Erlotinib and Temozolomide With Radiation Therapy in Treating Patients With Glioblastoma Multiforme or Other Brain Tumors

Study Overview
=================
Brief Summary
-----------------
This pilot phase II trial is studying the side effects and best dose of erlotinib when given with temozolomide and radiation therapy and to see how well they work in treating patients with glioblastoma multiforme or other brain tumors. Radiation therapy uses high-energy x-rays to damage tumor cells. Erlotinib may interfere with the growth of tumor cells, slow the growth of the tumor, and make the tumor cells more sensitive to radiation therapy. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining erlotinib and temozolomide with radiation therapy may kill more tumor cells.

Detailed Description
-----------------
PILOT STUDY OBJECTIVES: I. Determine the maximum tolerated dose of erlotinib administered with temozolomide and radiotherapy in patients with glioblastoma multiforme or other grade 4 brain tumors who are currently on enzyme-inducing anticonvulsant (EIAC) therapy vs no EIAC therapy. II. Determine the safety and tolerability of this regimen in these patients. III. Determine the toxic effects of this regimen in these patients. IV. Determine the efficacy of this regimen, in terms of 1-year survival, in these patients. PHASE II OBJECTIVES: I. Determine the response rate and time to progression in patients treated with this regimen. II. Determine the 6-month progression-free survival of patients treated with this regimen. III. Determine the toxic effects of this regimen in these patients. OUTLINE: This is a multicenter, dose-escalation pilot study of erlotinib followed by a phase II study. Patients are stratified according to concurrent enzyme-inducing anticonvulsant drug use (yes vs no). PILOT STUDY: Patients receive oral erlotinib once daily. After 1 week of erlotinib alone, patients also receive oral temozolomide once daily for 6 weeks and undergo concurrent radiotherapy 5 days a week for 6 weeks. After completion of radiotherapy, patients continue to receive erlotinib once daily alone in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after the completion of radiotherapy, patients also receive oral temozolomide once daily for 5 days. Temozolomide treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of erlotinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. PHASE II: Once the MTD of erlotinib is determined, additional patients are treated with erlotinib at the MTD, temozolomide, and radiotherapy as above. Patients are followed every 3 months for 5 years and then annually for 10 years.

Official Title
-----------------
A Pilot and Phase II Study of OSI-774 and Temozolomide in Combination With Radiation Therapy in Glioblastoma Multiforme

Conditions
-----------------
Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma

Intervention / Treatment
-----------------
* Drug: erlotinib hydrochloride
* Radiation: 3-dimensional conformal radiation therapy
* Drug: temozolomide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed diagnosis of 1 of the following: Glioblastoma multiforme (grade 4 astrocytoma) Gliosarcomas Other grade 4 astrocytoma variants (e.g., giant cell) Must be enrolled at least 1 week, but no more than 4 weeks, after prior biopsy or surgery Performance status - ECOG 0-2 Performance status - Karnofsky 60-100% At least 6 months Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Hemoglobin ≥ 9 g/dL Total bilirubin ≤ upper limit of normal (ULN) AST no greater than 2.5 times ULN Creatinine no greater than 1.5 times ULN No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia No inability to take oral medications No requirement for IV alimentation No active uncontrolled peptic ulcer disease No abnormalities of the cornea (e.g., dry eye syndrome or Sjögren's syndrome) No congenital abnormality (e.g., Fuch's dystrophy) No abnormal slit-lamp examination using a vital dye (e.g., fluorescein or Bengal-Rose) No abnormal corneal sensitivity test (e.g., Schirmer test or similar tear production test) No prior allergy or intolerance to dacarbazine No other active malignancy requiring treatment No other concurrent uncontrolled illness No ongoing or active infection No psychiatric illness or social situation that would preclude study compliance Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No prior chemotherapy for any brain tumor No prior temozolomide No prior radiotherapy for any brain tumor No other concurrent investigational agents More than 21 days since prior major surgery (excluding neurosurgical biopsy or brain tumor resection) No prior surgical procedures affecting absorption No concurrent combination antiretroviral therapy for HIV-positive patients No concurrent warfarin

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (erlotinib hydrochloride, radiation, temozolomide)<br>Patients receive oral erlotinib once daily. After 1 week of erlotinib alone, patients also receive oral temozolomide once daily for 6 weeks and undergo concurrent radiotherapy 5 days a week for 6 weeks. After completion of radiotherapy, patients continue to receive erlotinib once daily alone in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after the completion of radiotherapy, patients also receive oral temozolomide once daily for 5 days. Temozolomide treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. | Drug: erlotinib hydrochloride<br>* Given orally<br>* Other names: OSI-774;Radiation: 3-dimensional conformal radiation therapy<br> <br> * Other names: 3D-CRT;Drug: temozolomide<br>* Given orally<br>* Other names: TMZ;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival |  | At 52 weeks | 
| Overall survival distribution | The overall survival distribution will be estimated using the method of Kaplan-Meier. The success probability, i.e., 12-month survival percentage, will be estimated as the number of evaluable patients still alive at 366 days divided by the total number of evaluable patients followed for at least 366 days. | From start of study therapy to death due to any cause, up to 15 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-to-disease progression | The time-to-progression distribution will be estimated using the Kaplan-Meier method. | From start of study therapy to documentation of disease progression, up to 15 years | 
| Maximum toxicity grade, assessed by Common Terminology Criteria for Adverse Events (CTCAE) | Frequency tables will be reviewed to determine toxicity patterns. | Up to 15 years |