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

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by Hospital Sant Joan de Deu
Sponsor:
Collaborators:
Fundació Sant Joan de Déu
Spanish National Health System
Information provided by (Responsible Party):
Hospital Sant Joan de Deu
ClinicalTrials.gov Identifier:
NCT01574092
First received: March 29, 2012
Last updated: October 7, 2014
Last verified: October 2014
  Purpose

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.


Condition Intervention Phase
Pediatric High Risk Gliomas
Drug: Combination of two marketed drugs (irinotecan and cisplatin)
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II, Single Arm, Open Label Clinical Trial With Irinotecan in Combination With Cisplatin in Pediatric Patients With Unfavorable Prognosis Gliomas

Resource links provided by NLM:


Further study details as provided by Hospital Sant Joan de Deu:

Primary Outcome Measures:
  • The primary objective of this study is to determine the safety and objective response rate (ORR). [ Time Frame: Clinical signs, AEs, SAEs, ARs, SARs, Imaging and Audiometry changes: from baseline to FUP month 12. ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • Duration of the response. [ Time Frame: 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). ] [ Designated as safety issue: No ]
    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).

  • Safety of the combined Irinotecan+Cisplatin therapy [ Time Frame: 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. ] [ Designated as safety issue: Yes ]
    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).

  • Possible associations of gene MGMT promoter and microsatellites instability with reference to response to study treatment [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.

  • To assess the applicability and efficacy of volumetric measurements as a treatment tumor-response indicator. [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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.

  • To assess the applicability and efficacy of metabolic study by PET-methionine [ Time Frame: Clinical signs: baseline (day-14to-9) and every week (w1to21)+FUP month 3,6,9,12. PET: Baseline day-14to -9 + w20). ] [ Designated as safety issue: No ]
    The aim of this secondary outcome measure is to assess the applicability and efficacy of the metabolic study by PET-methionine


Estimated Enrollment: 45
Study Start Date: November 2009
Estimated Study Completion Date: December 2014
Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Irinotecan plus Cisplatin combination
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)
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.
Other Names:
  • Irinotecan Hospira (20mg/ml)
  • Cisplating Ferrer Farma(10mg or 50mg presentations)

  Hide Detailed Description

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

Ages Eligible for Study:   6 Months to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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. -
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01574092

Contacts
Contact: OFELIA CRUZ, MD, PhD Ocruz@hsjdbcn.org

Locations
Spain
Hospital Sant Joan De Déu Recruiting
Esplugues de Llobregat, Barcelona, Spain, 08950
Contact: OFELIA CRUZ, MD, PhD         
Sponsors and Collaborators
Hospital Sant Joan de Deu
Fundació Sant Joan de Déu
Spanish National Health System
Investigators
Principal Investigator: OFELIA CRUZ, MD, PhD HOSPITAL DE SANT JOAN DE DÈU
  More Information

Additional Information:
Publications:

Responsible Party: Hospital Sant Joan de Deu
ClinicalTrials.gov Identifier: NCT01574092     History of Changes
Other Study ID Numbers: HSJD-GLIOMAS-IC
Study First Received: March 29, 2012
Last Updated: October 7, 2014
Health Authority: Spain: Spanish Agency of Medicines
Spain: Ministry of Health
Spain: Departament de Salut de la Generalitat de Catalunya
Spain: Ethics Committee

Keywords provided by Hospital Sant Joan de Deu:
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

Additional relevant MeSH terms:
Glioma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Camptothecin
Cisplatin
Irinotecan
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Radiation-Sensitizing Agents
Therapeutic Uses
Topoisomerase I Inhibitors
Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on November 24, 2014