The primary objective of this study is to evaluate the PK of POS administered orally at three dosage levels to immunocompromised children with expected neutropenia (selected oncology patients, aplastic anemia patients and patients which undergo a…
ID
Source
Brief title
Condition
- Other condition
- Leukaemias
- Fungal infectious disorders
Synonym
Health condition
stamceltransplantatie patienten
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of this study is to evaluate the PK of POS administered
orally at three dosage levels to immunocompromised children with neutropenia or
expected neutropenia aged 3 months to <18 years.
Secondary outcome
The secondary objective of this study is to evaluate the safety and
tolerability of POS administered orally at three dosage levels to
immunocompromised children with neutropenia or expected neutropenia aged 3
months to <18 years, and to compare the exposures to POS in pediatric subjects
to those from an adult population with similar underlying conditions.
Background summary
Children who are treated for certain malignancies or for aplastic anaemia or
who must undergo a stem cell transplant have an elevated risk of experiencing
an invasive fungal infection as a consequence of a combination of factors:
frequent and/or long-lasting neutropenia, perforation of the skin and mucosal
barrier by catheters and chemotherapy or immunosuppressive therapy and the
frequent use of broad-spectrum antibiotics. Prophylaxis against fungal
infection is therefore recommended in such patients, whereby we usually choose
an antifungal compound that protects against both Candida as well as
Aspergillus. This is currently chiefly being done with itraconazole, which is
only well absorbed from the intestines as a drink (Trisporal Oral Solution). We
use various compounds (such as fluconazole with Candida and voriconazole with
Aspergillus) for infections that break through this prophylaxis. Caspofungin is
also available nowadays, with activity against Aspergillus and Candida, as well
as (liposomal) amphotericin-B, which has disadvantages in the form of IV
administration and nephrotoxicity. Despite this therapeutic armamentarium, we
still lose patients to invasive fungal infections and an expansion of the
prophylactic and therapeutic possibilities are desired.
Posaconazole (POS) is a new, oral, broad-spectrum antifungal agent. The
mechanism of action is selective inhibition of the enzyme lanosterol 14
demethylase (CYP51A1), which is involved in ergosterol biosynthesis in yeasts
and moulds. POS has, in comparison to the standard treatments, a better
response and shows better survival with refractory aspergillosis in adults.
Clinical success has also been obtained with other refractory invasive mould
infections which are difficult to treat (including fusariosis,
chromoblastomycosis and coccidioidomycosis). POS, in comparison to fluconazole
or itraconazole, provides a better prophylaxis against invasive femoral
infections and a better survival of neutropenic patients. It also shows, in
comparison to FLU, a better prophylaxis and survival in recipients of a
Haematopoietic Stem Cell Transplant (HSCT) with Graft Versus Host Disease
(GVHD). POS is usually well tolerated by adults and a dose adjustment is not
necessary for patients with poor renal function. It has a limited capacity for
drug-drug interactions.
POS is authorised for use by adults, among others as prophylaxis and treatment
in oncology and stem cell transplant patients, whereby 600 mg (~9 mg/kg/day)
and 800 mg per day (~11.5 mg/kg/day) are recommended, respectively.
The present study also includes investigation of the pharmacokinetics of
posaconazole in children, whereby no sub-therapeutic dose levels will be used.
It is therefore expected that patients exposed to POS will also gain a
therapeutic advantage from the treatment. It could certainly be an advantage in
patients who have already received prophylaxis for a longer time with a
different antifungal compound, because POS can still be active in situations
whereby resistance has developed against other antifungal compounds.
A connection between POS efficacy and plasma levels was found in studies with
adults and that is why this study is necessary for the selection of a correct
dose in children.
Study objective
The primary objective of this study is to evaluate the PK of POS administered
orally at three dosage levels to immunocompromised children with expected
neutropenia (selected oncology patients, aplastic anemia patients and patients
which undergo a stamcell transplant) aged 3 months to <18 years. The
PK-profile will be compared with the data available from adults. The safety and
tolerability of POSA will also be evaluated in these children.
Study design
This will be a non-randomized, multicenter, open-label, sequential dose
escalation PK study. Subjects enrolled will be immunocompromised children with
neutropenia or expected neutropenia between the ages of 3 months to <18 years.
The youngest age group of 3 months to 2 years of age, will not be enrolled
until the PK and safety data from the 2 older age groups and first 2 dose
groups have been independently reviewed by the Sponsor and the external Data
Monitoring Committee. The third dose level will be definitively selected when
the data regarding the PK and the safety of the other 2 dose-levels is known.
The administration of posaconazole will take place for a maximum of 28 days,
which means that patients will use this rather than the standard antifungal
prophylaxis that they would normally receive in the context of their standard
treatment. This period is equivalent to the time required for recovery from an
intensive chemotherapy cure or a stem cell transplant.
Intervention
Dosing Groups for Age Group 1 (2 years to <7 years) and Age Group 2 (7 years to
<18 years)
Group 1: POS oral suspension 12 mg/kg/day orally divided into 2 doses (BID), up
to a maximum of 800 mg per day.
Group 2: POS oral suspension 18 mg/kg/day orally divided into 2 doses (BID), up
to a maximum of 1200 mg per day.
Group 3: POS oral suspension 18 mg/kg/day orally divided into 3 doses (TID), up
to a maximum of 1200 mg per day.
Dosing Groups for Age Group 3 (3 months to <2 years)
Group 1: POS oral suspension 12 mg/kg/day orally divided into 3 doses (TID), up
to a maximum of 800 mg per day.
Group 2: POS oral suspension 18 mg/kg/day orally divided into 3 doses (TID), up
to a maximum of 1200 mg per day.
There is no planned third dosing group for Age Group 3.
Study burden and risks
Children will receive posaconazole rather than a standard antifungal treatment.
Administration will take place as a drink in both cases. The most important
burden consists of the collection of blood samples that will be collected from
a central line placed for the standard treatment. The most important
disadvantage of that is a mildly elevated risk of a line infection.
POS must preferably be administered with a fat-rich meal. This will not always
be possible in children being treated for the underlying condition concerned.
Another potential disadvantage could be that patients must switch antifungal
prophylaxis, because the maximum exposure to posaconazole is limited to 28
days. Patients will then again receive the standard prophylaxis, if there is an
indication for it.
Waarderweg 39
Haarlem 2031 BN
NL
Waarderweg 39
Haarlem 2031 BN
NL
Listed location countries
Age
Inclusion criteria
1. Children of either sex and of any race, 3 months to <18 years of age.;2. Subjects* parent or legally authorized representative must be willing to give written informed consent. Assent will be obtained from minors according to institutional practices.;3. Subjects must have documented or anticipated neutropenia (ANC <=500/mm3 [0.5 x 109/L]) expected to last for at least 7 days and only in the following clinical situations:
a. Acute leukemia (including new and relapse),
b. Myelodysplasia,
c. Severe aplastic anemia,
d. Autologous HSCT recipients,
e. High risk neuroblastoma,
f. Advanced stage non-Hodgkin*s lymphoma.
g. Recipients of allogeneic HSCT during the pre-engraftment period
(neutropenia period).;4. Male and female subjects of child-bearing potential must agree to use a medically accepted method of contraception throughout the study and for at least 30 days after stopping the medication, unless they are surgically or medically sterile or agree to abstain from sexual intercourse. Acceptable methods of contraception include 2 of the following:
a. Condoms (male or female) with spermicide,
b. Diaphragm or cervical cap (if acceptable according to local standard of care) with spermicide
(females),
c. Hormonal contraceptives or intrauterine device with spermicide (females).
Exclusion criteria
1. Subjects with proven IFI, as defined by the MSG/EORTC criteria (see Appendix 3), prior to study entry.;2. Subjects with Grade 3 or Grade 4 nausea and/or vomiting at Screening.;3. Subjects who have received POS within the past 10 days prior to Screening.;4. Subjects receiving prohibited drugs (please refer to Table3).;5. Subjects whose laboratory tests are outside normal limits, as follows:
a. AST or ALT >5 times the upper limit of normal (ULN)
b. Serum total bilirubin >2.5 x ULN
c. Calculated creatinine clearance <30 mL/min. Creatinine clearance will be calculated using the
following equation: Creatinine clearance = k*height (cm)/serum creatinine (mg/dL)
Where k = 0.45 for a full term baby less than 1 year old; 0.55 for children up to 12 years old; 0.55
for females between the ages of 13 and 21 years; 0.7 for males between the ages of 13 and 21
years.;6. Subjects with QTc prolongation:
a. Symptomatic QTc prolongation >450 msec (males) or >470 msec (females)
b. Any QTc prolongation of >500 msec;7. Subjects who are unable to receive study drug enterally.;8. Female subjects who are pregnant, intend to become pregnant during the course of the study, or are breast-feeding.;9. Subjects with a history of anaphylaxis attributed to the azole class of antifungal agents.;10. Subjects with any clinically significant condition or situation, other than the condition being studied that, in the opinion of the investigator, would interfere with the study evaluations or optimal participation in the study, including receiving less than 7 days of POS.;11. Subjects who have already participated in this study or are participating in any Phase 1 clinical study or any study for a medication that has not yet received regulatory approval. Note: If the medication has received a regulatory approval for use in adults, then the medication would be considered to have received a regulatory approval for the purpose of this criterion. Any medication received by eligible subjects must also be aligned with the protocol guidance for prohibited medications (Table 3). ;12. Subjects who are part of the study staff personnel or family members of the study staff personnel.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2007-004645-15-NL |
| CCMO | NL31381.000.10 |
| Other | zie aanvullende opmerkingen |