TY - JOUR
T1 - Exploratory study of carboplatin plus the copper-lowering agent trientine in patients with advanced malignancies
AU - Fu, Siqing
AU - Hou, Ming Mo
AU - Wheler, Jennifer
AU - Hong, David
AU - Naing, Aung
AU - Tsimberidou, Apostolia
AU - Janku, Filip
AU - Zinner, Ralph
AU - Piha-Paul, Sarina
AU - Falchook, Gerald
AU - Kuo, MacUs Tien
AU - Kurzrock, Razelle
PY - 2014/6
Y1 - 2014/6
N2 - 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.
AB - 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.
KW - Carboplatin
KW - Ceruloplasmin
KW - Copper
KW - Platinum resistance
KW - Trientine
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U2 - 10.1007/s10637-013-0051-8
DO - 10.1007/s10637-013-0051-8
M3 - Article
C2 - 24306314
AN - SCOPUS:84904646532
SN - 0167-6997
VL - 32
SP - 465
EP - 472
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 3
ER -