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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05309668
Recruitment Status : Recruiting
First Posted : April 4, 2022
Last Update Posted : August 8, 2022
Sponsor:
Collaborator:
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
AstraZeneca

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.

Condition or disease Intervention/treatment Phase
Neurofibromatosis Type 1 Drug: Selumetinib granule formulation Drug: Selumetinib capsule formulation Phase 1 Phase 2

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

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 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. 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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 44 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : January 21, 2022
Estimated Primary Completion Date : October 19, 2023
Estimated Study Completion Date : July 9, 2027


Arm Intervention/treatment
Experimental: Selumetinib single arm
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

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.


Drug: Selumetinib capsule formulation
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.




Primary Outcome Measures :
  1. Selumetinib AUC0-12 derived after single dose administration [ Time Frame: 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) ]
    To determine the pharmacokinetics of selumetinib after administration of the selumetinib granule formulation

  2. Adverse Events graded by CTCAE Ver 5.0 [ Time Frame: from screening until 30 days after last dose ]
    To assess the safety and tolerability of the selumetinib granule formulation.


Secondary Outcome Measures :
  1. Palatability using the parent-reported observer palatability questionnaire [ Time Frame: 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) ]
    To assess the palatability of the selumetinib granule formulation

  2. N-desmethyl selumetinib AUC0 12 derived after single dose administration [ Time Frame: 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) ]
    To further evaluate the PK of the granule formulation

  3. Selumetinib and N-desmethyl selumetinib AUC0-12 derived after multiple dose administration [ Time Frame: 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) ]
    To further evaluate the PK of the granule formulation.

  4. Selumetinib and N-desmethyl selumetinib Cmax derived after single and multiple dose administration [ Time Frame: 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) ]
    To further evaluate the PK of the granule formulation.

  5. Selumetinib and N-desmethyl selumetinib AUC0-6 derived after single and multiple dose administration [ Time Frame: 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) ]
    To further evaluate the PK of the granule formulation.

  6. Objective Response Rate [ Time Frame: 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) ]
    To evaluate the efficacy of the selumetinib granule formulation by assessment of Objective Response Rate

  7. Selumetinib and N-desmethyl selumetinib AUClast derived after single and multiple dose administration [ Time Frame: 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) ]
    To further evaluate the PK of the granule formulation.

  8. Selumetinib and N-desmethyl selumetinib tmax derived after single and multiple dose administration [ Time Frame: 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) ]
    To further evaluate the PK of the granule formulation.

  9. Selumetinib and N-desmethyl selumetinib tlast derived after single and multiple dose administration [ Time Frame: 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) ]
    To further evaluate the PK of the granule formulation.

  10. Selumetinib AUC0-24 derived after single dose administration [ Time Frame: 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) ]
    To further evaluate the PK of the granule formulation.

  11. Selumetinib CL/F derived after single dose administration [ Time Frame: 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) ]
    To further evaluate the PK of the granule formulation.

  12. Selumetinib Vz/F derived after single dose administration [ Time Frame: 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) ]
    To further evaluate the PK of the granule formulation.

  13. Selumetinib t1/2 derived after single dose administration [ Time Frame: 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) ]
    To further evaluate the PK of the granule formulation.

  14. Selumetinib and N-desmethyl selumetinib Rac Cmax derived after multiple dose administration [ Time Frame: 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) ]
    To further evaluate the PK of the granule formulation.

  15. Selumetinib and N-desmethyl selumetinib Rac AUC derived after multiple dose administration [ Time Frame: 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) ]
    To further evaluate the PK of the granule formulation.

  16. Selumetinib CL/F derived after multiple dose administration [ Time Frame: 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) ]
    To further evaluate the PK of the granule formulation.

  17. Selumetinib Vss/F derived after multiple dose administration [ Time Frame: 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) ]
    To further evaluate the PK of the granule formulation.

  18. Parent-to-metabolite ratio for AUC after single and multiple dose administration. [ Time Frame: 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) ]
    To further evaluate the PK of the granule formulation.

  19. Parent to metabolite ratio for Cmax after single and multiple dose administration. [ Time Frame: 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) ]
    To further evaluate the PK of the granule formulation.


Other Outcome Measures:
  1. Selumetinib and N-desmethyl selumetinib BSA normalised AUC0-6 after single and multiple dose administration [ Time Frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on week 5 (Cycle 2, Day 1, each cycle is 28 days). ]
    To further evaluate the PK of the granule formulation.

  2. Selumetinib and N-desmethyl selumetinib BSA normalised AUC0-12 after single and multiple dose administration [ Time Frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on week 5 (Cycle 2, Day 1, each cycle is 28 days). ]
    To further evaluate the PK of the granule formulation.

  3. Selumetinib and N-desmethyl selumetinib BSA normalised AUC0-24 after single dose administration [ Time Frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1) ]
    To further evaluate the PK of the granule formulation.

  4. Selumetinib and N-desmethyl selumetinib BSA normalised AUClast after single and multiple dose administration [ Time Frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on week 5 (Cycle 2, Day 1, each cycle is 28 days). ]
    To further evaluate the PK of the granule formulation.

  5. Selumetinib and N-desmethyl selumetinib BSA normalised Cmax after single and multiple dose administration [ Time Frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on week 5 (Cycle 2, Day 1, each cycle is 28 days). ]
    To further evaluate the PK of the granule formulation.

  6. Selumetinib and N-desmethyl selumetinib dose normalised AUC0-6 after single and multiple dose administration [ Time Frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on week 5 (Cycle 2, Day 1, each cycle is 28 days). ]
    To further evaluate the PK of the granule formulation.

  7. Selumetinib and N-desmethyl selumetinib dose normalised AUC0-12 after single and multiple dose administration [ Time Frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on week 5 (Cycle 2, Day 1, each cycle is 28 days). ]
    To further evaluate the PK of the granule formulation.

  8. Selumetinib and N-desmethyl selumetinib dose normalised AUC0-24 after single dose administration [ Time Frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1) ]
    To further evaluate the PK of the granule formulation.

  9. Selumetinib and N-desmethyl selumetinib dose normalised AUClast after single and multiple dose administration [ Time Frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on week 5 (Cycle 2, Day 1, each cycle is 28 days). ]
    To further evaluate the PK of the granule formulation.

  10. Selumetinib and N-desmethyl selumetinib dose normalised Cmax after single and multiple dose administration [ Time Frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on week 5 (Cycle 2, Day 1, each cycle is 28 days). ]
    To further evaluate the PK of the granule formulation.

  11. Selumetinib and N-desmethyl selumetinib BSA normalised AUC0-6 after multiple dose administration [ Time Frame: Capsule dosing Day 7 (range Day 4 to 14) pre-dose and 0.5, 1.5, 3, 6, and 10-12 hours post-dose ]
    To further evaluate the PK of the capsule formulation.

  12. Selumetinib and N-desmethyl selumetinib BSA normalised AUC0-12 after multiple dose administration [ Time Frame: Capsule dosing Day 7 (range Day 4 to 14) pre-dose and 0.5, 1.5, 3, 6, and 10-12 hours post-dose ]
    To further evaluate the PK of the capsule formulation.

  13. Selumetinib and N-desmethyl selumetinib BSA normalised AUClast after multiple dose administration [ Time Frame: Capsule dosing Day 7 (range Day 4 to 14) pre-dose and 0.5, 1.5, 3, 6, and 10-12 hours post-dose ]
    To further evaluate the PK of the capsule formulation.

  14. Selumetinib and N-desmethyl selumetinib BSA normalised Cmax after multiple dose administration [ Time Frame: Capsule dosing Day 7 (range Day 4 to 14) pre-dose and 0.5, 1.5, 3, 6, and 10-12 hours post-dose ]
    To further evaluate the PK of the capsule formulation.

  15. Selumetinib and N-desmethyl selumetinib dose normalised AUC0-6 after multiple dose administration [ Time Frame: Capsule dosing Day 7 (range Day 4 to 14) pre-dose and 0.5, 1.5, 3, 6, and 10-12 hours post-dose ]
    To further evaluate the PK of the capsule formulation.

  16. Selumetinib and N-desmethyl selumetinib dose normalised AUC0-12 after multiple dose administration [ Time Frame: Capsule dosing Day 7 (range Day 4 to 14) pre-dose and 0.5, 1.5, 3, 6, and 10-12 hours post-dose ]
    To further evaluate the PK of the capsule formulation.

  17. Selumetinib and N-desmethyl selumetinib dose normalised AUClast after multiple dose administration [ Time Frame: Capsule dosing Day 7 (range Day 4 to 14) pre-dose and 0.5, 1.5, 3, 6, and 10-12 hours post-dose ]
    To further evaluate the PK of the capsule formulation.

  18. Selumetinib and N-desmethyl selumetinib dose normalised Cmax after multiple dose administration [ Time Frame: Capsule dosing Day 7 (range Day 4 to 14) pre-dose and 0.5, 1.5, 3, 6, and 10-12 hours post-dose ]
    To further evaluate the PK of the capsule formulation.

  19. Selumetinib and N-desmethyl selumetinib Cmax after multiple dose administration [ Time Frame: Capsule dosing Day 7 (range Day 4 to 14) pre-dose and 0.5, 1.5, 3, 6, and 10-12 hours post-dose ]
    To further evaluate the PK of the capsule formulation.

  20. Selumetinib and N-desmethyl selumetinib AUC0-6 after multiple dose administration [ Time Frame: Capsule dosing Day 7 (range Day 4 to 14) pre-dose and 0.5, 1.5, 3, 6, and 10-12 hours post-dose ]
    To further evaluate the PK of the capsule formulation.

  21. Selumetinib and N-desmethyl selumetinib AUC0-12 after multiple dose administration [ Time Frame: Capsule dosing Day 7 (range Day 4 to 14) pre-dose and 0.5, 1.5, 3, 6, and 10-12 hours post-dose ]
    To further evaluate the PK of the capsule formulation.

  22. Selumetinib and N-desmethyl selumetinib AUClast after multiple dose administration [ Time Frame: Capsule dosing Day 7 (range Day 4 to 14) pre-dose and 0.5, 1.5, 3, 6, and 10-12 hours post-dose ]
    To further evaluate the PK of the capsule formulation.

  23. Selumetinib and N-desmethyl selumetinib tmax after multiple dose administration [ Time Frame: Capsule dosing Day 7 (range Day 4 to 14) pre-dose and 0.5, 1.5, 3, 6, and 10-12 hours post-dose ]
    To further evaluate the PK of the capsule formulation.

  24. Selumetinib and N-desmethyl selumetinib tlast after multiple dose administration [ Time Frame: Capsule dosing Day 7 (range Day 4 to 14) pre-dose and 0.5, 1.5, 3, 6, and 10-12 hours post-dose ]
    To further evaluate the PK of the capsule formulation.

  25. Selumetinib and N-desmethyl selumetinib CL/F after multiple dose administration [ Time Frame: Capsule dosing Day 7 (range Day 4 to 14) pre-dose and 0.5, 1.5, 3, 6, and 10-12 hours post-dose ]
    To further evaluate the PK of the capsule formulation.

  26. Selumetinib and N-desmethyl selumetinib Vss/F after multiple dose administration [ Time Frame: Capsule dosing Day 7 (range Day 4 to 14) pre-dose and 0.5, 1.5, 3, 6, and 10-12 hours post-dose ]
    To further evaluate the PK of the capsule formulation.

  27. Selumetinib and N-desmethyl selumetinib parent to metabolite ratio for AUC0-6 after multiple dose administration [ Time Frame: Capsule dosing Day 7 (range Day 4 to 14) pre-dose and 0.5, 1.5, 3, 6, and 10-12 hours post-dose ]
    To further evaluate the PK of the capsule formulation.

  28. Selumetinib and N-desmethyl selumetinib parent to metabolite ratio for AUC0-12 after multiple dose administration [ Time Frame: Capsule dosing Day 7 (range Day 4 to 14) pre-dose and 0.5, 1.5, 3, 6, and 10-12 hours post-dose ]
    To further evaluate the PK of the capsule formulation.

  29. Selumetinib and N-desmethyl selumetinib parent to metabolite ratio for Cmax after multiple dose administration [ Time Frame: Capsule dosing Day 7 (range Day 4 to 14) pre-dose and 0.5, 1.5, 3, 6, and 10-12 hours post-dose ]
    To further evaluate the PK of the capsule formulation.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   1 Year to 6 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05309668


Contacts
Layout table for location contacts
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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United States, Arizona
Research Site Not yet recruiting
Phoenix, Arizona, United States, 85060
United States, Indiana
Research Site Not yet recruiting
Indianapolis, Indiana, United States, 46202
United States, Maryland
Research Site Not yet recruiting
Rockville, Maryland, United States, 20852
United States, Pennsylvania
Research Site Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
Research Site Not yet recruiting
Houston, Texas, United States, 77030
United States, Virginia
Research Site Not yet recruiting
Richmond, Virginia, United States, 23219
Germany
Research Site Recruiting
Berlin, Germany, 13353
Research Site Recruiting
Hamburg, Germany, 20246
Research Site Recruiting
München, Germany, 80337
Research Site Recruiting
Tübingen, Germany, 72076
Italy
Research Site Not yet recruiting
Milano, Italy, 20133
Research Site Not yet recruiting
Roma, Italy, 00165
Research Site Not yet recruiting
Torino, Italy, 10126
Netherlands
Research Site Recruiting
Rotterdam, Netherlands, 3015 GD
Russian Federation
Research Site Suspended
Moscow, Russian Federation, 119620
Research Site Suspended
Moscow, Russian Federation, 125412
Research Site Suspended
St Petersburg, Russian Federation, 197341
Spain
Research Site Recruiting
Barcelona, Spain, 08950
Sponsors and Collaborators
AstraZeneca
Merck Sharp & Dohme LLC
Investigators
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Study Director: Study physician Study physician, MD AstraZeneca
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT05309668    
Other Study ID Numbers: D1346C00004
First Posted: April 4, 2022    Key Record Dates
Last Update Posted: August 8, 2022
Last Verified: July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neurofibromatoses
Neurofibromatosis 1
Neurofibroma
Nerve Sheath Neoplasms
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Peripheral Nervous System Diseases
Neuromuscular Diseases
Peripheral Nervous System Neoplasms
Nervous System Neoplasms