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Phase II, Single Arm, Open Label Clinical Trial With Irinotecan in Combination With Cisplatin in Pediatric Patients With Unfavorable Prognosis Gliomas

Phase 2
6 Months
18 Years
Open (Enrolling)
Pediatric High Risk Gliomas

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Trial Information

Phase II, Single Arm, Open Label Clinical Trial With Irinotecan in Combination With Cisplatin in Pediatric Patients With Unfavorable Prognosis Gliomas

Tumours of the brain and of the central nervous system (CNS) are the most common solid
tumours in children. Amongst these, gliomas are the most frequent, although this term covers
different histological subtypes, the most frequent being astrocytoma. However, they are rare
diseases of low prevalence.

The mortality rate of pediatric CNS cancer has not decreased in the same proportion as other
tumours in children. High grade gliomas have a unfavorable prognosis with few therapeutic
options. The objective response rate (ORR) of these tumours to chemotherapy ranges from 11%
to 27%, in the best of cases. Relapsed high-grade gliomas and intrinsic brain stem tumours
have a uniformly fatal outcome despite all the treatments tested. The treatment of adults
with de novo glioblastoma after surgical resection is local radiotherapy concomitant to
temozolomide. This approach in children is still under clinical assessment. In the case of
low-grade astrocytomas, the indication for adjuvant therapy is limited to patients with
unresectable tumours that also cause a neurological lesion. Although they are slow growing
tumours, they can cause severe morbidity and are life-threatening. Radiotherapy has known
side effects on the nervous system in children. Chemotherapy is used to delay or avoid
radiotherapy in these patients.

Most of the radiological studies that evaluate treatment response of gliomas focus on
measuring the area of the lesion. However, nowadays new imaging strategies and functional
tests such as PET can be applied. The uptake of the 11C methionine tracer in tumour tissue
is more selective than that of glucose and provides good delineation for the evaluation of
these tumours.

There are few studies on the molecular and genetic characteristics of gliomas in children.
In adults, it has been reported that microsatellite instability is a predictive factor of
the tumour response to irinotecan, because the defect in the DNA repair proteins results in
a greater sensitivity to the drug. Furthermore, in adults, 30-40% of the high grade
astrocytomas show MGMT promotor methylation and as a consequence the methylated tumours are
more sensitive to the effect of alkylating drugs. Due to the lack of pediatric studies on
MGMT promoter methylation and on microsatellites the question as to whether their
determination has the same importance as in high grade glioma in adults cannot be answered.

Irinotecan is a prodrug of the camptothecin family. Phase I and Phase II clinical trials
using irinotecan in pediatric patients with different neoplasias demonstrate that irinotecan
is well tolerated. The weekly administration of irinotecan and cisplatin in Phase I trials
showed that treatment is well tolerated and the dose reached was 65 mg/m2 of irinotecan
weekly together with cisplatin 30 mg/m2 weekly.

The interest in the cisplatin/irinotecan combination in brain tumours motivated a previous
pilot study at our hospital, with encouraging results. This experience, together with the
need for new strategies for high-risk pediatric gliomas has motivated the conduct of this

The impact of this study, if treatment proves to be effective, will be highly significant,
given the poor response of gliomas to the adjuvant treatment used so far. Pediatric gliomas
are of low incidence and may be considered as "orphan" diseases, and therefore as low
priority as regards funding. However, because of their unfavorable prognosis these diseases
have high clinical and social repercussions, especially high grade gliomas and high risk low
grade gliomas, with less mortality but a high incidence of sequelae.

Other information relevant to the study

Phase II, single arm, open label trial, conducted at one institution, on the combination of
two marketed drugs (irinotecan and cisplatin) in a new therapeutic indication.

Patients will receive weekly a 30 mg/m2 dose of cisplatin and a 65 mg/m2 dose of irinotecan
(one cycle), up to a total of 16 cycles.

After 8 treatment cycles, Cohort 1 (recently diagnosed high-grade glioma) and Cohort 3
(intrinsic brain stem tumour) patients will be evaluated for treatment response and if there
is disease progression they will be withdrawn from the trial and will receive conventional
treatment with radiotherapy together with temozolomide (Stupp 2005). Patients with disease
progression at any time during the trial will also be withdrawn. Patients who respond will
continue until completing the 16 cycles of irinotecan and cisplatin at the end of which they
will continue with conventional therapy. Cohort 2 (recurrent high-grade glioma) and Cohort 4
(high risk low-grade glioma) patients will also be evaluated after 8 cycles and if there is
disease progression they will be withdrawn from the trial, if not they will complete the
full 16 cycles.

Inclusion Criteria

Inclusion criteria:

1. Histological confirmation of neoplasia, except for intrinsic brain stem tumour and
optic pathway glioma in one patient with neurofibromatosis type 1 (NF1).

2. Pertaining to one of the diagnostic groups: Cohort 1: Recently diagnosed high grade
glioma. Cohort 2: Recurrent high grade glioma. Cohort 3: Intrinsic brain stem tumour.
Cohort 4: High risk low grade glioma.

3. Measurable primary or metastatic tumours with at least one 10 mm diameter lesion in
two MR dimensions.

4. Absence of prior treatment with cisplatin or irinotecan.

5. Aged between 6 months to 18 years.

6. Lansky/Karnofsky performance status ≥ 70% (Appendix 6.1). Neurological deficits
secondary to the tumour should be stable before entering the trial.

7. Patients receiving dexamethasone should be on a stable or decreasing regimen before

8. Life expectancy ≥ 3 months.

9. Adequate organic function, including haematological, renal and hepatic function.

10. Wash-out period of at least 3 weeks after chemotherapy and 6 weeks after nitrosoureas
or radiotherapy. Recovery from all toxic effects of previous treatments.

11. Subjects of fertile age should use an effective birth control method throughout the
entire study. Women of child-bearing age will be included after a negative pregnancy
test result.

12. Informed consent of the parents or legal representative, and informed consent of the
mature minor.

Exclusion criteria:

1. Concurrent administration of any other anti-cancer treatment.

2. Pre-existing, non-controlled diarrhoea

3. Pregnancy or lactation

4. Treatment in another clinical trial.

5. Serious concomitant disease that could compromise the completion of the trial. -

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The primary objective of this study is to determine the safety and objective response rate (ORR).

Outcome Description:

The primary objective is to determine the safety and objective response rate (ORR), defined according to the criteria given in the CPMP/EWP/205/95/Rev.3/Corr.2, of irinotecan + cisplatin in pediatric patients with gliomas, through clinical signs and MR. The primary variable is the ORR.

Outcome Time Frame:

Clinical signs, AEs, SAEs, ARs, SARs, Imaging and Audiometry changes: from baseline to FUP month 12.

Safety Issue:


Principal Investigator


Investigator Role:

Principal Investigator

Investigator Affiliation:



Spain: Spanish Agency of Medicines

Study ID:




Start Date:

November 2009

Completion Date:

March 2014

Related Keywords:

  • Pediatric High Risk Gliomas
  • Pediatric
  • Pediatrics
  • Gliomas
  • Glioma
  • Brain tumor
  • Brain cancer
  • Cisplatin
  • Cisplatino
  • Irinotecan
  • Brain stem tumor
  • Brainstem gliomas
  • Intrinsic brain stem tumor
  • Childhood brain stem glioma
  • Glioma