Primary objective:• Evaluate PK parameters of the oral suspension of temozolomide in the paediatric population aged 1 year and over.Secondary objectives:• Evaluate the safety of the oral suspension of temozolomide,• Evaluate the acceptability of the…
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Brief title
Condition
- Other condition
Synonym
Health condition
pediatric cancers such as malignant glioma and also relapsed or refractory neuroblastoma, rhabdomyosarcoma, medulloblastoma, and Ewing sarcoma
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoints:
Investigated PK parameters will be TMZ apparent clearance (CL/F), distribution
volume (V/F) and absorption rate constant (Ka). These PK parameters will be
used to derive key estimates of exposure such as TMZ area under the curve
between 2 intakes (AUC0-t) and, if feasible, maximum concentration (Cmax) for
each included subject and elimination half-life (t1/2), and the total AUC0-*.
Population PK parameters will be estimated by a population analysis performed
with NONMEM (7.4). Individual Bayesian estimates of the PK parameters will be
used to calculate individual AUC24, Cmax, and t1/2.
A total of 6 blood samples of 1 ml* will be drawn per patient in a single
daytime hospitalisation. Blood samples will be collected in prechilled K2-EDTA
tubes prior to Kimozo administration and at 0.10-0.20 (6-12 min), 0.33-0.66
(20-40 min), 0.75-1.5 (45-90 min), 2.0-3.0 and 6.0-8.0 hours post-dose. The
administered dose and exact time for each sample will be recorded. Should a
patient be naïve to any prior treatment with TMZ, the pre-treatment sample is
not necessary.
*a minimum of 750 µL for blood sampling is required to collect 100 µL of plasma
in duplicate
Secondary outcome
Secondary endpoints:
• Acceptability
The acceptability of the oral suspension of temozolomide will be scored with a
standardized assessment tool: CAST - ClinSearch Acceptability Score Test®. This
tool measures 9 observational drivers of medicine acceptability.
A paper diary will be filled-in to assess palatability/acceptability of the
oral suspension of temozolomide.
• Safety
Safety events recorded by the caregiver in the patient diary will be medically
controlled on a monthly basis by the principal investigator before collection
of data into the CRF.
Safety follow-up: 21 or 28 days (or up to the next temozolomide cycle),
including buccal tolerance (at day 5 and until day 21 or 28). Patient diary
will be used to collect data.
After completion, patients will be proposed to receive Kimozo as a
compassionate-use treatment for 5 additional treatment cycles. Safety data will
be collected during this compassionate period.
• Activity
The clinical activity of the oral suspension of temozolomide during the
compassionate use period will be described according to the standard follow-up
exams and tests (i.e. complete or partial response, disease progression, stable
disease)
Background summary
Temozolomide (TMZ) obtained market authorization in the European Union (EU) in
1999. In adults, it is used for the treatment of newly diagnosed glioblastoma
multiforme concomitantly with radiotherapy and subsequently as monotherapy
treatment. It is also indicated for the treatment of recurrent (post standard
therapy) malignant glioma, such as glioblastoma multiforme or anaplastic
astrocytoma, in both adults and paediatric patients above three years of
age[3]. In paediatric patients, it is also used off-label to treat tumours such
as rhabdomyosarcoma, medulloblastoma, sarcoma, Ewing sarcoma and relapsed or
refractory neuroblastoma (NB). The efficacy and safety of the drug in NB have
been demonstrated in multiple published clinical trials. Today it is considered
as the mainstay of therapy and is used as such in the major ongoing clinical
trials conducted in Europe and in
the USA and is recommended in major guidelines for this condition.
TMZ is a pro-drug. At physiologic pH, it spontaneously hydrolyses into
3-methyl-(triazen-1- yl)imidazole-4-carboxamide (MTIC), which spontaneously
fragments into 4-amino-5-imidazole carboxamide (AIC) and methyldiazonium, the
alkylating agent which transfer methyl groups to DNA nucleotides, causing a
cytotoxic effect on rapidly proliferating cells.
The most commonly administered paediatric regimens of TMZ are:
• As single agent: 150 mg/m²/day for 5 days, with subsequent dose escalation to
200 mg/m²/day in the absence of significant myelosuppression, every 28 days.
• In combination with topotecan: 150 mg/m²/day for 5 days, every 28 days.
• In combination with irinotecan: 100 mg/m²/day for 5 days, every 21 days.
ORPHELIA Pharma is developing Kimozo, a new formulation of temozolomide (TMZ),
intended for paediatric use from the age of one year.
Study objective
Primary objective:
• Evaluate PK parameters of the oral suspension of temozolomide in the
paediatric population aged 1 year and over.
Secondary objectives:
• Evaluate the safety of the oral suspension of temozolomide,
• Evaluate the acceptability of the oral suspension of temozolomide.
• Describe the activity of the oral suspension of temozolomide over the course
of a 6-month-treatment period (complete or partial response, disease
progression, stable disease) according to the standard follow up exams and
tests recommended for each indication
Study design
Non-randomized, international, multi-centre, open-label, singlearm study
Intervention
A total of 6 blood samples of 1 ml will be drawn per patient in a single
daytime hospitalisation. Blood samples will be collected in prechilled K2-EDTA
tubes prior to Kimozo administration and at 0.10-0.20 (6-12 min), 0.33-0.66
(20-40 min), 0.75-1.5 (45-90 min), 2.0-3.0 and 6.0-8.0 hours post-dose.
Study burden and risks
Risks ad benefits are described in section E 9 of the ARB form.
Boulevard Saint-Michel 85
Paris 75005
FR
Boulevard Saint-Michel 85
Paris 75005
FR
Listed location countries
Age
Inclusion criteria
Paediatric patients already receiving commercially available temozolomide-based
treatment or naïve paediatric patients requiring temozolomide-based treatment
as per investigator*s decision (all indications with 5-day treatment per 21- or
28-day cycle). Indications include those described in the Temodal SmPC (i.e.
malignant glioma such as glioblastoma and anaplastic astrocytoma). For patients
having no therapeutic alternatives, the IMP may be used in off-label
indications in accordance with current treatment protocols recommended by
European and International Medical Associations (e.g. SIOPEN, EPSSG, COG,
European ITCC, SIOP,*). Such indications include but are not limited to
primarily neuroblastoma, medulloblastoma and also rhabdomyosarcoma, or Ewing
sarcoma
• Male and female patients aged 1 to less than 18 years
• Patients who have signed the informed consent or for which one, both parents
or legal guardian (depending on local legislation) have signed the informed
consent.
• Patients having records of coverage by a health insurance
• Life expectancy >= 3 months
• Adequate haematological function:
o haemoglobin >= 80 g/L (transfusion support authorized)
o neutrophil count >= 1.0 x 109 cells/L
o platelet count >= 100 x 109 cells/L (without transfusion support)
o in case of bone marrow involvement: neutrophils >= 0.5 x 109 cells/L and
platelets >=75 x 109 cells/L
• Adequate renal function:
o Creatine clearance >= 60 mL/min.1.73m² according to the Schwartz formula [1]
or its modified form
[2]
• Adequate hepatic function:
o bilirubin <=1.5 x ULN
o AST and ALT <= 2.5 x ULN (AST, ALT 5xULN in case of liver metastases)
• Lansky Score >= 70%
Exclusion criteria
• Patient treated with sodium valproate within two weeks prior to receiving
Kimozo or patients who are coadministrated on day one of Kimozo administration
with sodium valproate as it decreases the clearance of temozolomide.
• Patients with (naso)gastric tube administration of Kimozo
• Patients already enrolled in studies investigating temozolomide or other
investigational new drugs.
• A post-menarche female with a positive blood/urine pregnancy test at
inclusion.
• Known contraindication or hypersensitivity to temozolomide or any chemically
close substance.
• Persons who are living in a facility by order of a court or an administrative
order.
• Patients infected by a SARS-CoV-2 variant.
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 | EUCTR2020-003733-38-NL |
| ClinicalTrials.gov | NCT04610736 |
| CCMO | NL75513.041.21 |