Phase 1 clinical and pharmacokinetics evaluation of oral CI-1033 in patients with refractory cancer.
OBJECTIVE
To determine the tolerability and pharmacokinetics of oral CI-1033, a pan-erbB tyrosine kinase inhibitor, administered over 14 consecutive days of a 21-day cycle.


METHODS
Phase 1, multicenter trial involving patients with solid tumors that are refractory to standard therapy. CI-1033 was administered initially at 300 mg/day to a minimum cohort of three patients. Dose escalation proceeded at </=40% increments. Patients were evaluated for toxicity, pharmacokinetic profile, and evidence of response.


RESULTS
Thirty-two patients entered the trial and were evaluable for safety assessment. Dose-limiting toxicity (diarrhea, rash, and/or anorexia) occurred at the 560 mg dose level; the maximum tolerated dose was 450 mg. No patients achieved objective responses and six patients achieved stable disease. Plasma CI-1033 concentrations increased with increasing dose. CI-1033 was not eliminated in urine to any appreciable extent.


CONCLUSIONS
CI-1033 is suitable for phase 2 testing at the 450 mg/day dose level when administered for 14 days in a 21-day cycle. The pharmacokinetic profile is consistent with biologically relevant plasma concentrations over the dosing interval.
Nemunaitis
John
J
Mary Crowley Medical Research Center/Texas Oncology PA, Dallas, Texas, USA. jnemunaitis@mcmrc.com
Eiseman
Irene
I
Cunningham
Casey
C
Senzer
Neil
N
Williams
Adrienne
A
Lenehan
Peter F
PF
Olson
Stephen C
SC
Bycott
Paul
P
Schlicht
Michael
M
Zentgraff
Rebecca
R
Shin
Dong M
DM
Zinner
Ralph G
RG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000855:Anorexia / Q000139:chemically induced; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009025:Morpholines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors
D009025:Morpholines; C420268:Canertinib; D011505:Protein-Tyrosine Kinases