Clinical trial NCT01574092: Irinotecan in Combination With Cisplatin in Pediatric Patients With Unfavorable Prognosis Gliomas
Official title: Phase II, Single Arm, Open Label Clinical Trial With Irinotecan in Combination With Cisplatin in Pediatric Patients With Unfavorable Prognosis Gliomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pediatric High Risk Gliomas
Keywords: Pediatric
Pediatrics
Gliomas
Glioma
Brain tumor
Brain cancer
Cisplatin
Cisplatino
Irinotecan
Brain stem tumor
Brainstem gliomas
Intrinsic brain stem tumor
PAEDIATRIC HIGH GRADE GLIOMA
Childhood brain stem glioma
Lead sponsor: Hospital Sant Joan de Deu
Sponsor class: OTHER
Collaborators: name: Fundació Sant Joan de Déu
name: Spanish National Health System
First posted: 2012-04-10
Enrollment: 39
Sex: ALL
Minimum age (years): 6
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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 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 study.

Detailed description: 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 study.

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.

Eligibility 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 inclusion.
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. -

Primary outcomes:
measure: The primary objective of this study is to determine the safety and objective response rate (ORR).
timeFrame: Clinical signs, AEs, SAEs, ARs, SARs, Imaging and Audiometry changes: from baseline to FUP month 12.
Secondary outcomes:
measure: Duration of the response.
timeFrame: Clinical signs: baseline and every week (w1to21)+FUP month 3,6,9,12. Imaging (RM Baseline+w10&20+FUP month 3,6,9,12/PET: Baseline+w20).
measure: Safety of the combined Irinotecan+Cisplatin therapy
timeFrame: Clinical signs, AEs, SAEs, ARs, SARs: baseline and every week (w1to21)+FUP month 3,6,9,12.Blood (hemo/chem):baseline&every week (w 1 to 21, except w10). Audiometry: baseline+w20+m6+m12.
measure: Possible associations of gene MGMT promoter and microsatellites instability with reference to response to study treatment
timeFrame: Clinical signs: baseline and every week (w1to21)+FUP month 3,6,9,12. Imaging (RM Baseline+w10&20+FUP month 3,6,9,12/PET: Baseline+w20). Genomic study: baseline (week-14 to-9)
measure: To assess the applicability and efficacy of volumetric measurements as a treatment tumor-response indicator.
timeFrame: Clinical signs: baseline (day-14to-9) and every week (w1to21)+FUP month 3,6,9,12. Imaging (RM Baseline day-14to -9 +w10&20+FUP month 3,6,9,12.
measure: To assess the applicability and efficacy of metabolic study by PET-methionine
timeFrame: Clinical signs: baseline (day-14to-9) and every week (w1to21)+FUP month 3,6,9,12. PET: Baseline day-14to -9 + w20).
Other outcomes:
Locations:
city: Esplugues de Llobregat
country: Spain
facility: Hospital Sant Joan De Déu
state: Barcelona
Study officials:
affiliation: HOSPITAL DE SANT JOAN DE DÈU
name: OFELIA CRUZ, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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