Neoplasms

All Conditions

Nervous System Diseases

Rare Diseases

Glioma

Brain Neoplasms

Brain Stem Neoplasms

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Childhood Brain Stem Glioma

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Irinotecan

Cisplatin

Topoisomerase I Inhibitors

Enzyme Inhibitors

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.

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.

Combination of two marketed drugs (irinotecan and cisplatin)

OFELIA CRUZ, MD, PhD

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.

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.

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

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

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.

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).

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).

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.

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.

The aim of this secondary outcome measure is to assess the applicability and efficacy of the metabolic study by PET-methionine

Fundació Sant Joan de Déu

Spanish National Health System

Hospital Sant Joan de Deu

Central Nervous System Neoplasms

Nervous System Neoplasms

fresh-frozen and fixed tumor samples and correspondent normal tissue from patients affected with this tumor.(peripheral blood is applicable only to patients with focal brainstem gliomas and patients who undergo biopsy of a diffuse brainstem glioma at diagnosis)

Alberto Broniscer, MD

This multi-institutional study will prospectively collect tumor and constitutional tissue samples from patients with diffuse brainstem glioma and other types of brainstem gliomas either during therapy or at autopsy to perform an extensive analysis of genetic and molecular abnormalities in these tumors.

Since very little is known about the biology of diffuse brainstem glioma, the goal of this protocol is to undertake a systematic analysis of DNA abnormalities, and of RNA and protein expression in prospectively collected fresh-frozen and fixed tumor samples and correspondent normal tissue from patients affected with this tumor.

OBJECTIVES:

* Perform genome-wide analysis of DNA gains and losses and RNA expression in tumor samples and normal tissue from patients with diffuse brain stem glioma.
* Identify regions of genomic gain or loss using either array comparative genomic hybridization or single nucleotide polymorphism arrays.
* Investigate genome-wide expression patterns of RNA derived from tumor samples and normal tissue from these patients via Affymetrix gene expression profiling.
* Validate the results of the genome-wide analysis by conducting further evaluation of candidate genes or by investigating the expression of relevant gene products at the RNA and protein levels.
* Perform analysis of mutations in candidate tumor-suppressor genes and oncogenes (including whole genome sequencing studies) using direct sequence analysis of tumor DNA and confirm the tumor-specific nature of these mutations by analyzing the correspondent constitutional DNA.
* Confirm genomic gains or losses identified by means of fluorescence in situ hybridization (FISH) performed on tissue microarray using non-neoplastic brain tissue from each patient as control when available.
* Explore protein expression patterns identified by immunohistochemistry or western blot and compare them to normal brain stem tissue.
* To obtain a follow-up (questionnaire and/or telephone interview) after autopsy with parent(s), legal guardian(s), or family members of research participants in the United States to assess aspects associated with this procedure, including potential benefits and drawbacks

tumor and constitutional tissue samples from patients with diffuse brainstem glioma and other types of brainstem gliomas

DNA Analysis of Tumor Tissue Samples From Patients With Diffuse Brain Stem Glioma

Comprehensive Molecular Analysis of Tumor Samples Derived From Patients With Diffuse Brainstem Glioma - A Pilot Study

Tissue samples will be obtained at autopsy.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Irinotecan in Combination With Cisplatin in Pediatric Patients With Unfavorable Prognosis Gliomas	NCT01574092	Pediatric High ...	Combination of ...	6 Months - 18 Years	Hospital Sant Joan de Deu
Irinotecan in Combination With Cisplatin in Pediatric Patients With Unfavorable Prognosis Gliomas	NCT01574092	Pediatric High ...	Combination of ...	6 Months - 18 Years	Hospital Sant Joan de Deu
DNA Analysis of Tumor Tissue Samples From Patients With Diffuse Brain Stem Glioma	NCT00899834	Brain Tumors Central Nervous...		- 18 Years	St. Jude Children's Research Hospital

Spots Global Cancer Trial Database for childhood brain stem glioma