A phase 1 trial of XK469: toxicity profile of a selective topoisomerase IIbeta inhibitor.
OBJECTIVE
XK469, a member of the quinoxaline family of antitumor agents, is believed to be unique in its ability to selectively target topoisomerase IIbeta. Based on encouraging pre-clinical data, a phase I trial was conducted to determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD).


METHODS
A 2B accelerated titration schema was employed. XK469 was administered as a 5 or 20 min IV infusion on days 1-5 every 21 days. The starting dose was 9 mg/m(2). Pharmacokinetics (PK) were conducted in cycles 1-3.


RESULTS
22 patients (21 evaluable, mean age: 56 years, median performance status: 1) were enrolled. At dose level 11 (260 mg/m(2)/daily X 5), 1/6 patients experienced a DLT of grade 4 neutropenia. At 346 mg/m(2)/daily X 5, 2/2 patients experienced DLT's with one episode of febrile neutropenia and one grade 3 infection. The MTD was identified as 260 mg/m(2)/day. XK469 peak plasma levels and systemic exposure were proportional to dose indicating linear pharmacokinetics. However, secondary peaks in the PK profiles and a rapid decline in drug level from 23 to 24 h occurred in some patients. Drug infusion in the afternoon followed by dense sampling of levels during the elimination phase supported the hypothesis that the drug was being sequestered. No anti-tumor activity was identified.


CONCLUSIONS
Traditional PK sampling designs were inadequate to describe XK469 disposition. XK469 and related structures work through a unique mechanism of action. A further understanding of the specific mechanism of these compounds might uncover a unique avenue for future drug development.
Alousi
Amin M
AM
Karmanos Cancer Institute, Wayne State University School of Medicine, 4th Floor HWCRC, 4100 John R, Detroit, MI 48201, USA.
Boinpally
Ramesh
R
Wiegand
Richard
R
Parchment
Ralph
R
Gadgeel
Shirish
S
Heilbrun
Lance K
LK
Wozniak
Antionette J
AJ
DeLuca
Pamela
P
LoRusso
Patricia M
PM
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003131:Combined Modality Therapy; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D011485:Protein Binding; D011810:Quinoxalines / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D059005:Topoisomerase II Inhibitors; D016896:Treatment Outcome
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D011810:Quinoxalines; D059005:Topoisomerase II Inhibitors; C118180:XK 469; D004250:DNA Topoisomerases, Type II