Erlotinib Compared With Temozolomide or Carmustine in Treating Patients With Recurrent Glioblastoma Multiforme

OBJECTIVES:

Primary

• Compare the therapeutic activity of erlotinib vs temozolomide or carmustine in patients with recurrent glioblastoma multiforme.
• Compare 6-month progression-free survival in patients treated with these drugs.

Secondary

• Compare the safety of these drugs in these patients.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to participating center. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral erlotinib* once daily on day 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

NOTE: *Patients treated with enzyme inducing anti-epileptic drugs (EIAEDs) receive a higher dose of erlotinib than patients not receiving any anti-epileptic drugs or EIAEDs.

• Arm II: Patients who have not received prior temozolomide are assigned to receive temozolomide. Patients who have received prior temozolomide are assigned to receive carmustine. Patients receive 1 of the following treatment regimens:

• Patients receive oral temozolomide* once daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
• Patients receive carmustine IV once daily on days 1-3. Treatment repeats every 56 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.

NOTE: *Chemotherapy-naïve patients receive a higher dose of temozolomide than patients who have received prior adjuvant chemotherapy.

Patients are followed every 8 weeks until disease progression and then every 3 months thereafter.

PROJECTED ACCRUAL: A total of 100-110 patients (50-55 per treatment arm) will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed glioblastoma multiforme

• Some oligodendroglial elements allowed provided they make up < 25% of the tumor
• Recurrent disease documented by MRI after prior radiotherapy
• At least 1 bidimensionally measurable target lesion ≥ 2 cm by MRI
• Undergone prior surgery for recurrent primary brain tumor more than 3 months before study entry

• Must have a clearly limited target lesion ≥ 2 cm OR evidence of progressive and measurable target lesion OR a second measurable target lesion outside the surgical area

PATIENT CHARACTERISTICS:

Age

• Over 18

Performance status

• Karnofsky 70-100%

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm ^3

Hepatic

• AST and ALT < 2.5 times upper limit of normal (ULN)
• Bilirubin < 1.5 times ULN

Renal

• Creatinine < 1.5 times ULN

Cardiovascular

• Clinically normal cardiac function
• No ischemic heart disease within the past 12 months
• No New York Heart Association grade III or IV cardiac insufficiency
• No unstable angina
• No arryhthmia

Pulmonary

• DLCO > 70% of predicted (for patients randomized to receive erlotinib [arm I] or carmustine [arm II])
• No history of pulmonary disease that would affect pulmonary function including any of the following:

• Chronic bronchopneumopathy
• Pleural effusion
• Interstitial pnuemonia
• Pulmonary lymphangitis

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after study participation
• No other malignancy except cone biopsied carcinoma of the cervix or adequately treated basal cell or squamous cell skin cancer
• No psychological, familial, sociological, or geographical factors that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior HER-targeted agents
• No concurrent growth factors for neutrophil count elevation
• No concurrent epoetin alfa

Chemotherapy

• Prior adjuvant temozolomide allowed
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas)
• No more than 1 prior adjuvant chemotherapy regimen
• No prior chemotherapy for recurrent disease

Endocrine therapy

• Must be on a stable or decreasing dose of corticosteroids for at least 2 weeks before study entry

Radiotherapy

• See Disease Characteristics
• More than 3 months since prior radiotherapy to the brain
• No prior high-dose radiotherapy (> 65 Gy), stereotactic radiosurgery, or internal radiotherapy unless disease recurrence confirmed

Surgery

• See Disease Characteristics

Other

• No prior participation in experimental therapies
• No concurrent CYP3A4 inhibitors (e.g., ketoconazole, erythromycin, troleandomycin, cimetidine, or grapefruit juice)
• No concurrent warfarin or other coumarin derivatives

• Concurrent low-molecular weight heparin allowed
• No other concurrent investigational drugs