Irinotecan in Combination With Cisplatin in Pediatric Patients With Unfavorable Prognosis Gliomas

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Pediatric High Risk Gliomas

Intervention / Treatment
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* Drug: Combination of two marketed drugs (irinotecan and cisplatin)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Histological confirmation of neoplasia, except for intrinsic brain stem tumour and optic pathway glioma in one patient with neurofibromatosis type 1 (NF1). 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. Measurable primary or metastatic tumours with at least one 10 mm diameter lesion in two MR dimensions. Absence of prior treatment with cisplatin or irinotecan. Aged between 6 months to 18 years. Lansky/Karnofsky performance status ≥ 70% (Appendix 6.1). Neurological deficits secondary to the tumour should be stable before entering the trial. Patients receiving dexamethasone should be on a stable or decreasing regimen before inclusion. Life expectancy ≥ 3 months. Adequate organic function, including haematological, renal and hepatic function. 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. 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. Informed consent of the parents or legal representative, and informed consent of the mature minor. Exclusion criteria: Concurrent administration of any other anti-cancer treatment. Pre-existing, non-controlled diarrhoea Pregnancy or lactation Treatment in another clinical trial. Serious concomitant disease that could compromise the completion of the trial. -

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Irinotecan plus Cisplatin combination<br>This is a open-label study with only one treatment experimental arm. The patients will be treated, in a weekly basis, with 30 mg/m2 of cisplatino plus 65 mg/m2 of irinotecán (one cycle), until a total of 16 cycles. | Drug: Combination of two marketed drugs (irinotecan and cisplatin)<br>* Irinotecan and Cisplatin will be administered weekly ambulatory, intravenous (iv), until to reach a total of 16 cycles. Cisplatin is administered first and then Irinotecan. Cisplatin 30 mg/m2/d (iv) in one hour,followed by Irinotecan 65 mg/m2/d iv in one hour. There is a one-week rest period every 4 cycles. The total treatment length including 16 cycles + rest weeks is 19 weeks.<br>* Other names: Cisplating Ferrer Farma(10mg or 50mg presentations);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary objective of this study is to determine the safety and objective response rate (ORR). | 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. | Clinical signs, AEs, SAEs, ARs, SARs, Imaging and Audiometry changes: from baseline to FUP month 12. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of the response. | The secondary variable has the aim to assess the duration of response by measuring the time to progression (TP), the time to treatment failure (TF) and overall survival (OS). | 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). | 
| Safety of the combined Irinotecan+Cisplatin therapy | The secondary variable aims to assess the safety of combined Irinotecan+Cisplatin therapy in study population (children and teens. Treatment safety will be assessed according to the Common Terminology Criteria for Adverse Events v3.0, (CTCAE). | 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. | 
| Possible associations of gene MGMT promoter and microsatellites instability with reference to response to study treatment | The secondary variable aims to search if there could be any possible association between silent MGMT and the inestability of microsatellites with refernce to the response reached with the combined Irinotecan plus Cisplatin therapy in paediatrics glioma. | 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) | 
| To assess the applicability and efficacy of volumetric measurements as a treatment tumor-response indicator. | The aim of this secondary outcome measure is to assess the applicability and efficacy of the volumetric study measurement during the radiology assessment with reference to the tumour response to the study treatment. | 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. | 
| To assess the applicability and efficacy of metabolic study by PET-methionine | The aim of this secondary outcome measure is to assess the applicability and efficacy of the metabolic study by PET-methionine | Clinical signs: baseline (day-14to-9) and every week (w1to21)+FUP month 3,6,9,12. PET: Baseline day-14to -9 + w20). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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, Pediatric