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Updated: Aug 16, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Dose-finding study of the multitargeted tyrosine kinase inhibitor SU6668 in patients with advanced malignancies
Bart C Kuenen1, Giuseppe Giaccone, Rita Ruijter
1Department of Medical Oncology, VU Medical Center, Amsterdam, Netherlands.
Purpose:
SU6668 is a tyrosine kinase inhibitor which targets platelet-derived growth factor receptor-beta, fibroblast growth factor receptor-1, vascular endothelial growth factor receptor-2, and KIT. We did a phase I study to define the maximum tolerated dose and to assess the pharmacokinetics of SU6668 administered orally thrice daily with food.
Patients And Methods:
Patients with histologically proven, advanced, and progressive solid tumors were included at a starting dose level of 400 mg/m2 thrice daily. The early onset of dose-limiting toxicities (DLT) required dose reductions to 100 and 200 mg/m2 thrice daily. Pharmacokinetics was done on days 1, 28, and 56.
Results:
Sixteen patients were included. Two of the first three patients developed DLTs, which consisted of grade 4 fatigue and grade 3 serositis-like pains. Six patients at dose level 100 mg/m2 thrice daily experienced no DLT. At dose level 200 mg/m2 thrice daily, two out of seven patients experienced DLTs consisting of grade 3 abdominal pain, grade 4 anorexia and grade 3 nausea/vomiting. Increasing doses resulted in a disproportional increase in area under the curve and C(max) (peak plasma concentration). Both variables, however, decreased significantly on days 28 and 56 compared with day 1 (P < 0.05). No objective responses were observed. Acute phase response, probably mediated by interleukin-6, was observed in serial blood samples.
Conclusions:
The maximum tolerated dose of SU6668 given orally, thrice daily under fed conditions, is 100 mg/m2. Because of the low plasma levels reached at this dose level, the efficacy of SU6668 as a single agent is not to be expected.
Insights
The maximum tolerated dose for oral SU6668 is 100 mg/m2 thrice daily. Low plasma levels at this dose suggest limited efficacy as a single agent for advanced solid tumors.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- SU6668 is a tyrosine kinase inhibitor targeting key growth factor receptors (PDGFR-β, FGFR-1, VEGFR-2, KIT).
- Targeting these receptors is a strategy in cancer therapy to inhibit tumor growth and angiogenesis.
Purpose of the Study:
- To determine the maximum tolerated dose (MTD) of orally administered SU6668.
- To evaluate the pharmacokinetics of SU6668 in patients with advanced solid tumors.
Main Methods:
- Phase I clinical trial enrolling patients with advanced solid tumors.
- Oral administration of SU6668 thrice daily with food, starting at 400 mg/m2.
- Dose escalation and reduction based on dose-limiting toxicities (DLTs); pharmacokinetic assessments on days 1, 28, and 56.
Main Results:
- The MTD was established at 100 mg/m2 thrice daily, with no DLTs observed at this dose.
- DLTs including fatigue and serositis-like pain occurred at higher doses.
- Pharmacokinetics showed dose-proportional increases in AUC and Cmax, but levels decreased over time; no objective responses were seen.
Conclusions:
- The MTD for oral SU6668 is 100 mg/m2 thrice daily under fed conditions.
- The observed low plasma levels at the MTD suggest limited potential for SU6668 as a single-agent therapy.
- Further investigation may be needed to explore SU6668 in combination regimens or different dosing schedules.
