Erlotinib and Sorafenib in Treating Patients With Progressive or Recurrent Glioblastoma Multiforme

Condition(s) targeted: Brain and Central Nervous System Tumors

Intervention: erlotinib hydrochloride (Drug); sorafenib tosylate (Drug); antiangiogenesis therapy (Procedure); biopsy (Procedure); diagnostic procedure (Procedure); enzyme inhibitor therapy (Procedure); gene expression analysis (Procedure); immunohistochemistry staining method (Procedure); laboratory biomarker analysis (Procedure); mass spectrometry (Procedure); mutation analysis (Procedure); pharmacological study (Procedure); protein tyrosine kinase inhibitor therapy (Procedure)

Phase: Phase 2

Status: Active, not recruiting

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
David M. Peereboom, MD, Study Chair, Affiliation: Case Comprehensive Cancer Center

RATIONALE: Erlotinib and sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving erlotinib together with sorafenib may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving erlotinib together with sorafenib works in treating patients with progressive or recurrent glioblastoma multiforme.

Official title: A Phase II Trial of Erlotinib (OSI-774) and Sorafenib (BAY 43-9006) for Patients With Progression or Recurrent Glioblastoma Multiforme

Study design: Treatment, Open Label

Primary outcome: Overall survival

Secondary outcome:

Six-month progression-free survival

Tumor response rate

Toxicity as measured by CTCAE v 3.0

Pharmacokinetics of erlotinib hydrochloride and sorafenib tosylate

Relationship between tumor and blood biomarkers and clinical outcome

Detailed description: 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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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

Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham, Birmingham, Alabama 35294, United States

H. Lee Moffitt Cancer Center and Research Institute at University of South Florida, Tampa, Florida 33612-9497, United States

Winship Cancer Institute of Emory University, Atlanta, Georgia 30322, United States

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231-2410, United States

Massachusetts General Hospital, Boston, Massachusetts 02114, United States

Josephine Ford Cancer Center at Henry Ford Hospital, Detroit, Michigan 48202, United States

Wake Forest University Comprehensive Cancer Center, Winston-Salem, North Carolina 27157-1096, United States

Case Comprehensive Cancer Center, Cleveland, Ohio 44106-5065, United States

Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania 19104-4283, United States

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: January 2007
Last updated: December 25, 2007