Pharmacokinetics, Safety and Efficacy of the Selumetinib Granule Formulation in Children Aged ≥1 to <7 Years With NF1-related Symptomatic, Inoperable PN

Study Overview
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Brief Summary
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This study is designed to define a dosing regimen and assess the pharmacokinetics(PK) and safety of the granule formulation; the study will also include descriptive analyses of exploratory efficacy endpoints. The study will inform the benefit risk profile of the granule formulation in children aged ≥ 1 to < 7 years with NF1 related symptomatic, inoperable PN.

Detailed Description
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This is a Phase I/II, single arm, open-label study in children aged ≥ 1 to < 7 years at study entry (date of ICF signature) with a clinical diagnosis of NF1 related symptomatic, inoperable PN. The study is designed to evaluate the PK, safety and tolerability of selumetinib given as a granule formulation. Participants will receive selumetinib for 25 cycles (or until they meet discontinuation criteria). Enrolment into the initial dose-finding phase will be stratified by age group: Cohort 1: participants aged between ≥ 4 and < 7 years Cohort 2: participants aged between ≥ 1 to < 4 years In addition to the Global Cohorts, 6 Japanese participants in Japan aged between ≥ 1 to < 7 years with NF1 related symptomatic, inoperable PN will be enrolled into the Japan Cohort. After completion of at least one cycle (28 days) of dosing in 3 evaluable participants in Cohort 1, Safety Review Committee(SRC) will review the emerging safety and PK data. Providing the single dose PK exposure is within the acceptable range and there are no safety concerns as determined by SRC then dosing in Cohort 2 will be initiated and additional participants will be dosed in Cohort 1. If the PK exposure is not within the acceptable range, the dose schema may be adjusted to ensure that selumetinib exposure is within the range observed in the SPRINT study; PK will be assessed against acceptance criteria in an additional 3 evaluable cohort 1 participants who received the adjusted dose. Cohort 2 will be initiated once the selumetinib granule formulation dose schema is identified for Cohort 1. The physiologically-based PK model will be updated, if required, based on emerging PK data. Additional SRC reviews will be held for each of the cohorts following at least one cycle of dosing in approximately 6 evaluable participants and again in approximately 10 evaluable participants. The SRC will evaluate the PK, safety and tolerability of the granule formulation for that dose schema. The Japan Cohort will not participate in the dose-finding phase. Participants who are aged ≥ 5 years at the end of 25 cycles of selumetinib will be considered to have completed the study for data analysis purposes. Participants who terminate treatment prior to Cycle 25 will be followed up to collect MRIs performed as standard of care and details of NF1-PN treatment information until the time when they would have completed 25 cycles of treatment, or they commence an alternative systemic NF1-PN treatment, whichever is the earliest. Any participant who is aged < 5 years after 25 cycles of selumetinib (or when they terminate treatment with selumetinib) will enter a safety follow-up phase. Participation in the safety follow-up will continue until they reach the age of 5 years or commence an alternative systemic NF1-PN treatment, whichever is the earlier. Participants can continue to receive selumetinib (capsule or sprinkle capsule) during the safety follow-up as long as they are considered to be receiving benefit in the opinion of their Investigator.

Official Title
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A Phase I/II, Single-Arm, Open Label Study to Evaluate the Pharmacokinetics, Safety/Tolerability and Efficacy of the Selumetinib Granule Formulation in Children Aged ≥1 to <7 Years With Neurofibromatosis Type 1 (NF1) Related Symptomatic, Inoperable Plexiform Neurofibromas (PN) (SPRINKLE)

Conditions
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Neurofibromatosis Type 1

Intervention / Treatment
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* Drug: Selumetinib granule formulation
* Drug: Selumetinib capsule formulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants aged ≥ 1 to < 7 years of age at the time their legally authorised representative (parent or guardian) signs the informed consent. All study participants must be diagnosed with NF1 with symptomatic inoperable PN as defined in protocol. Participants must have at least one measurable PN, defined as a PN of at least 3 cm measured in one dimension, which can be seen on at least 3 imaging slices and have a reasonably well-defined contour. Participants who have undergone surgery for resection of a PN are eligible provided the PN was incompletely resected and is measurable. The target PN will be defined as the clinically most relevant PN, which is symptomatic, inoperable and measurable by volumetric MRI analysis. Performance status: Participants must have a Lansky performance of ≥ 70 except in participants who are wheelchair bound or have limited mobility secondary to a need for mechanical breathing support (such as an airway PN requiring tracheostomy or continuous positive airway pressure) who must have a Lansky performance of ≥ 40. Participants must have a BSA ≥ 0.4 and ≤ 1.09 m2 at study entry (date of ICF signature). Mandatory provision of consent for the study signed and dated by a participant's legally authorised representative (parent or guardian) along with the paediatric assent form, if applicable. Exclusion Criteria: Participants with confirmed or suspected malignant glioma or MPNST. Participants with low grade glioma (including optic glioma) not requiring systemic therapy are permitted. History of malignancy except for malignancy treatment with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk of recurrence. Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of selumetinib. A life-threatening illness, medical condition, organ system dysfunction or laboratory finding which, in the Investigator's opinion, could compromise the participant's safety, interfere with the absorption or metabolism of selumetinib, or put the study outcomes at undue risk. Participants with clinically significant cardiovascular disease as defined in the protocol. Liver function tests: Bilirubin > 1.5 × the ULN for age with the exception of those with Gilbert syndrome (≥ 3 × ULN) or AST/ALT > 2 × ULN. Renal Function: Creatinine clearance or radioisotope glomerular filtration rate < 60 mL/min/1.73 m2 or Serum creatinine > 0.8 mg/dL (for participants aged ≥ 1 to < 4 years) or > 1.0 mg/dL (for participants aged ≥ 4 years). Participants with ophthalmological findings/condition as listed in the protocol. Have any unresolved chronic toxicity with CTCAE Grade ≥ 2 which are associated with previous therapy for NF1-PN (except hair changes such as alopecia or hair lightening) Participants who have previously been treated with a MEKi (including selumetinib) and have had disease progression, or due to toxicity have either discontinued treatment and/or required a dose reduction. Have inadequate haematological function defined as: An absolute neutrophil count < 1500/μL or Haemoglobin < 9g/dL or Platelets <100,000/μL or Have had a transfusion (of red cells or other blood derived products) within the 28 days prior to study entry (date of ICF signature). Have received or are receiving an IMP or other systemic NF1-PN target treatment (including MEKi) within 4 weeks prior to the first dose of study intervention, or within a period during which the IMP or systemic PN target treatment has not been cleared from the body (eg, a period of 5 'half-lives'), whichever is longer. Has received radiotherapy in the 6 weeks prior to start of study intervention or any prior radiotherapy directed at the target or non-target PN. Receiving herbal supplements or medications known to be strong or moderate inhibitors of the CYP3A4 and CYP2C19 enzymes or inducers of the CYP3A4 enzyme unless such products can be safely discontinued at least 14 days or 5 half-lives (whichever is longer) before the first dose of study medication. Inability to undergo MRI and/or contraindication for MRI examinations. Prosthesis or orthopaedic or dental braces that would interfere with volumetric analysis of target PN on MRI.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Selumetinib single arm<br>This study consists of a screening period (up to 28 days), a treatment period (25 cycles) and a long term safety follow-up for participants until they are 5 years old or commence an alternative systemic NF1-PN treatment, whichever is the earlier. Participants may continue treatment with selumetinib throughout the long term safety follow-up as long as they are considered to be receiving clinical benefit in the opinion of their Investigator. A safety follow up assessment will be performed 30 days after the last dose of study intervention for all study participants. | Drug: Selumetinib granule formulation<br>* Selumetinib granule formulation will be administered using BSA-based dosing. The granule formulation dose schema to be used in the study will be established in the dose finding phase. At enrolment participants must have a BSA within the range 0.40 to 1.09 m2; once participants attain a BSA between 1.10 and 1.29 m2 they will be encouraged to transition to the capsule formulation, if feasible, although all participants must remain on the granule formulation until after they have completed their third cycle of treatment.<br>Drug: Selumetinib capsule formulation<br>* Selumetinib capsule formulation will be administered using BSA-based dosing. Once participants attain a BSA between 1.10 and 1.29 m2 they will be encouraged to transition to the capsule formulation, if feasible, although all participants must remain on the granule formulation until after they have completed their third cycle of treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Selumetinib AUC0-12 derived after single dose administration | To determine the pharmacokinetics of selumetinib after administration of the selumetinib granule formulation | Pre-dose and 1, 2, 3, 4, 6, 8 and 10-12 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1) (each cycle is 28 days) | 
| Adverse Events graded by CTCAE Ver 5.0 | To assess the safety and tolerability of the selumetinib granule formulation. | from screening until 30 days after last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Palatability using the parent-reported observer palatability questionnaire | To assess the palatability of the selumetinib granule formulation | From the first day of study treatment (Cycle 1 Day 1) for one week, from week 25 (Cycle 7 Day 1) for one week (each cycle is 28 days) | 
| N-desmethyl selumetinib AUC0 12 derived after single dose administration | To further evaluate the PK of the granule formulation | Pre-dose and 1, 2, 3, 4, 6, 8 and 10-12 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1) (each cycle is 28 days) | 
| Selumetinib and N-desmethyl selumetinib AUC0-12 derived after multiple dose administration | To further evaluate the PK of the granule formulation. | Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on week5 (Cycle 2 Day 1)(each cycle is 28 days) | 
| Selumetinib and N-desmethyl selumetinib Cmax derived after single and multiple dose administration | To further evaluate the PK of the granule formulation. | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on week5 (Cycle 2, Day 1)(each cycle is 28 days) | 
| Selumetinib and N-desmethyl selumetinib AUC0-6 derived after single and multiple dose administration | To further evaluate the PK of the granule formulation. | Pre-dose and 1, 2, 3, 4 and 6 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on week5 (Cycle 2, Day 1)(each cycle is 28 days) | 
| Objective Response Rate | To evaluate the efficacy of the selumetinib granule formulation by assessment of Objective Response Rate | At screening, at week 17 (Cycle5 Day1), week 33 (Cycle9 Day1), week 49 (Cycle13 Day1), week 73 (Cycle19 Day1) and week 97 (Cycle25 Day1), end of treatment(each cycle is 28 days) | 
| Selumetinib and N-desmethyl selumetinib AUClast derived after single and multiple dose administration | To further evaluate the PK of the granule formulation. | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on week5 (Cycle 2, Day 1)(each cycle is 28 days) | 
| Selumetinib and N-desmethyl selumetinib tmax derived after single and multiple dose administration | To further evaluate the PK of the granule formulation. | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on week5 (Cycle 2, Day 1).(each cycle is 28 days) | 
| Selumetinib and N-desmethyl selumetinib tlast derived after single and multiple dose administration | To further evaluate the PK of the granule formulation. | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on week5 (Cycle 2, Day 1).(each cycle is 28 days) | 
| Selumetinib AUC0-24 derived after single dose administration | To further evaluate the PK of the granule formulation. | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1).(each cycle is 28 days) | 
| Selumetinib CL/F derived after single dose administration | To further evaluate the PK of the granule formulation. | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1).(each cycle is 28 days) | 
| Selumetinib Vz/F derived after single dose administration | To further evaluate the PK of the granule formulation. | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1).(each cycle is 28 days) | 
| Selumetinib t1/2 derived after single dose administration | To further evaluate the PK of the granule formulation. | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1).(each cycle is 28 days) | 
| Selumetinib and N-desmethyl selumetinib Rac Cmax derived after multiple dose administration | To further evaluate the PK of the granule formulation. | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on week5 (Cycle 2, Day 1).(each cycle is 28 days) | 
| Selumetinib and N-desmethyl selumetinib Rac AUC derived after multiple dose administration | To further evaluate the PK of the granule formulation. | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on week5 (Cycle 2, Day 1).(each cycle is 28 days) | 
| Selumetinib CL/F derived after multiple dose administration | To further evaluate the PK of the granule formulation. | Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on week5 (Cycle 2, Day 1).(each cycle is 28 days) | 
| Selumetinib Vss/F derived after multiple dose administration | To further evaluate the PK of the granule formulation. | Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on week5 (Cycle 2, Day 1).(each cycle is 28 days) | 
| Parent-to-metabolite ratio for AUC after single and multiple dose administration. | To further evaluate the PK of the granule formulation. | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on Cycle 1 Day 1. Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on week5 (Cycle 2, Day 1).(each cycle is 28 days) | 
| Parent to metabolite ratio for Cmax after single and multiple dose administration. | To further evaluate the PK of the granule formulation. | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on week5 (Cycle 2, Day 1).(each cycle is 28 days) |