Background:
Epithelial ovarian cancer (EOC) is the leading cause of gynecological
cancer-related deaths worldwide. Preclinical studies found that
copper-lowering agents could re-sensitize
platinum-resistant
cancer cells by enhancing the human
copper transporter 1 (hCtr1)-mediated uptake of
platinum. In the clinic, re-sensitization of
platinum-resistance in relapsed EOC has been discovered by the application of
trientine plus
platinum (NCT01178112). However, no pharmacokinetic data of
trientine has been reported in
cancer patients. Purpose: Our study aimed to explore the safety and activity of
trientine combined with
carboplatin and
pegylated liposomal doxorubicin (
PLD) in patients with EOC, tubal, and peritoneal
cancer who experienced
disease progression during
platinum-based
chemotherapy or showed relapse <12 months after completing first-line
chemotherapy. Also, we aimed to demonstrate pharmacokinetic parameters and to discover potential
biomarkers in our EOC patients. Methods: In this dose escalation study, 18 Asian patients in six dosing cohorts received fixed doses of
carboplatin (AUC 4) and
PLD (LipoDox®, TTY Biopharm Co. Ltd., Taipei, Taiwan) (40 mg/m2, day 1 per 4-week cycle), and escalated daily
trientine doses (range: 300-1800 mg; initiated 7 days before the 1st combination cycle) according to a 3 + 3 design. Results: No dose-limiting toxicity or treatment-related death was observed. Four patients (22.2%) developed grade 3
drug-related adverse events (AEs), whereas no grade 4 AEs were encountered.
Anemia and grade 2
dizziness were the most common hematological toxicity and neurotoxicity, respectively. In a pharmacokinetics comparison with healthy volunteers in the literature, our patients achieved greater absorption after oral trientinem, and more rapid elimination of
triethylenetetramine dihydrochloride at high doses. The clinical benefit rate was 33.3 and 50.0% in the
platinum-resistant and the partially
platinum-sensitive group, respectively. A high baseline serum
iron level and low serum
copper level might help differentiate subgroups of patients with different clinical responses. Nevertheless, no associations of the clinical response with the levels of serum hCtr1,
ceruloplasmin, or
copper were observed. Conclusion: Combination
therapy with
carboplatin,
trientine, and
PLD was well-tolerated and safe. Our results encourage the development of a future phase II trial. Clinical trial registration: ClinicalTrials.gov # NCT03480750.