Sunitinib in pediatric patients with advanced gastrointestinal stromal tumor: results from a phase I/II trial

Abstract

Background Sunitinib is approved for treatment of adults with imatinib-resistant gastrointestinal stromal tumor (GIST) or imatinib intolerance. Methods This single-arm, multicenter, multinational phase I/II clinical trial (NCT01396148) enrolled eligible patients aged 6 to < 18 years with advanced, unresectable GIST with non-mutant KIT , or who demonstrated disease progression or intolerance to imatinib. Patients received sunitinib 15 mg/m 2 per day, 4-weeks-on/2-weeks-off (schedule 4/2), for ≤ 18 cycles over 24 months. Intra-patient dose escalation to 22.5 and subsequently 30 mg/m 2 were permitted based on individual patient tolerability and supported by real-time pharmacokinetics (PK). Primary objective was PK characterization. Secondary objectives included safety, antitumor activity and PK/pharmacodynamic relationships. Results Six patients were enrolled with median (range) age of 14 (13–16) years. All six patients completed at least three treatment cycles, with one completing all 18 cycles. Five patients had a dose increase to 22.5 mg/m 2 ; two of them had a further dose increase to 30 mg/m 2 . The average daily dose at cycle 3 was 21.1 mg/m 2 ( n = 6). Steady-state plasma concentrations were reached by day 15, cycle 1. No tumor responses were observed, but three patients had stabilization of the disease (50%). Median progression-free survival was 5.8 months (95% CI 2.3—not reached). There were no serious adverse events. Conclusions The tolerable dose of sunitinib in chemotherapy-naïve pediatric patients is at least 20 mg/m 2 on schedule 4/2. The safety profile and PK of sunitinib in pediatric patients with GIST are comparable to those in adults.

Population pharmacokinetics–pharmacodynamics of sunitinib in pediatric patients with solid tumors

“…Rarer events with sunitinib treatment include left ventricular fraction (LVEF) decrease (incidence of 7% in patients with renal cell carcinoma), dose-dependent prolonged QT interval which may lead to an increased risk of ventricular arrhythmias such as Torsade de Pointes in < 0.1% of patients, and seizures in < 1% of patients [5]. To date, however, there is limited experience of sunitinib in pediatric patients, and the safety profile has not been fully defined [7][8][9][10][11][12].…”

Pharmacokinetic Targets for Therapeutic Drug Monitoring of Small Molecule Kinase Inhibitors in Pediatric Oncology

“…72,73 In a phase I/II study that investigated sunitinib in pediatric patients with advanced GIST, a longer median PFS in patients with higher C min (median PFS 2.6 months in lower exposure group and PFS 9.0 months in higher exposure group, n = 6) was found. 28 In a case series of pediatric patients with GIST, higher sunitinib doses were tolerated compared with the doses used in the clinical trials and toxicity profiles were similar to the ones observed in adult patients (treated with a 50 mg q.d. (4 weeks on/2 weeks off) flat dose).…”

“…Genetic mutations in KIT or PDGFR are rare in pediatric patients, and tumors are more often located in the stomach. 28 Adult studies showed a significant increase in progression-free-survival (PFS) with increased C min . 29 As it has been shown that the PK in pediatric and adult patients was similar in patients with CML and in patients with solid tumors, we propose the adult PK target of C min ≥ 1100 ng/mL for dose individualization in pediatric GIST as an exploratory target.…”

Population Pharmacokinetics of Sunitinib and its Active Metabolite SU012662 in Pediatric Patients with Gastrointestinal Stromal Tumors or Other Solid Tumors

“…Importantly, relationships between systemic exposure to the parent drug alone or the total drug (sunitinib and SU012662) and the response (efficacy and toxicities) have also been identified in adults [8][9][10] and in a single study in children [11]. However, to date, experience of sunitinib in pediatric patients is limited, with few pharmacokinetic studies reported [12][13][14][15]. Moreover, there have been no population pharmacokinetic analyses of sunitinib or SU012662 conducted in pediatric patients with GIST or other solid tumors.…”

“…This is the first population pharmacokinetic analysis in pediatric patients that includes patients with GIST, as well as those with other solid tumors, and was conducted to address regulatory requirements and one of the key binding elements of the Sunitinib Pediatric Investigation Plan as agreed with the European Medicines Agency Pediatric Committee. Although the non-compartmental pharmacokinetic results from all three studies have been previously published in four separate articles [12][13][14][15], this population analysis pooled pharmacokinetic data from all three studies. Such population pharmacokinetic analyses further enable the characterization of the pharmacokinetics of sunitinib and SU012662 in this patient population and help to predict the dose(s) that provides comparable plasma exposures to sunitinib and SU012662 in adults receiving the approved daily dose.…”