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

Abstract

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.

• Authors: Siqing Fu, Ming-Mo Hou, Jennifer Wheler, David Hong, Aung Naing, Apostolia Tsimberidou, Filip Janku, Ralph Zinner, Sarina Piha-Paul, Gerald Falchook, Macus Tien Kuo, Razelle Kurzrock
• Journal: Investigational new drugs (Invest New Drugs) Vol. 32 Issue 3 Pg. 465-72 (Jun 2014) ISSN: 1573-0646 [Electronic] United States
• PMID: 24306314 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• Antineoplastic Agents
• Chelating Agents
• Copper
• Carboplatin
• Ceruloplasmin
• Trientine

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects)
• Carboplatin (administration & dosage, adverse effects)
• Ceruloplasmin (metabolism)
• Chelating Agents (administration & dosage, adverse effects)
• Copper (blood)
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (blood, drug therapy)
• Treatment Outcome
• Trientine (administration & dosage, adverse effects)