Key result
Continuous once-daily dosing of ABT-869 was tolerable at doses ≤0.25 mg/kg/d, with dose-limiting toxicities including hypertension and proteinuria at 0.3 mg/kg/d.
Why the study?
What is the safety, tolerability, and maximum-tolerated dose of ABT-869 in patients with refractory solid malignancies?
What is the safety, tolerability, and maximum-tolerated dose of ABT-869 in patients with refractory solid malignancies?
ABT-869 is tolerable at doses up to 0.25 mg/kg/d continuously and shows promising clinical and antiangiogenic biomarker activity in refractory solid malignancies.
Supports ≤0.25 mg/kg/d continuous dosing in refractory solid tumors; leaves open randomized confirmation of net benefit.
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.
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Wong et al. (2009) studied Refractory solid malignancies (n=33). ABT-869 was evaluated on Safety and tolerability (dose-limiting toxicities). Continuous once-daily dosing of ABT-869 was tolerable at doses ≤0.25 mg/kg/d, with dose-limiting toxicities including hypertension and proteinuria at 0.3 mg/kg/d.
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