A phase I study of the metal ionophore clioquinol in patients with advanced hematologic malignancies.
Clioquinol is a small-molecule metal ionophore that inhibits the proteasome through a metal-dependent mechanism. Here, we report a phase I study of clioquinol in patients with refractory hematologic malignancies. Neuropathy and abdominal pain were dose-limiting toxicities. Minimal pharmacodynamic effects were observed, and there were no clinical responses.


BACKGROUND
Clioquinol is a small-molecule metal ionophore that inhibits the enzymatic activity of the proteasome and displays preclinical efficacy in hematologic malignancies in vitro and in vivo. Therefore, we conducted a phase I clinical trial of clioquinol in patients with refractory hematologic malignancies to assess its safety and determine its biological activity in this patient population.


METHODS
Patients with refractory hematologic malignancies were treated with increasing doses of oral clioquinol twice daily for 15 doses. Plasma and intracellular levels of clioquinol were measured. Enzymatic activity of the proteasome was measured before and after drug administration.


RESULTS
Sixteen cycles of clioquinol were administered to 11 patients with 5 patients reenrolled at the next dose level as per the permitted intrapatient dose escalation. Dose-limiting neurotoxicity and abdominal pain were observed at a dose of 1600 mg twice daily. Intracellular drug levels were low. Minimal inhibition of the proteasome was observed. No clinical responses were observed.


CONCLUSIONS
In patients with refractory hematologic malignancies, the maximal tolerated dose of clioquinol was determined. Minimal inhibition of the proteasome was observed at tolerable doses, likely due to low intracellular levels of the drug.
Princess Margaret Hospital, Ontario Cancer Institute, Toronto, Ontario, Canada. aaron.schimmer@utoronto.ca
Aaron D
AD
Schimmer
Yulia
Y
Jitkova
Marcela
M
Gronda
Zezhou
Z
Wang
Joseph
J
Brandwein
Christine
C
Chen
Vikas
V
Gupta
Andre
A
Schuh
Karen
K
Yee
Jian
J
Chen
Suzanne
S
Ackloo
Tristan
T
Booth
Sharon
S
Keays
Mark D
MD
Minden
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D007464:Clioquinol / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D019337:Hematologic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007476:Ionophores / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
D007476:Ionophores; D007464:Clioquinol; D046988:Proteasome Endopeptidase Complex