Evaluation of Pharmacokinetics, Safety, and Efficacy of Selumetinib Granule Formulation in Pediatric Patients with NF1-Related Inoperable Plexiform Neurofibromas
- Trial ID
- 2023-506357-38-00
- Protocol
- SPRINKLE D1346C00004
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the **pharmacokinetics** (PK) of selumetinib following the administration of its granule formulation. Additionally, the study aims to assess the safety and tolerability of this formulation. These objectives are clinically relevant as they provide critical insights into the drug's absorption, distribution, metabolism, and excretion, which are essential for optimizing dosing regimens and ensuring patient safety in children with Neurofibromatosis Type 1 (NF1) related symptomatic, inoperable plexiform neurofibromas.
Secondary objectives include:
- Assessing the palatability of the selumetinib granule formulation, which is important for ensuring compliance in pediatric populations.
- Further evaluating the PK of selumetinib and its N-desmethyl metabolite after administration of the granule formulation, which aids in understanding the drug's metabolic profile.
- Evaluating the efficacy of the selumetinib granule formulation by assessing the objective response rate (ORR) as determined by independent central review per REiNS criteria, which is crucial for determining the therapeutic benefit of the treatment.
Participants
The clinical trial involves a total of **10 participants** diagnosed with **Neurofibromatosis Type 1 (NF1) Related Plexiform Neurofibromas (PN)**. The study population includes both male and female subjects, aged between 1 and 6 years, who are considered a vulnerable population due to their age and medical condition. Participants were selected based on specific criteria, including the presence of symptomatic inoperable PN, with at least one measurable PN of at least 3 cm in one dimension. The trial requires participants to have a Lansky performance status of ≥ 70, except for those with limited mobility due to mechanical breathing support, who must have a Lansky performance of ≥ 40. Additionally, participants must have a body surface area (BSA) between 0.4 and 1.09 m² at the time of study entry. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that all participants have provided informed consent through their legally authorized representatives, with pediatric assent obtained where applicable.
Plans and Procedures
The clinical trial is designed to evaluate the **pharmacokinetics**, safety, and tolerability of the **selumetinib** granule formulation in children aged 1 to less than 7 years with **Neurofibromatosis Type 1 (NF1)** related symptomatic, inoperable plexiform neurofibromas (PN). This is a Phase I/II, single-arm, open-label study. The trial is expected to commence on April 18, 2024, and conclude by April 28, 2028. Participants will be involved in the study for the duration necessary to achieve the primary and secondary endpoints, which include the assessment of **selumetinib** area under the curve (AUC) and safety evaluations through adverse events (AEs), clinical safety laboratory assessments, and various physical examinations.
The study will begin with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of symptomatic inoperable PN, and performance status. Participants must have a measurable PN and a body surface area (BSA) within the specified range. Following the screening, participants will undergo a series of study visits to monitor the pharmacokinetics and safety of **selumetinib**. These visits will include assessments of plasma concentrations, PK parameters, and parent-reported observer palatability assessments. The end-of-study visit will finalize data collection and ensure participant safety post-treatment.
Participant involvement is expected to last until the completion of the study objectives, with conditions for early termination including significant adverse events or withdrawal of consent. The trial will adhere to rigorous safety monitoring protocols, with regular evaluations of vital signs, ECG, ECHO, ophthalmologic assessments, and MRI/X-ray imaging. The study aims to provide comprehensive data on the efficacy and safety of **selumetinib** in the specified pediatric population, contributing valuable insights into the management of NF1-related PN.
Treatment
The clinical trial involves the administration of **Selumetinib**, an antineoplastic agent, in the form of a hard capsule. The active substance, **Selumetinib**, is of chemical origin and is also known as selumetinib hyd-sulfate. The pharmaceutical form is a hard capsule, and the route of administration is oral. The trial includes both pediatric and non-pediatric formulations, with the pediatric formulation specifically designed for children aged ≥ 1 to < 7 years with Neurofibromatosis Type 1 (NF1) related symptomatic, inoperable plexiform neurofibromas (PN). The dosage and frequency of administration are determined based on the study protocol, with a focus on evaluating the pharmacokinetics, safety, and tolerability of the selumetinib granule formulation.
In addition to the experimental treatment, the study may include standard-of-care therapies as deemed necessary by the clinical investigators. No placebo or comparator treatment is explicitly mentioned in the trial data. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol. The trial is conducted under the orphan drug designation EU/3/18/2050, highlighting its focus on a rare condition. The sponsor product code for Selumetinib is AZD6244, and it is developed by AstraZeneca AB. The trial aims to provide comprehensive data on the efficacy and safety of Selumetinib in the specified patient population.
Efficacy
The efficacy of the clinical trial involving **Selumetinib** will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the pharmacokinetic parameter, specifically the area under the curve (AUC0-12) derived after a single dose administration of **Selumetinib**. Safety and tolerability will also be evaluated through adverse events (AEs), clinical safety laboratory assessments, physical examinations, weight, vital signs, ECG, ECHO, ophthalmologic assessments, MRI/X-ray, and performance status. The assessments related to AEs will include occurrence/frequency, relationship to study intervention, CTCAE grade, seriousness, death, AEs leading to discontinuation of study intervention, and AEs of special interest.
Secondary endpoints include parent-reported observer palatability assessments and various pharmacokinetic parameters of **Selumetinib** such as AUC0-6, AUC0-12, AUC0-24, Cmax, Rac Cmax, Rac AUC0-12, Vss/F, Vz/F, t½λz, AUClast, CL/F, tmax, and tlast. Additionally, plasma concentrations and pharmacokinetic parameters of N desmethyl **Selumetinib** will be measured, including Cmax, AUC0-6, AUC0-12, AUClast, tmax, tlast, Rac Cmax, and Rac AUC0-12. The parent-to-metabolite ratio for AUC0-6, AUC0-12, AUC0-24, and Cmax will also be evaluated. The Objective Response Rate (ORR) will be assessed as part of the secondary endpoints. These efficacy parameters will be collected and analyzed according to the clinical study protocol, with specific timepoints and methods detailed in the clinical study plan (CSP).
Inclusion and Exclusion Criteria
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. 2. All study participants must be diagnosed with symptomatic inoperable PN as defined in protocol. 3. 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. 4. 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. 5. Participants must have a BSA ≥ 0.4 and ≤ 1.09 m2 at study entry (date of ICF signature). 6. 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 treatment with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and low 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 judged by the Investigator, any evidence of disease, including any participant known to have hepatitis B, hepatitis C, or HIV which, in the Investigator's opinion, makes it undesirable for the participant to take part in the study. Total bilirubin > 1.5 × the ULN for age except for those with Gilbert syndrome (≥ 3 × ULN) or AST/ALT > 2 × ULN. 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). An absolute neutrophil count < 1500/μL or Haemoglobin < 9g/dL or Platelets < 100,000/μL or had a transfusion (of red cells or other blood derived products) within the 28 days prior to study entry (date of ICF signature). Participants with ophthalmological findings/condition. 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 had disease progression, or due to toxicity either discontinued treatment and/or required a dose reduction. Had major surgery within 4 weeks of the first dose of study intervention, with the exception of surgical placement for vascular access. Have planned major surgery during the treatment period. Received or are receiving an IMP or other systemic NF1-PN target treatment (including MEKi) within 4 weeks of 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 (e.g., a period of 5 'half-lives'), whichever is longer. Receiving supplements or medications known to be strong or moderate inhibitors or inducers of CYP3A4 or strong or moderate inhibitors of CYP2C19 enzymes 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. Received radiotherapy within 6 weeks of start of study intervention or any prior radiotherapy directed at the target or non-target PN. Received growth factors within 1 week of date of ICF signature. Participation in another clinical study with an investigational product administered within 30 days of first dose of study intervention. Known severe hypersensitivity or history of allergic reactions to selumetinib or compounds of similar chemical or biologic composition.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 18 Apr 2024 | 9 |
 Italy | Not Recruiting | 18 Apr 2024 | 9 |
 Spain | Not Recruiting | 18 Apr 2024 | 8 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
SELUMETINIB | Test | — | ORAL USE | — | — | SUB32237 |
Selumetinib | Test | CAPSULE | ORAL USE | — | — | PRD11229177 |
SELUMETINIB | Test | — | ORAL USE | — | — | SUB32237 |
Selumetinib | Test | CAPSULE | ORAL USE | — | — | PRD11229126 |