Entrectinib dose confirmation in pediatric oncology patients: pharmacokinetic considerations

Based on the promising results in adult patients, the unmet medical need, and the rarity of pediatric patients with tumors harboring the NTRK gene fusions, the pediatric program was submitted for accelerated approval in various regions in parallel with the adult NTRK indication. While substantial efforts were being made to develop an age-appropriate formulation, waiting for the optimal formulation would have significantly delayed access to entrectinib in the pediatric population and therefore clinical development continued with the available formulations of entrectinib capsules. The capsule formulation (F2A) used for adults was only available as a 200 mg dose, whereas the F1 formulation (without acidulant) was available as a 100 mg and 200 mg dose. The majority of the patients in the current study received the F1 formulation due to the availability of the 100 mg capsule needed to dose pediatric patients appropriately. In addition, capsule formulation (F1) could be opened and mixed with food for those pediatric patients unable to swallow capsules. The commercial formulation F06 was developed for both adult and pediatric patients who were able to swallow capsules.

In pediatric patients, although there was considerable interpatient variability, entrectinib and M5 exposures increased with dose after a single dose of entrectinib across the dose range tested (250 to 750 mg/m2). The initial recommended phase 2 dose (RP2D) of 550 mg/m2 with the clinical F1 formulation was identified based only on safety (MTD) (N = 16) using a traditional 3 + 3 MTD study design (Part A) [10]. The decision on the RP2D did not take into account systemic exposures from the dose escalation (Part A) (250 mg/m2 to 750 mg/m2). The dose recommendation for the commercial F06 formulation was based on a more robust approach by using all the available data, pharmacokinetics and safety in the context of the exposure/efficacy/safety response data available in adults and pediatrics (manuscript in preparation). In order to provide a dose recommendation with the F06 formulation, a population modeling approach built with adult patients treated with the F2A formulation (clinical adult formulation, STARTRK-2) was used to predict the pediatric dose that matches the adult target exposure receiving 600 mg QD of F2A (adult RP2D). Since F2A and F06 have shown bioequivalence, the estimated dose with F2A formulation is the same for F06 formulation and the recommended dose with F06 is 300 mg/m2 [7]. The 300 mg/m2 dose with F06 triggered questions of potentially underdosing pediatric patients since F1 and F06 have shown to be comparable in healthy adults under controlled dietary conditions helping the performance of F1 (data not shown).

A comparison between the pharmacokinetics in pediatric and adult patients (from STARTRK-1) suggested that pediatric patients receiving 400 mg/m2 QD entrectinib using the non-acidulant containing F1 formulation had lower exposures compared to adults receiving the same dose/formulation and also lower exposures than adults receiving the recommended flat dose of 600 mg QD (F2A) (approximately 300 mg/m2 for a 70 kg adult). Mean systemic exposure (AUCss) in pediatric patients following a dose of 550 mg/m2 F1 was slightly higher than adult systemic exposure when dosed with 600 mg F2A (acidulant containing). It is worth noting that a 600 mg dose in adults corresponds to approximately 300 mg/m2; therefore, the systemic exposure in pediatric patients following a dose of 550 mg/m2 F1 was expected to be higher than the observed systemic exposure in adults following 600 mg. These results are then consistent with the plausible underperformance of the F1 formulation in the pediatric study described here.

Entrectinib is a basic, lipophilic molecule with significant pH-dependent solubility. The F1 formulation did not contain an acidulant, which made this formulation very sensitive to gastric conditions such as meal size, bile salt solubilization and increased pH caused by comedications [8]. Variability was high in both adult and pediatric patient populations when entrectinib was administered as the F1 formulation [7, 8]. However, the acidulant containing F06 formulation aids dissolution and reduces the sensitivity of entrectinib to type of meals [8]. Due to the smaller gut size in children, the fraction of dose absorbed may be more sensitive to changes in entrectinib solubilization than in adults. This hypothesis is supported by simulations with a mechanistic absorption model developed in GastroPlus [8], which estimated that the reduced bile salt concentrations corresponding to a light meal compared to a high fat meal would result in a drop in simulated fraction absorbed of 37% for a 3-year-old, but only 21% for an adult/young teenager (data not shown). Thus, when the F1 formulation is administered with a lighter meal or sprinkled into just yogurt, the bioavailability in young children may be expected to be more sensitive and variable than in adults. This may partly explain the overall lower systemic exposure in the STARTRK-NG study; however, meal size and composition were not captured in the study. The higher exposure observed in adults compared to pediatric patients following 400 mg/m2 with F1 could be attributed to different meal size and composition in the adult population helping the absorption of entrectinib with the non-acidulant F1 formulation [8]. In addition, the request to investigators to avoid the concomitant use of gastric acid reducing agents in the STARTRK-1 adult study could have contributed to the better F1 performance in that study.

When looking at the individual data from study STARTRK-NG, 4 out of 12 pediatric patients dosed with 400 mg/m2 received either gastric acid reducing agents (n = 1), dexamethasone (n = 2) and/or had dose reduction/interruption (n = 3). All these factors are expected to contribute to the lower systemic exposure observed in the 400 mg/m2 group. In addition, 5 out of 12 pediatric patients treated with 550 mg/m2 on Cycle 1, Day 1 had dose reductions/interruptions during Cycle 1, which were ongoing on Cycle 2, Day 1, resulting in lower systemic exposure than would have been expected had they received 550 mg/m2 throughout. Furthermore, it is unknown if pediatric patients receiving entrectinib sprinkled onto food ate the entire portion of food. Finally, one pediatric patient received entrectinib via nasogastric administration; however, no formal assessment has been conducted on the impact of entrectinib absorption when using nasogastric administration with F1. This work, together with the modeling approaches described elsewhere (manuscript in preparation), also highlights the need to revisit the traditional MTD approach to select RP2D for molecularly targeted agents. An integrated approach leveraging pediatric, adult systemic exposure and safety together with robust modeling approaches should be implemented early on in the pediatric program to guide dose selection (RP2D). For this to happen, emerging pharmacokinetics data from the pediatric dose escalation study need to be available and integrated in a validated pharmacokinetics model at the time of the RP2D selection.

In summary, the observed pediatric systemic exposures following administration with 300 mg/m2 entrectinib with F06 in pediatric patients were comparable to the adult systemic exposure receiving 600 mg QD, and were above the reported IC50s [11]. The presence of the acidulant in the F06 formulation has largely resolved the sensitivity of entrectinib to gastric environment conditions, thus resolving the problem of high variability observed with the F1 formulation. In addition, the emerging efficacy data from all patients who received the recommended dose of F06 have shown overall responses from partial responses to complete responses [10]. Similar efficacy has been demonstrated in adult patients treated with entrectinib [12]. With the recommended dose of 300 mg/m2 with F06, or the equivalent based upon the child’s body surface area, children achieve comparable systemic exposure to adults following 600 mg flat dose QD and they thereby reach the target efficacious exposure range while minimizing the risk of overexposure.

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