Erlotinib Alone or in Combination With Radiation Therapy in Treating Young Patients With Refractory or Relapsed Malignant Brain Tumors or Newly Diagnosed Brain Stem Glioma

Phase I Studies of TARCEVA™ (ERLOTINIB HYDROCHLORIDE, OSI-774) as Single Agent in Children With Refractory and Relapsed Malignant Brain Tumors and in Combination With Irradiation in Newly Diagnosed Brain Stem Glioma

RATIONALE: Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving erlotinib together with radiation therapy may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of erlotinib when given alone or together with radiation therapy in treating young patients with refractory or relapsed malignant brain tumors or newly diagnosed brain stem glioma.

Study Overview

• Status: Unknown
• Conditions: Brain and Central Nervous System Tumors
• Intervention / Treatment: Genetic: polymorphism analysis; Other: pharmacological study; Radiation: radiation therapy; Other: laboratory biomarker analysis; Genetic: mutation analysis; Drug: erlotinib hydrochloride

Detailed Description

OBJECTIVES:

Primary

• Establish the maximum tolerated dose of single-agent erlotinib hydrochloride in pediatric patients with refractory or relapsed malignant brain tumors and in combination with radiotherapy in pediatric patients with newly diagnosed brain stem glioma.

Secondary

• Determine dose-limiting toxicities of these regimens.
• Define the safety profile of these regimens.
• Characterize the pharmacokinetic behavior of erlotinib hydrochloride in these patients.
• Evaluate the efficacy of these regimens.
• Correlate expression and mutations of epidermal growth factor receptor with treatment response.

OUTLINE: This is a multicenter, nonrandomized, open-label, dose-escalation study of erlotinib hydrochloride. Patients are assigned to 1 of 2 treatment groups according to disease.

• Group 1 (refractory or relapsed malignant brain tumors): Patients receive oral erlotinib hydrochloride once daily on days 1-21. Treatment repeats every 21 days in the absence of unacceptable toxicity or disease progression.

Cohorts of 3-6 patients receive escalating doses of erlotinib hydrochloride until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity (DLT).

• Group 2 (newly diagnosed brain stem glioma): Patients receive oral erlotinib hydrochloride once daily on days 1-21. Treatment repeats every 21 days in the absence of unacceptable toxicity or disease progression. Beginning on day 1, patients also undergo radiotherapy 5 days a week for 6 weeks .

Cohorts of 1-2 patients receive escalating doses of erlotinib hydrochloride until the MTD is determined. The MTD is defined as the dose resulting in 25% of patients experiencing DLT at 6 weeks.

Blood is collected for pharmacokinetic assessments and pharmacogenetic genotyping for analysis of enzyme polymorphisms. Tumor tissue may be assessed for epidermal growth factor receptor mutations.

After completion of study treatment, patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 48 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Anticipated): 48
• Phase: Phase 1

Contacts and Locations

Study Locations

• 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
    • 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: 1 year to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following:

  • Histologically or cytologically confirmed malignant brain tumor

    • Refractory to first-line therapy or relapsed after conventional therapy
    • No effective conventional therapy exists

  • Histologically confirmed brain stem glioma

    • Newly diagnosed disease
    • No pilocytic glioma
• Measurable or evaluable disease

PATIENT CHARACTERISTICS:

• WHO performance status 0-2 OR Lansky play scale 50-100%

  • Patients with motor paresis due to disease are eligible
  • Neurological deficits must be stable for ≥ 1 week
• Life expectancy ≥ 8 weeks
• Absolute neutrophil count > 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 8 g/dL
• AST/ALT ≤ 2.5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 times ULN
• Creatinine < 1.5 times ULN OR creatinine clearance ≥ 70 mL/min
• No other serious, uncontrolled illness
• No active infection
• No organ toxicity ≥ grade 2 except alopecia and neurological symptoms due to disease

• Must be able to take oral medication

  • Patients with newly diagnosed brain stem glioma with difficulty swallowing may be eligible
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No evidence of pulmonary dysfunction or pre-existing lung disease
• No myocardial infarction within the past year
• No severe cardiac pathology

• No significant ophthalmologic abnormality including, but not limited to, any of the following:

  • Severe dry eye syndrome
  • Keratoconjunctivitis sicca
  • Sjögren's syndrome
  • Severe exposure keratitis
  • Any other disorder likely to increase the risk of corneal epithelial lesions

PRIOR CONCURRENT THERAPY:

• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas)
• More than 6 weeks since prior radiotherapy
• No concurrent warfarin
• No other concurrent anticancer or investigational agents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Maximum tolerated dose of erlotinib hydrochloride when given alone and in combination with radiotherapy

Secondary Outcome Measures

Outcome Measure
Safety
Efficacy
Dose-limiting toxicities
Pharmacokinetic behavior of erlotinib hydrocloride
Correlation of expression and mutations of epidermal growth factor receptor with treatment response

Collaborators and Investigators

• Sponsor: Children's Cancer and Leukaemia Group
• Investigators: Darren Hargrave, MD, Royal Marsden NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start: May 1, 2005

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 20, 2013
• Last Update Submitted That Met QC Criteria: September 19, 2013
• Last Verified: June 1, 2007

More Information

Terms related to this study

• Keywords: untreated childhood brain stem glioma; childhood infratentorial ependymoma; childhood supratentorial ependymoma; recurrent childhood supratentorial primitive neuroectodermal tumor; recurrent childhood cerebellar astrocytoma; recurrent childhood cerebral astrocytoma; recurrent childhood ependymoma; recurrent childhood brain tumor; recurrent childhood medulloblastoma; recurrent childhood visual pathway and hypothalamic glioma; childhood craniopharyngioma; childhood central nervous system germ cell tumor; childhood choroid plexus tumor; childhood grade I meningioma; childhood grade II meningioma; childhood grade III meningioma; childhood low-grade cerebral astrocytoma; recurrent childhood pineoblastoma; recurrent childhood subependymal giant cell astrocytoma
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma; Brain Neoplasms; Nervous System Neoplasms; Central Nervous System Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Erlotinib Hydrochloride
• Other Study ID Numbers: CDR0000481539; CCLG-NAG-2005-09; ITCC-003; EU-20617; CCLG-CPP-05-07; ROCHE-MO18461; EUDRACT-2004-005247-10