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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Astrazeneca AB

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

17 Feb 2022 → ongoing

Decision date (initial)

2024-05-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

AstraZeneca AB

External identifiers

EU CT number

2023-506357-38-00

EudraCT number

2020-005608-20

ClinicalTrials.gov

NCT05309668

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Efficacy, Pharmacokinetic, Safety

To determine the PK of selumetinib after administration of the selumetinib granule formulation. To assess the safety and tolerability of the selumetinib granule formulation.

Secondary objectives 1

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

Conditions and MedDRA coding

Neurofibromatosis Type 1 (NF1) Related Plexiform Neurofibromas (PN)

Study design 1 period

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-001585-PIP01-13

Plan to share IPD

Yes

IPD plan description

Researchers from AstraZeneca AB, other health related companies, and universities might ask to use information from SPRINKLE study, including the study participants’ information for other medical, healthcare or scientific related research. The researchers may combine the results from this study with results from other studies. AstraZeneca AB shares only coded personal data of those participants whose parent or legal guardian agreed on that and documented their will in Study Information and Consent Form for Parent/Legal Guardian.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 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 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

1. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Selumetinib AUC0-12 derived after single dose administration. Safety and tolerability will be evaluated in terms of AEs, clinical safety laboratory assessments, physical examination, weight, vital signs, ECG, ECHO, ophthalmologic assessment, MRI/X-ray, and performance status. 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.

Secondary endpoints 1

1. Parent-reported observer palatability assessment. Plasma concentrations and PK parameters of selumetinib including: AUC0-6, AUC0-12, AUC0-24, Cmax, Rac Cmax, Rac AUC0-12, Vss/F, Vz/F, t½λz, AUClast, CL/F, tmax and tlast. Plasma concentrations and PK parameters of N desmethyl selumetinib including: Cmax, AUC0-6, AUC0-12, AUClast, tmax, tlast, Rac Cmax and Rac AUC0-12. Parent-to-metabolite ratio for AUC0-6, AUC0-12 and AUC0-24 and Cmax. Objective Response Rate (ORR). See CSP for more details.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Astrazeneca AB

Sponsor organisation

Astrazeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

Astrazeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

Astrazeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Locations

3 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 20 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications