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

Brain Diseases

Central Nervous System Diseases

Anti-Inflammatory Agents

Antirheumatic Agents

Analgesics

Rofecoxib

Cyclooxygenase 2 Inhibitors

Cyclooxygenase Inhibitors

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

Starting dose for patients age 3-14 years 10.0 mg/1.73 m2 and for patients above 14 years of age 12.5 mg for 5 days per week for 6 weeks during radiation treatment, and 7 days per week for 6 months after radiation treatment.

Vioxx

Eric L. Chang, MD

It is of interest to determine whether COX-2 inhibitors given with radiation therapy can prolong the progression-free survival in brain stem glioma. Diffuse pontine brainstem gliomas are more common in children, but are also seen in adults. However, the use of commercially available COX-2 inhibitors has not been evaluated in the pediatric population and the proper dosing in pediatrics is unknown. Therefore a Phase I study will need to be conducted as a first step. Rofecoxib is an FDA approved COX-2 inhibitor for use in adults. This phase I study is designed to determine the maximum tolerated dose of Rofecoxib given concurrently with standard radiation therapy for diffuse pontine brainstem glioma.

Rofecoxib is a non-steroidal anti-inflammatory drug.

Patients in this study will take a certain amount of rofecoxib by mouth either once or twice a day during treatment with radiation therapy. They will continue to take rofecoxib for 6 months after the end of radiation therapy. Different dose levels will be given to different patients based on a statistical dose escalation (increase) program run on a computer called the Continuous Reassessment Method. At least 3 patients will be treated on each dose level starting at the lowest level. All patients are required to fill out a medication diary, documenting the dose of rofecoxib they are taking and the time they take it.

Patients will receive radiation therapy once a day, five days a week for six weeks.

During treatment, patients will have a weekly exam, including blood work and urine tests. The blood work will include liver and kidney function tests as well as coagulation (blood clotting) tests.

Patients will be taken off study if intolerable side effects occur, including bleeding and/or severe allergic response.

During the 6 months after completion of radiation, while patients are still receiving rofecoxib, monthly medical histories, physical exams, blood tests, and urine tests will be performed. Patients will have a MRI at 1, 3, and 6 months after completion of radiation therapy.

The first year after completion of rofecoxib therapy, patients will be interviewed and examined with blood and urine tests and MRI every 3 months. During 1-3 years following completion of rofecoxib therapy, this will be repeated every 6 months. After 3 years following completion of rofecoxib, follow-ups will occur yearly.

This is an investigational study. Rofecoxib is currently approved by the FDA for use in adults only. A maximum of 30 patients will take part in this study at UTMDACC.

Study of Vioxx and Radiation Therapy for Brainstem Glioma

Phase I Study of Vioxx and Radiation Therapy for Brainstem Glioma

Maximum Tolerated Dose defined using each level's dose limiting toxicity (DLT) and continuous reassessment method (CRM).

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
Study of Vioxx and Radiation Therapy for Brainstem Glioma	NCT00038389	Glioma Brain Neoplasms	Vioxx	3 Years - 85 Years	M.D. Anderson Cancer Center
Study of Vioxx and Radiation Therapy for Brainstem Glioma	NCT00038389	Glioma Brain Neoplasms	Vioxx	3 Years - 85 Years	M.D. Anderson Cancer Center
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

Spots Global Cancer Trial Database for brain stem tumor