Clinical trial NCT00360854: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Brain and Central Nervous System Tumors
Keywords: untreated childhood brain stem glioma
recurrent childhood cerebellar astrocytoma
recurrent childhood cerebral astrocytoma
recurrent childhood ependymoma
recurrent childhood medulloblastoma
recurrent childhood supratentorial primitive neuroectodermal tumor
recurrent childhood visual pathway and hypothalamic glioma
childhood central nervous system germ cell tumor
childhood choroid plexus tumor
childhood craniopharyngioma
childhood grade I meningioma
childhood grade II meningioma
childhood grade III meningioma
childhood low-grade cerebral astrocytoma
childhood infratentorial ependymoma
childhood supratentorial ependymoma
recurrent childhood brain tumor
recurrent childhood subependymal giant cell astrocytoma
recurrent childhood pineoblastoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-08-07
Enrollment: 48
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Maximum tolerated dose of erlotinib hydrochloride when given alone and in combination with radiotherapy
Secondary outcomes:
measure: Dose-limiting toxicities
measure: Safety
measure: Pharmacokinetic behavior of erlotinib hydrocloride
measure: Efficacy
measure: Correlation of expression and mutations of epidermal growth factor receptor with treatment response
Other outcomes:
Locations:
city: Dublin
country: Ireland
facility: Our Lady's Hospital for Sick Children Crumlin
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
state: England
city: Bristol
country: United Kingdom
facility: Institute of Child Health at University of Bristol
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital at Cambridge University Hospitals NHS Foundation Trust
state: England
city: Leeds
country: United Kingdom
facility: Leeds Cancer Centre at St. James's University Hospital
state: England
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
state: England
city: Liverpool
country: United Kingdom
facility: Royal Liverpool Children's Hospital, Alder Hey
state: England
city: London
country: United Kingdom
facility: Middlesex Hospital
state: England
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children NHS Trust
state: England
city: Manchester
country: United Kingdom
facility: Central Manchester and Manchester Children's University Hospitals NHS Trust
state: England
city: Newcastle-Upon-Tyne
country: United Kingdom
facility: Sir James Spence Institute of Child Health
state: England
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre
state: England
city: Oxford
country: United Kingdom
facility: Oxford Radcliffe Hospital
state: England
city: Sheffield
country: United Kingdom
facility: Children's Hospital - Sheffield
state: England
city: Southampton
country: United Kingdom
facility: Southampton University Hospital NHS Trust
state: England
city: Sutton
country: United Kingdom
facility: Royal Marsden NHS Foundation Trust - Surrey
state: England
city: Belfast
country: United Kingdom
facility: Royal Belfast Hospital for Sick Children
state: Northern Ireland
city: Aberdeen
country: United Kingdom
facility: Royal Aberdeen Children's Hospital
state: Scotland
city: Edinburgh
country: United Kingdom
facility: Royal Hospital for Sick Children
state: Scotland
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Sick Children
state: Scotland
city: Cardiff
country: United Kingdom
facility: Childrens Hospital for Wales
state: Wales
Study officials:
affiliation: Royal Marsden NHS Foundation Trust
name: Darren Hargrave, MD
References: