Originally published as JCO Early Release 10.1200/JCO.2008.21.7125 on August 31 2009

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Phase I and Biomarker Study of ABT-869, a Multiple Receptor Tyrosine Kinase Inhibitor, in Patients With Refractory Solid Malignancies

From the Department of Hematology-Oncology, National University Health System, National University of Singapore; Cancer Science Institute of Singapore; Nanyang Technological University; National Cancer Center, Singapore; and Abbott Laboratories, Abbott Park, IL.

Corresponding author: Boon-Cher Goh, MD, Department of Hematology-Oncology, National University Hospital, 5 Lower Kent Ridge Rd, Singapore 119074; e-mail: Boon_Cher_Goh{at}nuh.com.sg.

Purpose 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.

Patients and 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).

Conclusion 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.

Supported in part by Grants No. BMRC 01/1/26/18/060, SCS-PN0022, and SCS-CN0079 from the Biomedical Research Council of Singapore.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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