title: A phase I study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer.
abstract: BACKGROUND
  This investigator-initiated study explores the safety, maximum tolerated dose, clinical response, and pharmacokinetics of hydroxychloroquine (HCQ) with and without erlotinib in patients with advanced non-small-cell lung cancer.
  
  
  METHODS
  Patients with prior clinical benefit from an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor were randomized to HCQ or HCQ plus erlotinib in a 3 + 3 dose-escalation schema.
  
  
  RESULTS
  Twenty-seven patients were treated, eight with HCQ (arm A) and 19 with HCQ plus erlotinib (arm B). EGFR mutations were detected in 74% of the patients and 85% had received two or more prior therapies. Arm A had no dose-limiting toxicities, but the maximum tolerated dose was not reached as this arm closed early to increase overall study accrual. In arm B, one patient each experienced grade 3 rash, nail changes, skin changes, nausea, dehydration, and neutropenia; one had grade 4 anemia; and one developed fatal pneumonitis, all considered unrelated to HCQ. There were no dose-limiting toxicities, therefore the highest tested dose for HCQ with erlotinib 150 mg was 1000 mg daily. One patient had a partial response to erlotinib/HCQ, for an overall response rate of 5% (95% confidence interval, 1-25). This patient had an EGFR mutation and remained on therapy for 20 months. Administration of HCQ did not alter the pharmacokinetics of erlotinib.
  
  
  CONCLUSIONS
  HCQ with or without erlotinib was safe and well tolerated. The recommended phase 2 dose of HCQ was 1000 mg when given in combination with erlotinib 150 mg.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA, USA.
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Goldberg
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
authors.forename: Joel W
authors.initials: JW
authors.lastname: Neal
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.forename: Subba
authors.initials: S
authors.lastname: Digumarthy
authors.forename: Panos
authors.initials: P
authors.lastname: Fidias
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Temel
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Heist
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
authors.forename: Patricia O
authors.initials: PO
authors.lastname: McCarthy
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lynch
authors.forename: Sreenath
authors.initials: S
authors.lastname: Sharma
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Settleman
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D000068338:Everolimus; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006886:Hydroxychloroquine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D011379:Prognosis; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution
chemical_list: D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D006886:Hydroxychloroquine; D000068338:Everolimus; C512478:EGFR protein, human; D066246:ErbB Receptors; D020123:Sirolimus