• Overall survival [ Designated as safety issue: No ]
  

• Six-month progression-free survival [ Designated as safety issue: No ]
  
• Tumor response rate [ Designated as safety issue: No ]
  
• Toxicity as measured by CTCAE v 3.0 [ Designated as safety issue: Yes ]
  
• Pharmacokinetics of erlotinib hydrochloride and sorafenib tosylate [ Designated as safety issue: No ]
  
• Relationship between tumor and blood biomarkers and clinical outcome [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary:

• Determine the efficacy of erlotinib hydrochloride and sorafenib tosylate, in terms of overall survival, in patients with progressive or recurrent glioblastoma multiforme.

Secondary

• Determine the toxicity of this regimen in these patients.
• Determine the tumor response rate in patients treated with this regimen.
• Determine the 6-month progression-free survival of patients treated with this regimen.
• Determine the pharmacokinetics of this regimen in these patients.
• Determine the relationship between tumor and blood biomarkers and clinical outcome in patients treated with this regimen.
• Determine the effect of enzyme-inducing anticonvulsant drugs on the pharmacokinetics and metabolism of sorafenib tosylate and erlotinib hydrochloride.
• Determine the magnitude of variability in the steady-state pharmacokinetics of this regimen between patients.

OUTLINE: This is a multicenter, open-label, phase II study.

Patients receive oral erlotinib hydrochloride once daily and oral sorafenib tosylate twice daily on days 1-28. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.

Tumor tissue and blood samples are collected prior to beginning treatment. Samples are analyzed by immunohistochemistry, gene expression, and DNA mutation and genomic analyses of the epidermal growth factor receptor, ras-raf-ERK, and PI3K-Akt-mTOR pathways to identify markers that correlate with patient outcomes. Blood samples are also collected on day 15 of course 1 for pharmacokinetic studies. Samples are analyzed by reversed-phase isocratic high-performance liquid chromatography with electrospray ionization mass spectrometry to determine the concentration of erlotinib hydrochloride and sorafenib tosylate and its known metabolites.

After completion of study therapy, patients are followed every 2 months.

PROJECTED ACCRUAL: A total of 56 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed supratentorial glioblastoma multiforme

  • Progressive or recurrent disease after radiotherapy with or without chemotherapy* NOTE: *Patients with prior low-grade glioma who have progressed to high-grade glioma as evidenced by biopsy after radiotherapy with or without chemotherapy are eligible
• Measurable disease, defined as contrast-enhancing progressive or recurrent disease by MRI or CT scan within the past 3 weeks
• Must be able and willing to provide tissue and blood samples

PATIENT CHARACTERISTICS:

• Karnofsky performance status 60-100%
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Creatinine ≤ 1.7 mg/dL
• Bilirubin ≤ 1.5 mg/dL
• Transaminases ≤ 4 times ULN
• PT and PTT normal
• PT INR ≤ 1.5 (unless on full-dose warfarin)
• Mini Mental State Exam score ≥ 15

• No concurrent serious infection or medical illness that would preclude study treatment or patient safety including, but not limited to, the following:

  • Uncontrolled hypertension, defined as systolic blood pressure (BP) > 140 mm Hg or diastolic BP > 90 mm Hg

    • Well-controlled hypertension allowed
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
• No psychiatric illness or social situation that would preclude compliance with study requirements
• No evidence of bleeding diathesis or coagulopathy

• No known corneal abnormalities, including the following:

  • History of dry eye syndrome, Sjögren's syndrome, or other corneal abnormalities
  • Congenital abnormality (e.g., Fuch's dystrophy)
  • Abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal-Rose)
  • Abnormal corneal sensitivity test (i.e., Schirmer test or similar tear production test)

• No condition that would preclude the ability to swallow pills, including any of the following:

  • Gastrointestinal tract disease resulting in an inability to take oral medication
  • Requirement for IV alimentation
  • Prior surgical procedures affecting absorption
  • Active peptic ulcer disease
• No history of allergic reaction to compounds of similar chemical or biological composition as erlotinib hydrochloride or sorafenib tosylate
• No other malignancy within the past 5 years except curatively treated carcinoma in situ or basal cell carcinoma of the skin
• No significant traumatic injury within the past 21 days
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 2 months after completion of study treatment

PRIOR CONCURRENT THERAPY:

• Recovered from prior therapy
• No more than 2 prior treatments
• At least 3 months since prior radiotherapy
• At least 3 weeks since prior non-nitrosourea-containing chemotherapy
• At least 6 weeks since prior nitrosourea-containing chemotherapy
• More than 21 days since prior major surgery
• No prior erlotinib hydrochloride, sorafenib tosylate, or any other agent targeting the epidermal growth factor receptor

• At least 10 days since prior and concurrent cytochrome P450-inducing anticonvulsants including, but not limited to, the following:

  • Phenytoin
  • Carbamazepine
  • Phenobarbital
  • Primidone
  • Oxcarbazepine
• No other concurrent antitumor therapy (steroid therapy allowed)
• No other concurrent medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of erlotinib hydrochloride or sorafenib tosylate
• No other concurrent investigational agents
• No concurrent prophylactic hematopoietic colony-stimulating factors

• Concurrent full-dose anticoagulants allowed provided the following criteria are met:

  • INR is in range (2 to 3) on a stable dose of oral anticoagulant or low molecular weight heparin
  • No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
• Concurrent prophylactic anticoagulation (i.e., low-dose warfarin) allowed provided INR < 1.1 times upper limit of normal (ULN)
• No concurrent antiretroviral therapy for HIV-positive patients