Phase I study of copper-binding agent ATN-224 in patients with advanced solid tumors.
OBJECTIVE
Copper chelation reduces the secretion of many angiogenic factors and reduces tumor growth and microvascular density in animal models. ATN-224 is a second-generation analogue of ammonium tetrathiomolybdate. The aim of our phase I study was to reduce serum copper levels, as measured by ceruloplasmin, to 5 to 15 mg/dL (normal 16-60) in 14 to 21 days, to determine the pharmacokinetic profile of ATN-224 and to evaluate dose-limiting toxicities.


METHODS
Cohorts of patients were treated with escalating oral doses of ATN-224 until copper depletion followed by a titrated maintenance dose.


RESULTS
Eighteen patients received 78 cycles of ATN-224. Mean baseline ceruloplasmin was 39.6 mg/dL. The maximum administered dose was 330 mg/d where grade 3 fatigue was dose-limiting. At the maximum tolerated dose of 300 mg/d, the median time to achieve target ceruloplasmin was 21 days, and toxicities included grade 3 anemia, grade 3 neutropenia, fatigue, and sulfur eructation. ATN-224 treatment caused a significant reduction (> 90%) in RBC superoxide dismutase 1 activity and circulating endothelial cells. Pharmacokinetic data indicate greater absorption of ATN-224 and more rapid ceruloplasmin reduction when administered with a proton pump inhibitor. Stable disease of > 6 months was observed in 2 patients.


CONCLUSIONS
Oral ATN-224 is a well-tolerated therapy and at a loading dose of 300 mg/d leads to a reduction of serum ceruloplasmin levels in 80% patients within 21 days. A loading dose of 300 mg/d for 2 weeks followed by a titrated maintenance dose will be the recommended starting dose for phase II study.
Lowndes
Sarah A
SA
Cancer Research UK Department of Medical Oncology, Churchill Hospital, Oxford, United Kingdom.
Adams
Avril
A
Timms
Anthony
A
Fisher
Nita
N
Smythe
Jon
J
Watt
Suzanne M
SM
Joel
Simon
S
Donate
Fernando
F
Hayward
Carolyn
C
Reich
Steven
S
Middleton
Mark
M
Mazar
Andrew
A
Harris
Adrian L
AL
D000328:Adult; D000368:Aged; D002570:Ceruloplasmin / Q000187:drug effects; D002614:Chelating Agents / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015913:Chelation Therapy; D002794:Choline / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003300:Copper / Q000097:blood*; D016207:Cytokines / Q000097:blood / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008982:Molybdenum / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy*; D013482:Superoxide Dismutase / Q000097:blood / Q000187:drug effects
D002614:Chelating Agents; D016207:Cytokines; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; D013482:Superoxide Dismutase; D002570:Ceruloplasmin; D002794:Choline