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)
- Conditions
- A genetic disorder characterized by the presence of multiplefrequently symptomless but occasionally malignanttumors formed on a nerve cell sheath1002766410029209
- Registration Number
- NL-OMON56067
- Lead Sponsor
- Astra Zeneca
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 5
- 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. - All participants must have a diagnosis of NF1 with symptomatic
inoperable PN where: a) Participants must have PN and at least one other
diagnostic criterion for NF1 b) Inoperable is defined as a PN that cannot be
completely surgically removed without a risk of substantial morbidity due to
encasement of, or close proximity to, vital structures, invasiveness, or high
vascularity of the PN; or unacceptable risk from the general anaesthetic as
assessed by the investigator c) Symptomatic is defined as clinically
significant symptoms or complications caused by the PN, as judged by the
investigator; symptoms may include, but are not limited to, pain, motor
dysfunction and disfigurement (examples of complications include PN displacing
trachea, or PN causing bladder obstruction and hydronephrosis). - 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. - 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 - Participants must have a BSA >= 0.4 and
<= 1.09 m2 at study entry (date of ICF signature). - 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, when
applicable
- Participants with confirmed suspected malignant glioma or MPNST. Participants
with optic glioma not requiring chemotherapy or radiation therapy are
permitted. - 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. - 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 (such as severe or uncontrolled systemic disease, known
moderate or severe hepatic impairment, active infection, active bleeding
diatheses, or renal transplant, 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. - Participants
with the following ophthalmological findings/conditions: • Current or past
history of RPED/CSR or RVO; • Intraocular pressure >21 mmHg (or ULN adjusted by
age) or uncontrolled glaucoma (irrespective of IOP). • Participants with known
glaucoma and increased IOP who do not have meaningful vision (light perception
only or no light perception) and are not experiencing pain related to the
glaucoma, may be eligible after discussion with the Medical Monitor. •
Participants with any other significant abnormality on ophthalmic examination
should be discussed with the Sponsor for potential eligibility. •
Ophthalmological findings secondary to long*standing optic pathway glioma (such
as visual loss, optic nerve pallor or strabismus) or longstanding orbito*
temporal PN (such as visual loss, strabismus) will NOT be considered a
significant abnormality for the purposes of the study. - 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) -
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. - Have 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. - 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. - 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. - Has received growth facto
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>To determine the PK of selumetinib after administration of the selumetinib<br /><br>granule formulation the Selumetinib AUC0-12 will be derived after single dose<br /><br>administration.<br /><br>Safety and tolerability of the selumetinib granule formulation will be<br /><br>evaluated in terms of AEs, clinical safety laboratory assessments (clinical<br /><br>chemistry, haematology, urinalysis), physical examination, weight, vital signs,<br /><br>ECG, ECHO, ophthalmologic assessment, knee (or wrist) MRI/X-ray, and<br /><br>performance status.</p><br>
- Secondary Outcome Measures
Name Time Method <p>- To assess the palatability of the selumetinib granule formulation<br /><br>- To further assess the PK of selumetinib and N-desmethyl selumetinib<br /><br>metabolite after administration of the selumetinib granule formulation.<br /><br>- To evaluate the efficacy of the selumetinib granule formulation by assessment<br /><br>of ORR as determined by ICR per REiNS criteria.</p><br>