Phase I and biomarker study of ABT-869, a multiple receptor tyrosine kinase inhibitor, in patients with refractory solid malignancies.
OBJECTIVE
To determine the safety and tolerability of ABT-869 at escalating doses and its effects on biomarkers relevant for antiangiogenic activity in patients with solid malignancies.


METHODS
Patients with solid malignancies refractory to or for which no standard effective therapy exists were enrolled onto escalating-dose cohorts and treated with oral ABT-869 once daily continuously.


RESULTS
Thirty-three patients were studied at doses of 10 mg/d, 0.1 mg/kg/d, 0.25 mg/kg/d, and 0.3 mg/kg/d. Dose-limiting toxicities in the first cycle (21 days) included grade 3 fatigue in a patient at 10 mg/d, grade 3 proteinuria and grade 3 hypertension in two separate patients at 0.25 mg/kg/d, and grade 3 hypertension and grade 3 proteinuria in two separate patients at 0.3 mg/kg/d, which was the maximum-tolerated dose. Other significant treatment-related adverse events included asthenia, hand and foot blisters, and myalgia. Oral clearance of ABT-869 was linear, with a mean of 2.7 +/- 1.2 L/h and half-life of 18.4 +/- 5.7 hours, with no evidence of drug accumulation at day 15. Two patients with lung cancer and one patient with colon cancer achieved partial response. Stable disease for more than four cycles was observed in 16 patients (48%). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) showed dose-dependent reduced tumor vascular permeability that correlated with drug exposure. By day 15 of treatment, circulating endothelial cells were significantly reduced (P = .007), whereas plasma vascular endothelial growth factor was increased (P = .004).


CONCLUSIONS
ABT-869 by continuous once-daily dosing was tolerable at doses </= 0.25 mg/kg/d. Biomarker evidence of antiangiogenic activity and DCE-MRI evidence of tumor antiangiogenesis were observed together with promising clinical activity.
Wong
Chiung-Ing
CI
Department of Hematology-Oncology, National University Hospital, National University of Singapore, Singapore 119074.
Koh
Tong-San
TS
Soo
Ross
R
Hartono
Septian
S
Thng
Choon-Hua
CH
McKeegan
Evelyn
E
Yong
Wei-Peng
WP
Chen
Chien-Shing
CS
Lee
Soo-Chin
SC
Wong
John
J
Lim
Robert
R
Sukri
Norita
N
Lim
Siew-Eng
SE
Ong
Ai-Bee
AB
Steinberg
Joyce
J
Gupta
Neeraj
N
Pradhan
Rajendra
R
Humerickhouse
Rod
R
Goh
Boon-Cher
BC
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D007191:Indazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D014408:Biomarkers, Tumor; D007191:Indazoles; D010671:Phenylurea Compounds; D042461:Vascular Endothelial Growth Factor A; C513486:linifanib; D020794:Receptor Protein-Tyrosine Kinases