Irinotecan in Combination With Cisplatin in Pediatric Patients With Unfavorable Prognosis Gliomas
Condition: Pediatric High Risk Gliomas
MeSH terms: Glioma
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Combination of two marketed drugs (irinotecan and cisplatin)
Intervention type(s): Drug
Intervention description(s): 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 intervention name(s): Irinotecan Hospira (20mg/ml); Cisplating Ferrer Farma(10mg or 50mg presentations)
Intervention MeSH terms: Irinotecan
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
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