Cisplatin and Temozolomide in Treating Young Patients With Malignant Glioma

Phase II Study of the Combination of Cisplatin + Temozolomide in Malignant Glial Tumours in Children and Adolescents at Diagnosis or in Relapse

RATIONALE: Drugs used in chemotherapy, such as cisplatin and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving cisplatin together with temozolomide works in treating young patients with malignant glioma.

Study Overview

• Status: Unknown
• Conditions: Brain and Central Nervous System Tumors
• Intervention / Treatment: Radiation: radiation therapy; Drug: temozolomide; Other: laboratory biomarker analysis; Drug: cisplatin; Other: immunohistochemistry staining method; Genetic: loss of heterozygosity analysis; Genetic: fluorescence in situ hybridization

Detailed Description

OBJECTIVES:

Primary

• Determine the objective response rate (complete and partial response) in pediatric patients with malignant gliomas treated with temozolomide and cisplatin.

Secondary

• Identify genetic, metabolic, and proteomic profiles that will provide an insight into the molecular pathways involved in the pathogenesis of these tumors.
• Link genetic changes with clinical details, histopathology, and patient outcome, thereby developing a biological basis for diagnosis, prognosis, and treatment monitoring.
• Evaluate relapse-free survival at 1 and 2 years in patients treated at diagnosis.
• Evaluate the duration of clinical response in patients treated at relapse.
• Study the health status and quality of life of these patients.
• Evaluate long-term toxicity of this therapeutic combination.
• Evaluate the ability of magnetic resonance spectroscopy vs CT scan to predict response in patients with high-grade astrocytomas.

OUTLINE: This is a multicenter, open-label, nonrandomized, parallel-group study. Patients are stratified according to disease status (newly diagnosed vs relapsed). Patients with newly diagnosed disease are further stratified according to spread of disease (localized and measurable vs diffuse unmeasurable).

• Stratum I (newly diagnosed disease): Patients receive CISTEM chemotherapy comprising cisplatin IV over 3 hours on day 1 and oral temozolomide once daily on days 2-6. Treatment repeats every 28 days for up to 7 courses. Patients who achieve responsive or stable disease after 2 courses receive 2 more courses of CISTEM chemotherapy and then undergo radiotherapy 5 days a week for 6 weeks. After completion of radiotherapy, patients may receive up to 3 more courses of CISTEM chemotherapy for a total of 7 courses.
• Stratum II (relapsed disease): Patients receive CISTEM chemotherapy for up to 7 courses as in stratum I. Patients who reach the maximum dose allowed for cisplatin may receive oral temozolomide alone indefinitely.

Tissue and blood samples are obtained at baseline and examined by immunohistochemistry, fluorescent in situ hybridization (FISH), and loss of heterozygosity. The tumor tissue is analyzed for p53, MSH2, MLH1, and MGMT.

After completion of study treatment, patients are followed periodically for 2 years.

PROJECTED ACCRUAL: A total of 87 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Anticipated): 87
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Villejuif, France, F-94805
    • Institut Gustave Roussy
• Ireland
  • Dublin, Ireland, 12
    • Our Lady's Hospital for Sick Children Crumlin
• United Kingdom
  • England
    • Birmingham, England, United Kingdom, B4 6NH
      • Birmingham Children's Hospital
    • Bristol, England, United Kingdom, BS2 8AE
      • Institute of Child Health at University of Bristol
    • Bristol, England, United Kingdom, BS2 8BJ
      • Bristol Royal Hospital for Children
    • Cambridge, England, United Kingdom, CB2 2QQ
      • Addenbrooke's Hospital at Cambridge University Hospitals NHS Foundation Trust
    • Leeds, England, United Kingdom, LS9 7TF
      • Leeds Cancer Centre at St. James's University Hospital
    • Leicester, England, United Kingdom, LE1 5WW
      • Leicester Royal Infirmary
    • Liverpool, England, United Kingdom, L12 2AP
      • Royal Liverpool Children's Hospital, Alder Hey
    • London, England, United Kingdom, WC1N 3JH
      • Great Ormond Street Hospital for Children NHS Trust
    • London, England, United Kingdom, W1T 3AA
      • Middlesex Hospital
    • Manchester, England, United Kingdom, M27 4HA
      • Central Manchester and Manchester Children's University Hospitals NHS Trust
    • Newcastle-Upon-Tyne, England, United Kingdom, NE1 4LP
      • Sir James Spence Institute of Child Health
    • Nottingham, England, United Kingdom, NG7 2UH
      • Queen's Medical Centre
    • Oxford, England, United Kingdom, 0X3 9DU
      • Oxford Radcliffe Hospital
    • Sheffield, England, United Kingdom, S10 2TH
      • Children's Hospital - Sheffield
    • Southampton, England, United Kingdom, SO16 6YD
      • Southampton University Hospital NHS Trust
    • Sutton, England, United Kingdom, SM2 5PT
      • Royal Marsden NHS Foundation Trust - Surrey
  • Northern Ireland
    • Belfast, Northern Ireland, United Kingdom, BT12 6BE
      • Royal Belfast Hospital for Sick Children
  • Scotland
    • Aberdeen, Scotland, United Kingdom, AB25 2ZG
      • Royal Aberdeen Children's Hospital
    • Edinburgh, Scotland, United Kingdom, EH9 1LF
      • Royal Hospital for Sick Children
    • Glasgow, Scotland, United Kingdom, G3 8SJ
      • Royal Hospital for Sick Children
  • Wales
    • Cardiff, Wales, United Kingdom, CF14 4XW
      • Childrens Hospital for Wales

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 20 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed diagnosis of 1 of the following grade III or grade IV malignant glial tumors*:

  • Glioblastoma
  • Anaplastic astrocytoma
  • Anaplastic oligodendroglioma
  • Anaplastic oligoastrocytoma
  • Anaplastic ganglioglioma

  • Anaplastic mixed tumor

    • Glial component is essential NOTE: *Malignant gliomas occurring as a second primary malignancy allowed
• Newly diagnosed or recurrent disease
• No malignant brain stem tumors

• Incompletely resected tumors

  • No completely resected tumors
• Measurable or evaluable disease by conventional MRI

PATIENT CHARACTERISTICS:

• Lansky performance status 40-100%
• Organ toxicity ≤ grade 2
• Absolute neutrophil count ≥ 1,000/mm³
• Platelet count ≥ 100,000/mm³
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN
• Prothrombin ≥ 50%
• Fibrinogen ≥ 1.5 g/L

• Creatinine normal for age

  • Creatinine ≤ 65 µmol/L (4-15 years of age)
  • Creatinine ≤ 110 µmol/L (15-20 years of age)
• Audiogram with toxicity grade ≤ 2
• ECG normal
• Negative pregnancy test
• Fertile patients must use effective contraception
• No severe or life-threatening infection
• No uncontrolled developing or symptomatic intracranial hypertension

PRIOR CONCURRENT THERAPY:

• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas) or radiotherapy for patients with relapsed disease
• No prior cisplatin or temozolomide
• No other concurrent anticancer therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Masking: NONE

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Response rate after 2 courses

Secondary Outcome Measures

Outcome Measure
Overall survival
Relapse-free survival
Best response in patients receiving more than 2 courses
Rate of progression at 6 months and 1 and 2 years

Collaborators and Investigators

• Sponsor: Children's Cancer and Leukaemia Group
• Investigators: Steve Lowis, MD, PhD, BA, MRCP, MRCPCH, Bristol Royal Hospital for Children; Jacques Grill, MD, PhD, Gustave Roussy, Cancer Campus, Grand Paris; Anthony Michalski, MD, Great Ormond Street Hospital For Children NHS Foundation Trust; David A. Walker, Queen's Medical Center

Study record dates

Study Major Dates

• Study Start: April 1, 2004

Study Registration Dates

• First Submitted: August 3, 2006
• First Submitted That Met QC Criteria: August 3, 2006
• First Posted (ESTIMATE): August 7, 2006

Study Record Updates

• Last Update Posted (ESTIMATE): September 17, 2013
• Last Update Submitted That Met QC Criteria: September 16, 2013
• Last Verified: November 1, 2006

More Information

Terms related to this study

• Keywords: childhood high-grade cerebral astrocytoma; untreated childhood cerebellar astrocytoma; childhood oligodendroglioma; recurrent childhood cerebellar astrocytoma; recurrent childhood cerebral astrocytoma; recurrent childhood brain tumor; childhood low-grade cerebral astrocytoma
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms; Neoplasms by Site; Nervous System Neoplasms; Central Nervous System Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Cisplatin; Temozolomide
• Other Study ID Numbers: CDR0000482280; CCLG-CNS-2004-02; EU-20622