Exploratory study of carboplatin plus the copper-lowering agent trientine in patients with advanced malignancies

Purpose: 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. Experimental Design: 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.