A Pilot and Phase II Study of OSI-774 and Temozolomide in Combination With Radiation Therapy in Glioblastoma Multiforme
A Pilot and Phase II Study of OSI-774 and Temozolomide in Combination With Radiation Therapy in Glioblastoma Multiforme
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.
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.
Inclusion Criteria:
Histologically confirmed diagnosis of 1 of the following:
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
Ann Arbor, Michigan 48106, United States