title: A phase I study of high-dose rosuvastatin with standard dose erlotinib in patients with advanced solid malignancies.
abstract: BACKGROUND
  Synergistic cytotoxicity with high-dose statins and erlotinib has been demonstrated in preclinical models across a number of tumour types. In this phase I study, we evaluated the safety and potential anti-tumour activity of escalating doses of rosuvastatin in combination with the standard clinical dose of erlotinib in heavily pretreated patients with advanced solid tumours.
  
  
  METHODS
  This was a single-center, phase I open-label study to determine the safety and recommended phase two dose (RPTD) of rosuvastatin in combination with 150 mg/day standard dose of erlotinib. Using a 3 + 3 study design and 28-day cycle, escalating doses of rosuvastatin from 1 to 8 mg/kg/day × 2 weeks (cycle 1) and 3 weeks (subsequent cycles) given concurrently with erlotinib were evaluated. In order to expand the experience and to gain additional safety and pharmacokinetic data, two expansions cohorts using concurrent or alternating weekly dosing regimens at the RPTD were also evaluated.
  
  
  RESULTS
  All 24 patients enrolled were evaluable for toxicity, and 22 for response. The dose-limiting toxicity (DLT) of reversible muscle toxicity was seen at the 2 mg/kg/day dose level. Maximal tolerated dose (MTD) was determined to be 1 mg/kg/day. Thirty-three percent of patients developed at least 1 ≥ grade 2 muscle toxicity (rhabdomyolysis: 1/24, myalgia: 7/24) resulting in one study-related death. Durable stable disease for more than 170 days was seen in 25 % of patients that received concurrent treatment and were evaluable for response (n = 16). Plasma erlotinib levels on study were unaffected by the addition of rosuvastatin.
  
  
  CONCLUSIONS
  The observed disease stabilization rate of 25 % with combination therapy in this heavily pretreated population is encouraging, however, the high levels of muscle toxicities observed limited this combination strategy.
authors.affiliation: Ottawa Hospital Research Institute, Centre for Cancer Therapeutics, Ottawa, Canada. ggoss@toh.on.ca.|The Ottawa Hospital Cancer Centre, Ottawa, Canada. ggoss@toh.on.ca.|Department of Medicine, University of Ottawa, Ottawa, Canada. ggoss@toh.on.ca.
authors.forename: Glenwood D
authors.identifier: http://orcid.org/0000-0002-5122-9011
authors.initials: GD
authors.lastname: Goss
authors.affiliation: The Ottawa Hospital Cancer Centre, Ottawa, Canada.|Department of Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Jonker
authors.affiliation: The Ottawa Hospital Cancer Centre, Ottawa, Canada.|Department of Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Laurie
authors.affiliation: Ottawa Hospital Research Institute, Centre for Cancer Therapeutics, Ottawa, Canada.|Division of Gynecologic Oncology, The Ottawa Hospital, Ottawa, Canada.
authors.forename: Johanne I
authors.initials: JI
authors.lastname: Weberpals
authors.affiliation: University Health Network, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Canada.
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
authors.affiliation: Ottawa Hospital Research Institute, Centre for Cancer Therapeutics, Ottawa, Canada.
authors.forename: Johanna N
authors.initials: JN
authors.lastname: Spaans
authors.affiliation: Ottawa Hospital Research Institute, Centre for Cancer Therapeutics, Ottawa, Canada.
authors.forename: Charles
authors.initials: C
authors.lastname: la Porte
authors.affiliation: Ottawa Hospital Research Institute, Centre for Cancer Therapeutics, Ottawa, Canada. jdimitroulakos@ohri.ca.|The Ottawa Hospital Cancer Centre, Ottawa, Canada. jdimitroulakos@ohri.ca.|Faculty of Medicine and the Department of Biochemistry, University of Ottawa, Ottawa, Canada. jdimitroulakos@ohri.ca.
authors.forename: Jim
authors.initials: J
authors.lastname: Dimitroulakos
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D000069347:Erlotinib Hydrochloride / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D000068718:Rosuvastatin Calcium / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000068718:Rosuvastatin Calcium; D000069347:Erlotinib Hydrochloride
keywords: Epidermal growth factor receptor; Erlotinib; Pharmacokinetics; Statins; Therapeutics