A number of studies of SU5416 utilized in adults, either alone or in combination with traditional therapy, have been published [16
]. We here report the results of the first pediatric phase I study of a small molecule inhibitor of VEGF in patients with central nervous system tumors. Due to the known pathways involved in the metabolism of this compound, patients were stratified by the presence or absence of the use of enzyme inducing anticonvulsant drugs (EIACDs).
Dose-limiting toxicities were observed at 145mg/m2/dose in stratum I, consisting predominantly of grade 3 transaminase elevations, in addition to a single grade 3 episode of hallucinations. These toxicities may have been related to cremophor rather than SU5416. The starting dose of 110mg/m2/dose was based on initiating pediatric clinic trials at 80% of the adult MTD, which has been identified at 145mg/m2/dose.
The pharmacokinetics of SU5416 in adult cancer patients has been characterized in several phase I clinical trials [17
]. These studies have shown that SU5416 is rapidly eliminated from plasma and that pharmacokinetic parameters determined for the first infusion of drug appear to be independent of the administered dose. At doses ranging from 20 to 145 mg/m2
, mean values of the apparent terminal phase half-life ranged from 0.58 to 0.87 h and the total body clearance ranged from 25.8 to 44.8 liter/h/m2
in the studies that have been reported. The clearance of SU5416 increased by more than 50% upon repeated administration when the interval between successive doses was less than 7 days [20
]. Hepatic metabolism by cytochrome P450 (CYP) enzymes is an important route of elimination for SU5416, with CYP3A4 being the major isozyme catalyzing the initial oxidation of the compound [33
]. The increased clearance observed with daily and twice weekly dosing results from the induction of CYP3A4 and may be due to either the SU5416 itself or the co-administration of dexamethasone used to prevent hypersensitivity reactions [20
The pharmacokinetic behavior of SU5416 has not been previously studied in children or patients with CNS malignancies. The total body clearance for the initial dose of SU5416 in pediatric cancer patients who were not receiving EIACDs, 26.1 ± 12.5 liter/h/m2
, was within the range of reported values for adults. Similarly, as observed in the clinical studies of the drug in adult patients, repeated administration at a dosing interval of 7 days did not result in any significant changes in the pharmacokinetics of SU5416. Moreover, there was no evidence to suggest that the pharmacokinetics of SU5416 was affected by the concomitant use of EIACDs. The absence of a clinically significant pharmacokinetic interaction between these anticonvulsants and SU5416 is indeed surprising in consideration of the presumably prominent role of CYP3A4 in the elimination of SU5416, as evidenced by the autoinduction of its clearance upon frequent repeated administration. Increased systemic clearance of other chemotherapeutic agents that are metabolized by CYP3A4 in brain cancer patients receiving these anticonvulsants includes the epipodophyllotoxins, vinca alkaloids, taxanes, and the camptothecins [40
The toxicity profile of SU5416 is similar to that reported in adult clinical trials with this agent, as well as other trials with drugs that are dissolved in cremaphor. Severe grade 3 headache, which was prevalent in the adult protocols assessing SU5416, was less frequent in the pediatric population, and was only reported in the first two cycles, especially in those not receiving appropriate pre-medication. A number of toxicities were the result of the cremophor used to solubilize SU5416, although only two significant allergic reactions were reported, in contrast to what was observed in adults. The significant toxicity of cremophor may have prevented a significant dose escalation of SU5416, thus limiting the latter’s activity as evaluated in this phase I trial. In spite of this potential limitation, SU5416 demonstrated potentially interesting activity as measured by stable disease of sufficient duration to suggest clinical benefit in several of the patients treated. Such findings may be meaningful in a phase I dose escalation study of this nature with a heterogeneous population of patients and tumor types. The clinical benefit observed in this protocol was related to prolonged disease stabilization, which is an effect similar to that with SU5416 in pre-clinical models.
The clinical development of SU5416 has been halted, in part due to the limited single agent activity of this highly specific VEGFR inhibitor, as well as the significant toxicity related to the SU5416 dependant co-administration in cremaphor. The results reported herein represent the first demonstration of a small molecule inhibitor of angiogenesis used in pediatric patients. We were able to demonstrate that pediatric patients tolerate dose levels of this drug in a range that is similar to that observed in adults. Furthermore, there was significant overlap in the pharmacokinetic and toxicity profiles between the two populations. As new VEGF signal inhibitory molecules become available, these results will be used to guide these newer trials in terms of identifying activity.