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Updated: Jun 20, 2026
A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells
Published on: November 12, 2019
Phase I and biomarker study of ABT-869, a multiple receptor tyrosine kinase inhibitor, in patients with refractory
Chiung-Ing Wong1, Tong-San Koh, Ross Soo
1Department of Hematology-Oncology, National University Hospital, National University of Singapore, Singapore 119074.
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
Insights
ABT-869 demonstrated antiangiogenic activity in patients with solid tumors. The drug was tolerable at doses up to 0.25 mg/kg/d, showing promising clinical activity and reduced tumor vascular permeability.
Area of Science:
- Oncology
- Pharmacology
- Biomarkers
Background:
- Solid tumors pose a significant therapeutic challenge.
- Antiangiogenic therapies aim to inhibit tumor growth by targeting new blood vessel formation.
- Understanding drug safety and efficacy is crucial for advancing cancer treatment.
Purpose of the Study:
- To evaluate the safety and tolerability of ABT-869 in patients with solid malignancies.
- To assess the antiangiogenic effects of ABT-869 through biomarker analysis.
- To determine the maximum-tolerated dose (MTD) of ABT-869.
Main Methods:
- A phase I clinical trial involving escalating doses of oral ABT-869.
- Patients with refractory solid tumors received continuous daily dosing.
- Safety, tolerability, pharmacokinetic, and pharmacodynamic assessments were performed.
Main Results:
- Thirty-three patients were treated at doses up to 0.3 mg/kg/d. The MTD was determined to be 0.3 mg/kg/d due to dose-limiting toxicities.
- Significant adverse events included fatigue, proteinuria, and hypertension.
- Pharmacokinetics showed linear clearance and no accumulation.
- Tumor vascular permeability decreased dose-dependently (DCE-MRI).
- Biomarkers indicated antiangiogenic activity: reduced circulating endothelial cells and increased VEGF.
Conclusions:
- ABT-869 was tolerable at doses up to 0.25 mg/kg/d with continuous daily dosing.
- Evidence of antiangiogenic activity was observed through biomarkers and DCE-MRI.
- Promising clinical activity, including partial responses and stable disease, was noted.
