Phase I Study to Assess the Effect of Food on the PK and Gastrointestinal Tolerability of Selumetinib in Adolescent Children With Neurofibromatosis Type 1 Related Plexiform Neurofibromas

Overview

This study in adolescent participants with NF1 who have inoperable PN is designed to evaluate the effect of a low fat meal on steady state selumetinib exposure; to assess the effect on GI tolerability when selumetinib is dosed under fed and fasted conditions; and potentially, to confirm an appropriate dosing recommendation of selumetinib with a low fat meal that maintains efficacy with acceptable safety. These results may support labelling statements with regard to posology and food.

Selumetinib is approved by the FDA for the treatment of paediatric patients 2 years of age and older with NF1 who have symptomatic, inoperable PN. The efficacy of selumetinib in the treatment of NF1 related inoperable PN in paediatric participants was demonstrated in the SPRINT study in which selumetinib was taken at 25 mg/m2 bid under fasted conditions (fast for 2 hours before each dose and 1 hour after each dose). Safety data from this study showed that selumetinib has a generally predictable and manageable safety profile in this population. Gastrointestinal AEs were commonly reported but were predominantly mild/moderate in severity, predictable, and generally did not affect the ability of participants to remain on treatment. However, GI AEs in this paediatric study were reported at a higher frequency than that reported in an analysis of selumetinib in adult oncology participants. Dosing in a fed state is known to reduce GI tolerability for some oncology drugs; such a dosing regimen has an added benefit of improving compliance and adherence to dosing posology. Food-effect studies conducted in healthy participants (Study D1532C00069) and adult participants with cancer (Study D1532C00020) show that consumption of a high fat meal reduces absorption of selumetinib: in healthy participants Cmax was reduced by 50% and AUC by 16%; and in participants with cancer Cmax was reduced by 62% and AUC by 19%. A further study in adult healthy participants (D1532C00089) found that a low fat, low calorie meal reduces the rate of absorption (Cmax reduced by 65% and tmax delayed by 2.5 hours) and the extent of absorption (AUC reduced by 38%) after a single dose of selumetinib. The finding that a low fat meal had a greater impact on exposure than a high fat meal is unusual and without a clear explanation although in vitro dissolution data suggest that the capsule shell disintegration may be impacted by food. The study is designed to evaluate the steady state systemic exposure and safety (especially GI tolerability) of selumetinib 25 mg/m2 bid given with a low fat meal versus the same dose given in a fasted state. A third treatment period (T3) will be initiated if there is a significant reduction in exposure (AUC0-12, SS between T2 vs T1) when selumetinib is given with a low fat meal compared with a fasted state; T3 will evaluate the PK and safety of an adjusted dose of selumetinib when given with a low fat meal. The recommendation as to whether to initiate T3, and the dose to be used in T3, will be made by a DRC. This recommendation will be reviewed with FDA before dosing in T3 is initiated. Approximately 20 participants will be enrolled to achieve 16 evaluable participants completing T2. An evaluable participant is defined as having received study treatment and provided the last required PK sample in T2. A Data Review Committee(DRC) will review the PK and safety data from T1 and T2 and determine whether T3 is required. If T3 is required the DRC will select the dose to be used. The recommendation will be reviewed with FDA before dosing in T3 is initiated.