Primary objectives:- To determine the PK of selumetinib after administration of the selumetinib granule formulation. - To assess the safety and tolerability of the selumetinib granule formulation.
ID
Source
Brief title
Condition
- Congenital and hereditary disorders NEC
- Nervous system neoplasms benign
- Nervous system neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To determine the PK of selumetinib after administration of the selumetinib
granule formulation the Selumetinib AUC0-12 will be derived after single dose
administration.
Safety and tolerability of the selumetinib granule formulation 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.
Secondary outcome
- 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.
Background summary
Neurofibromatosis type 1 is an autosomal dominant disorder with an estimated
prevalence of 2.13/10,000 individuals in Europe (OrphaNet Report Services
2020). There are no studies estimating the prevalence of NF1 in the US and most
authors cite studies conducted in Europe. Neurofibromatosis type 1 is
characterised by diverse, progressive cutaneous, neurological, skeletal, and
neoplastic manifestations. Symptoms of NF1 generally manifest very early in
life and the subsequent increase in morbidity can be severe. Neurofibromatosis
type 1 arises from pathogenic variants of the NF1 gene encoding the tumour
suppressor protein neurofibromin, a GTPase-activating protein whose normal
function is to downregulate RAS activity (Ballester et al 1990, Bollag and
McCormick 1991, Cawthon et al 1990, Martin et al 1990, Viskochil et al 1990,
Wallace et al 1990). Constitutive activation of the RAS/RAF/MEK/ERK pathway is
implicated in cell proliferation and is central to driving cancer growth and
progression (Davies et al 2007). Neurofibromin 1 pathogenic variants lead to a
failure to inactivate RAS, and can result in PNs (Basu et al 1992, Cichowski et
al 2003). Affected individuals start life with one mutated (nonfunctional) copy
and one functional copy of NF1 in every cell in their body. Although many of
the clinical features of this syndrome are apparent from birth, complete loss
of gene function is needed for tumour formation through acquisition of a
somatic NF1 mutation in selected cells (Gutmann et al 2013, Ruggieri and Packer
2001). Plexiform neurofibromas develop in 20% to 50% of individuals with NF1.
Plexiform neurofibromas in NF1 patients are histologically benign Schwann-cell
tumours (Rutkowski et al 2000, Wu et al 2005) that, depending on the location
and the growth rate, bear all the characteristics typical of cancers. Most
NF1-related PNs are congenital or occur very early in life and are
characterised by slow growth, complex shape, and sometimes very large size (up
to 20% of body weight) (Korf 1999, Mautner et al 2008). Growth of PNs occurs
more rapidly in young children ( Akshintala et al 2020, Nguyen et al 2012,
Tucker et al 2009). Spontaneous regression of PNs is uncommon and although
occasionally seen in adolescents and young adults, it was not seen in young
children (Akshintala et al 2020, Gross et al 2018). Consequently, there is a
significant treatment need for young children with NF1-PN. These tumours can
cause severe morbidity such as pain, neurological dysfunction, and
disfigurement, and also have the potential to transform to MPNSTs (Nguyen et al
2011, Prada et al 2012). The lifetime incidence of MPNSTs in NF1 is 15.8%, and
many MPNSTs arise in pre-existing PNs (Uusitalo et al 2016); MPNST is a rare
disease in the general population with a lifetime incidence of 0.001% (Ferrari
et al 2007). Selumetinib (AZD6244, ARRY 142886, AR00142886, AR-142886-X [where
X refers to a sequential lot number], KOSELUGO®) is an oral, potent, and highly
selective, allosteric MEK1/2 inhibitor with a short half-life (Banerji et al
2010, Denton and Gustafson 2011). It is licensed for development by AstraZeneca
Pharmaceuticals from Array BioPharma and is being co-developed by AstraZeneca
and Merck & Co. Selumetinib can inhibit PN growth by blocking RAS signaling (
Gross et al 2018, Gross et al 2020, Weiss et al 1999, Widemann et al 2014).
Analysis of volumetric MRI data by NCI POB central review from a Phase I
open-label, single-arm, Investigator-sponsored study (Study 8799 [NCI
11-C-0161; SPRINT; NCT01362803]) in paediatric patients (aged 3 to 18 years at
enrolment) with NF1-related inoperable PN demonstrated durable tumour shrinkage
with confirmed tumour volume decreases of >= 20% from baseline (Dombi et al
2016). These observations led to the addition of a Phase II part to the study
to further evaluate the effect of selumetinib capsules on tumour response,
pain, quality of life, and physical functioning in paediatric patients (aged 2
to 18 years at enrolment) with NF1-related symptomatic inoperable PN. Analysis
of volumetric MRI data by NCI POB central review from SPRINT Phase II Stratum 1
showed durable tumour shrinkage along with clinical benefit (Gross et al 2020).
The NCI POB central analysis-assessed ORR was 66% (95% CI: 51.2 to 78.8) in the
SPRINT study. The median time to onset of response was 7.2 months (range 3.3
months to 1.6 years). The median DoR from onset of response was not reached; at
the time of DCO the median follow-up time was 22.1 months. Of the 33 patients
who had confirmed PR, 27 (81.8%) remained in response after 12 months; the
remaining 6 patients were censored and had not progressed. The median time from
treatment initiation to disease progression while on treatment was not reached.
At the time of DCO, 28 (56%) patients remained in confirmed PR, 2 (4%) had
unconfirmed PRs, 15 (30%) had stable disease and 3 (6%) had PD. Clinical
Outcome Assessments were generally improved with an overall reduction in pain,
improvement in motor function and mobility, improved bowel and bladder function
and overall improvement in quality of life assessments. Selumetinib showed good
tolerability with mainly mild or moderate AEs which were manageable long term
via supportive therapy and/or dose interruption or reduction. Selumetinib
(KOSELUGO®) capsules were approved for the treatment of paediatric patients >= 2
years of age with NF1 who have symptomatic, inoperable PN in the US on 10 April
2020 and a Conditional Marketing Authorisation was granted in Europe/EEA for
paediatric patients 3 years of age and older, via the European Centralised
Procedure in the EU on 17 June 2021. A detailed description of the chemistry,
pharmacology, efficacy, and safety of selumetinib is provided in the
Investigator*s Brochure.
Study objective
Primary objectives:
- To determine the PK of selumetinib after administration of the selumetinib
granule formulation.
- To assess the safety and tolerability of the selumetinib granule formulation.
Study design
This is 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).
Intervention
The study is open-label and single arm; there is no randomisation. 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 Selumetinib 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, as described in section
6.1.2 on page 43 of the protocol and this is summarized in figure 2 on page 16
of the protocol. 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.
Study burden and risks
Patients need to come to the hospital more often and visits are longer.
Patients will undergo the following actions during the study:
- History (including medical history)
- Physical examination (including standard neurological assessments)
- Vital signs (temperature, heart rate, respiratory rate, blood pressure,
oxygen saturation, measurement of weight and length)
- 12-lead ECG
- ECHO
- AE/SAE assessments
- Lansky performance status assessments
- Blood - and urine collections
- Questionnaires: FLACC/FPS-R, GIS-pNF, GIC-pNF, Pain medicatoin survey, PedsQL.
- Neurodevelopmental tests
- Palatability assessments
- Ophthalmology assessments
- MRI/Röntgen of knees (or wrists)
- Volumetric MRI (PN assessments)
The study drug can also cause side effects. Potential risks associated with
selumetinib:
- Gastrointestinal effects; diarrhoea, nausea and vomiting
- Retinal toxicity; vision blurred (reported in 10% of patients receiving
treatment with selumetinib), Central Serous Retinopathy, Retinal Pigment
Endothelial Detachment, Retinal Vein Occlusion
- Creatinine phosphokinase increase
- Skin toxicity; rash, dermatitis acneiform, dry skin
- LVEF decreases
- Transaminase increase
- Increased blood pressure
- Physeal dysplasia
- Fatigue
- Peripheral oedema
- Stomatitis
- Pyrexia
Potential risks associated with selumetinib in paediatric patients:
- (Blood) CK increase
- Rash maculo-papular
- Urticaria
- Vulval Cellulitis
- decreased ejection fraction
- Vomiting
- Diarrhoea
- Nausea
- Dry skin
- Fatigue
- Pyrexia
- Dermatitis acneiform
- Hypoalbuminaemia
- Stomatitis
- Headache
- Oropharyngeal pain
- AST increase
- Paronychia
- Pruritus
- Mucositis
- Dyspnoea
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Listed location countries
Age
Inclusion criteria
- 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
Exclusion criteria
- 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 factors in the 7 days
prior to study entry (date of ICF signature). - 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. - 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
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-005608-20-NL |
| CCMO | NL79097.078.21 |
| Other | volgt |