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
Conditions
Interventions
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 co
Sponsors
AstraZeneca AB
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male and female participants aged = 1 to =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
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 0.8 mg/dL (for participants aged = 1 to 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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.;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 | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 | — |
Countries
Germany, Italy, Netherlands, Russian Federation, Spain, United States
Contacts
Public ContactUnidad de Investigación Clínica
AstraZeneca Farmacéutica Spain, S.A.
Outcome results
None listed