Pharmacokinetics, Safety and Efficacy of the Selumetinib Granule Formulation in Children Aged ≥1 to

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Brief Title

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

Official Title

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)

Brief Summary

      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

      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

      After completion of at least one cycle (28 days) of dosing in the first 3 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 recruitment into Cohort 2 will be initiated and further
      participants will be recruited into 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; and a further 3 participants will be enrolled in Cohort 1
      at the adjusted dose and the PK will be assessed against acceptance criteria as before.
      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.

      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.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Selumetinib AUC0-12 derived after single dose administration

Secondary Outcome

 Palatability using the parent-reported observer palatability questionnaire

Condition

Neurofibromatosis Type 1

Intervention

Selumetinib granule formulation

Study Arms / Comparison Groups

 Selumetinib single arm
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

38

Start Date

January 21, 2022

Completion Date

July 9, 2027

Primary Completion Date

October 19, 2023

Eligibility Criteria

        Inclusion Criteria:

          1. 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 NF1 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:

          1. Participants with confirmed or suspected malignant glioma or MPNST. Participants with
             low grade glioma (including optic glioma) not requiring systemic therapy are
             permitted.

          2. 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.

          3. 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.

          4. 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.

          5. Participants with clinically significant cardiovascular disease as defined in the
             protocol.

          6. 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.

          7. 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).

          8. Participants with ophthalmological findings/condition as listed in the protocol.

          9. 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)

         10. 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.

         11. 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).

         12. 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.

         13. 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.

         14. 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.

         15. 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.
      

Gender

All

Ages

1 Year - 6 Years

Accepts Healthy Volunteers

No

Contacts

Study physician Study physician, MD, 1-877-240-9479, [email protected]

Location Countries

Germany

Location Countries

Germany

Administrative Informations


NCT ID

NCT05309668

Organization ID

D1346C00004


Responsible Party

Sponsor

Study Sponsor

AstraZeneca

Collaborators

 Merck Sharp & Dohme LLC

Study Sponsor

Study physician Study physician, MD, Study Director, AstraZeneca


Verification Date

March 2022