Pharmacokinetics, Safety 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)

• Register: EUCTR
• Last refreshed on: 2 March 2022
• Main ID: EUCTR2020-005608-20-ES
• Date of registration: 19/10/2021
• Prospective Registration: Yes
• Primary sponsor: AstraZeneca AB
• Public title: Pharmacokinetics, Safety 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)
• Scientific 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) - SPRINKLE
• Date of first enrolment: 16/02/2022
• Target sample size: 38
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-005608-20
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Germany, Italy, Netherlands, Russian Federation, Spain, United States

Contacts

• Name: Unidad de Investigación Clínica
• Affiliation: AstraZeneca Farmacéutica Spain, S.A.

• Name: Unidad de Investigación Clínica
• Affiliation: AstraZeneca Farmacéutica Spain, S.A.

Key inclusion & exclusion 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 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
Are the trial subjects under 18? yes
Number of subjects for this age range: 38
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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. 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).
9. Participants with ophthalmological findings/condition as listed in the protocol.
10. 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)
11. 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.
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. Receiving herbal supplements or medications known to be strong or moderate inhibitors or inducers of the CYP2C19 and CYP3A4 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.
14. 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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Not possible to specify

Neurofibromatosis Type 1 (NF1) Related Plexiform Neurofibromas (PN)
MedDRA version: 20.0 Level: LLT Classification code 10029270 Term: Neurofibromatosis, type 1 (von Recklinghausen's disease) System Organ Class: 100000004850

Intervention(s)

Product Name: Selumetinib granules in sprinkle capsules for opening 5 mg
Product Code: AZD6244
Pharmaceutical Form: Granules
INN or Proposed INN: Selumetinib
CAS Number: 943332-08-9
Current Sponsor code: AZD6244
Other descriptive name: selumetinib hyd-sulfate
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Product Name: Selumetinib granules in sprinkle capsules for opening 7.5 mg
Product Code: AZD6244
Pharmaceutical Form: Granules
INN or Proposed INN: Selumetinib
CAS Number: 943332-08-9
Current Sponsor code: AZD6244
Other descriptive name: selumetinib hyd-sulfate
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 7.5-

Trade Name: Koselugo 10mg
Product Name: Selumetinib capsules 10mg
Product Code: AZD6244
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Selumetinib
CAS Number: 943332-08-9
Current Sponsor code: AZD6244
Other descriptive name: selumetinib hyd-sulfate
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-

Trade Name: Koselugo 25mg
Product Name: Selumetinib capsules 25mg
Product Code: AZD6244
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Selumetinib
CAS Number: 943332-08-9
Current Sponsor code: AZD6244
Other descriptive name: selumetinib hyd-sulfate
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 24-

Primary Outcome(s)

Primary end point(s): 1. Selumetinib AUC0-12 derived after single dose administration
2. Safety and tolerability will be evaluated in terms of AEs, clinical safety laboratory assessments (clinical chemistry, haematology, urinalysis), physical examination, weight, vital signs, ECG, ECHO, ophthalmologic assessment, knee (or wrist) MRI/X-ray, and performance status.
3. Assessments related to AEs will include: occurrence/frequency; relationship to study intervention; CTCAE grade; seriousness; death; AEs leading to discontinuation of study intervention; AEs of special interest.

Timepoint(s) of evaluation of this end point: 1. PK: Cycle 1 Day 1
2. Safety: from screening until 30 days after last dose

Main Objective: 1. To determine the PK of selumetinib after administration of the selumetinib granule formulation.
2. To assess the safety and tolerability of the selumetinib granule formulation.

Secondary Objective: 1. To assess the palatability of the selumetinib granule formulation.
2. To further assess the PK of selumetinib and N desmethyl selumetinib metabolite after administration of the selumetinib granule formulation.
3. To evaluate the efficacy of the selumetinib granule formulation by assessment of ORR as determined by ICR per REiNS criteria.

Secondary Outcome(s)

Secondary end point(s): 1. Palatability using the parent-reported observer palatability assessment
2. Plasma concentrations and PK parameters of selumetinib including, but not limited to: Selumetinib AUC0-12 derived after multiple dose administration; Cmax, AUC0-6, AUClast, tmax, tlast derived after single and multiple dose administration; AUC0-24, CL/F, Vz/F and t1/2 after single dose administration; Rac Cmax, Rac AUC, CL/F and VSS/F derived after multiple dose administration.
3. Plasma concentrations and PK parameters of N desmethyl selumetinib including, but not limited to: Cmax, AUC0-6, AUC0-12, AUClast, tmax, tlast derived after single and multiple dose administration; Rac Cmax and Rac AUC derived after multiple dose administration; Parent to metabolite ratio for AUC and Cmax after single and multiple dose administration.
4. Objective Response Rate (ORR)

Timepoint(s) of evaluation of this end point: 1. Palatability: Cycle 1 Day 1 to Day 8 (1 week), Cycle 7 Day 1 to Day 8 (1 week)
2. PK: Cycle 1 Day 1, Cycle 2 Day 1, Cycle 5 Day 1, Cycle 13 Day 1, Cycle 25 Day 1 (1 cycle = 28 days)
3: ORR: Screening, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, Cycle 19 Day 1, Cycle 25 Day 1, End of Treatment

Secondary ID(s)

2020-005608-20-DE

D1346C00004

Source(s) of Monetary Support

AstraZeneca AB

Ethics review

Status: Approved
Approval date: 14/02/2022
Contact: