The maximum tolerated dose of sunitinib for pediatric patients without prior anthracycline exposure or prior cardiac radiation was 15 mg/m2
/day. This dose is lower than the approved adult dose of 50 mg/day (approximately 28 mg/m2
/day based on an average adult body surface area of 1.8 m2
). Previous case series have indicated that children with GIST are able to tolerate sunitinib doses of 25 – 50 mg (16
). The lower doses tolerated in this formal dose escalation study may reflect more intensive prior therapy in the patient population in the current study. In addition, adults treated with sunitinib require dose reductions in 11-50% of cases (5
). The typical reduced adult dose of 37.5 mg/day (approximately 21 mg/m2
/day based on an average adult body surface area of 1.8 m2
) is still greater than the pediatric dose determined in the current study. In addition, the toxicity profile of sunitinib in children may differ from the toxicity profile in adults. In the current study, myelosuppression and transaminase elevations were the most commonly reported toxicities compared to fatigue and gastrointestinal symptoms in adults (4
The pharmacokinetic data of the current study found that the apparent clearance of sunitinib was similar between children and adults (7
). These results are consistent with a recent population pharmacokinetic analysis of sunitinib in adults (median age 55 years; range 18 – 87) that showed that clearance did not correlate with age (27
). As a consequence of the lower doses tolerated in this study, steady state trough total drug concentrations fell below target concentrations (50 ng/mL) in many of the patients. While peak concentrations would be predicted to exceed target concentrations, these data suggest that kinase inhibition may be intermittent for some patients treated at the maximum tolerated dose in this study. It is possible that plasma drug concentrations may not reflect intratumoral drug concentrations and that there may be different target exposures required for anti-tumor activity in different model tumor types.
Due to cardiac toxicity, a recommended phase 2 dose was not determined in Part A of the study, which included patients with prior anthracycline exposure or prior cardiac radiation. Reports from adult patients treated with sunitinib demonstrate an incidence of grade 3 or symptomatic congestive heart failure of 7-15% (30
). As in the current study, the onset of cardiac toxicity is often early in the course of therapy with sunitinib (33
). While both patients in the current study recovered normal cardiac function after discontinuing sunitinib, not all adults have had reversible cardiac dysfunction (32
). The mechanism of cardiac toxicity with sunitinib remains unclear, though some preclinical studies have demonstrated an increase in myocyte apoptosis in response to sunitinib (30
). Since cardiac toxicity precluded the determination of a recommended sunitinib dose in patients with prior anthracycline exposure, future evaluation of this agent is likely to be limited to specific pediatric oncology populations who do not routinely receive therapy with anthracyclines, e.g. children with primary central nervous system tumors.
There were no objective anti-tumor responses in this trial. However, several patients with a variety of different tumors, including sarcoma and glioma, may have benefited as evidenced by stable disease for multiple cycles. Of note, the two patients with stable disease for 9 cycles had histologies which may demonstrate indolent growth: epithelioid sarcoma and ganglioglioma. In addition to recognized activity in GIST, sunitinib and other anti-angiogenic tyrosine kinase inhibitors (sorafenib and pazopanib) have shown clinical activity in several other subtypes of sarcoma, including desmoplastic small round cell tumor, alveolar soft part sarcoma, synovial sarcoma, and angiosarcoma (8
). Sunitinib has been effective in the management of adult patients with renal cell carcinoma and central nervous system metastases, indicating that this agent is distributed to central nervous system tumors (38
). Experience with sunitinib for primary central nervous system tumors is limited to studies demonstrating preclinical activity in glioma models (41
). Given a reported relationship between drug exposure and clinical benefit in adults (43
), it is possible that the lack of objective responses in the current study was a result of inadequate drug exposure given the lower doses tolerated in children versus adults. Intra-patient dose escalation may be possible in a less heavily pre-treated phase 2 population, which would result in increased sunitinib exposure, thereby maximizing the potential for anti-tumor activity.
As with previous studies, sunitinib resulted in consistent increases in plasma VEGF and placental growth factor along with decreases in soluble VEGFR2 and monocyte counts (10
). In contrast, changes in plasma SDF-1, total CECs, and CEC subsets noted in other studies could not be confirmed in the present study. Plasma endoglin concentrations decreased significantly with sunitinib treatment. Previous published studies have not described the effects of sunitinib on plasma endoglin levels. Since endoglin is expressed on tumor-associated endothelial cells and increased levels of plasma endoglin have been reported in patients with malignant tumors, (44
) plasma endoglin levels may provide another pharmacodynamic tool for evaluating patients treated with sunitinib.
In conclusion, cardiac toxicity precluded a determination of a recommended phase 2 dose of sunitinib in children with prior therapy with a potential for cardiac toxicity. The maximum tolerated dose of sunitinib in children without prior anthracycline exposure or radiation therapy involving a cardiac field is lower than in adults (15 mg/m2
versus 28 mg/m2
), despite similar apparent drug clearance. As a result, trough plasma concentrations at the MTD may be below “target” concentrations, as defined in preclinical studies. The implications of these findings are that further development of sunitinib in children with refractory malignancies is currently limited to a patient population without prior cardiotoxic therapy, specifically children with primary central nervous system tumors. In an attempt to maximize the potential for benefit from this agent in a planned phase II study in this population, a single intra-patient dose escalation is planned if the first cycle of therapy at 15 mg/m2
is well-tolerated. This strategy has successfully been employed for other anti-cancer agents (45
) and may allow specific patients to safely receive higher doses of sunitinib than those identified in the current study.