 2 patients with colorectal cancer had prolonged stable disease. The addition of HCQ did not significantly impact the PK profile of VOR. Treatment-related increases in the expression of CDKN1A and CTSD were more pronounced in tumor biopsies than peripheral blood mononuclear cells. Based on the safety and preliminary efficacy of this combination, additional clinical studies are currently being planned to further investigate autophagy inhibition as a new approach to increase the efficacy of HDAC inhibitors.
authors.affiliation: Cancer Therapy and Research Center at the University of Texas Health Science Center; San Antonio, TX USA.
authors.forename: Devalingam
authors.initials: D
authors.lastname: Mahalingam
authors.affiliation: Cancer Therapy and Research Center at the University of Texas Health Science Center; San Antonio, TX USA; Cedars-Sinai Medical Center; University of California, Los Angeles; Los Angeles CA USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Mita
authors.affiliation: Cancer Therapy and Research Center at the University of Texas Health Science Center; San Antonio, TX USA.
authors.forename: John
authors.initials: J
authors.lastname: Sarantopoulos
authors.affiliation: Cancer Therapy and Research Center at the University of Texas Health Science Center; San Antonio, TX USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Wood
authors.affiliation: Abramson Cancer Center and Department of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Amaravadi
authors.affiliation: University of the Sciences; Philadelphia, PA USA.
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Davis
authors.affiliation: Cancer Therapy and Research Center at the University of Texas Health Science Center; San Antonio, TX USA; Cedars-Sinai Medical Center; University of California, Los Angeles; Los Angeles CA USA.
authors.forename: Alain C
authors.initials: AC
authors.lastname: Mita
authors.affiliation: Cancer Therapy and Research Center at the University of Texas Health Science Center; San Antonio, TX USA.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Curiel
authors.affiliation: Cancer Therapy and Research Center at the University of Texas Health Science Center; San Antonio, TX USA.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Espitia
authors.affiliation: Cancer Therapy and Research Center at the University of Texas Health Science Center; San Antonio, TX USA.
authors.forename: Steffan T
authors.initials: ST
authors.lastname: Nawrocki
authors.affiliation: Cancer Therapy and Research Center at the University of Texas Health Science Center; San Antonio, TX USA; Robert H Lurie Comprehensive Cancer Center; Northwestern University; Chicago, IL USA.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.affiliation: Cancer Therapy and Research Center at the University of Texas Health Science Center; San Antonio, TX USA; Taussig Cancer Institute; Cleveland Clinic; Cleveland, OH USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Carew
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects; D003710:Demography; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D006886:Hydroxychloroquine / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; D006886:Hydroxychloroquine; D000077337:Vorinostat
keywords: autophagy; cancer; clinical trial; hydroxychloroquine; vorinostat