title: Exploratory study of carboplatin plus the copper-lowering agent trientine in patients with advanced malignancies.
abstract: OBJECTIVE
  Preclinical data showed that trientine, a copper-lowering agent, re-sensitized cancer cells to carboplatin through enhanced human copper transporter 1 (hCtr1) -mediated platinum uptake.
  
  
  METHODS
  We studied carboplatin and trientine in patients (n = 55; 45 who had failed platinum) with advanced malignancies (Phase I, modified 3 + 3 design).
  
  
  RESULTS
  The most common cancers were head and neck (n = 13), non-small cell lung (n = 10) and epithelial ovarian (n = 8). The median number of prior regimens was four. No dose-limiting toxicity or treatment-related deaths were observed at doses up to carboplatin AUC 6 given with trientine. Eight patients achieved stable disease (SD) ≥ 6 months (six platinum failures) and one patient with platinum-resistant ovarian cancer, partial response (PR) (total SD ≥ 6 months/PR = 9, 16.4 %). The mean nadir serum copper level in the nine patients with SD ≥ 6 months/PR was 0.55 μg/mL (95 % CI, 0.34-0.75) versus 1.22 μg/mL (95 % CI, 1.02-1.42) (p < 0.001) in 38 tested patients with progression. In patients who maintained their ceruloplasmin (major copper-carrying protein) levels at 5-15 mg/dL (n = 9), the median progression-free and overall survivals were 9.2 and 15.2 months versus 1.9 (p = 0.001) and 5.7 months (p = 0.033) in patients who did not (n = 38), respectively.
  
  
  CONCLUSIONS
  The combination of a copper-lowering agent with carboplatin was well tolerated and associated with antitumor activity, especially in patients in whom copper and/or ceruloplasmin levels were lowered. Further investigation of this strategy for reversing platinum resistance is warranted.
authors.affiliation: Department of Investigational Cancer Therapeutics, Unit 0455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA, siqingfu@mdanderson.org.
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.forename: Ming-Mo
authors.initials: MM
authors.lastname: Hou
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wheler
authors.forename: David
authors.initials: D
authors.lastname: Hong
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Apostolia
authors.initials: A
authors.lastname: Tsimberidou
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.forename: Ralph
authors.initials: R
authors.lastname: Zinner
authors.forename: Sarina
authors.initials: S
authors.lastname: Piha-Paul
authors.forename: Gerald
authors.initials: G
authors.lastname: Falchook
authors.forename: Macus Tien
authors.initials: MT
authors.lastname: Kuo
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D016190:Carboplatin / Q000008:administration & dosage* / Q000009:adverse effects; D002570:Ceruloplasmin / Q000378:metabolism; D002614:Chelating Agents / Q000008:administration & dosage* / Q000009:adverse effects; D003300:Copper / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D016896:Treatment Outcome; D014266:Trientine / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D003300:Copper; D016190:Carboplatin; D002570:Ceruloplasmin; D014266:Trientine