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A Phase 2 Trial of Erlotinib (OSI-774) and Sorafenib (BAY 43-9006) for Patients With Progression or Recurrent Glioblastoma Multiforme

Phase 2
18 Years
Not Enrolling
Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor

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Trial Information

A Phase 2 Trial of Erlotinib (OSI-774) and Sorafenib (BAY 43-9006) for Patients With Progression or Recurrent Glioblastoma Multiforme


I. The primary objective of this trial is to estimate the overall survival rate associated
with this combined regimen in treating adult patients with recurrent glioblastoma


I. To assess and estimate the toxicities. II. Tumor response rate. III. To estimate 6-month
progression free survival. IV. To describe the pharmacokinetics of this route of
administration. V. For the Molecular Targeted Combinations Correlative (MTC2) Study
Initiative: To determine the relationship between tumor and blood biomarkers and clinical
outcome of patients treated with the combination of targeted agents.

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

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

Inclusion Criteria:

- Patients must have histologically confirmed supratentorial glioblastoma multiforme
which is progressive or recurrent after radiation therapy ± chemotherapy; patients
with previous low grade glioma who progressed after radiotherapy ± chemotherapy and
are biopsied and found to have a high grade glioma are eligible

- Patients must have tissue specimens available and agree to have their blood and
tissue blocks (or slides) submitted for the combined correlative studies

- Patients must have measurable contrast enhancing progressive or recurrent
glioblastoma multiforme by MRI or CT imaging (Within 14 days before starting

- Patients must have recovered from toxicity of prior therapy. An interval of at least
3 months must have elapsed since the completion of the most recent course of
radiation therapy, while at least 3 weeks must have elapsed since the completion of a
non-nitrosourea containing chemotherapy regimen, and at least 6 weeks since the
completion of a nitrosourea containing chemotherapy regimen; NOTE: For a
non-cytotoxic, FDA approved agents (i.e. Celebrex, thalidomide, etc.) therapy could
be started 2 weeks after discontinuing this agent provided the patient has fully
recovered from all toxicity associated with the agent; for investigational,
non-cytotoxic agents a minimum of 3 weeks must have elapsed before the patient will
be eligible for this study

- Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be
able to care for himself/herself with occasional help from others)

- Absolute Neutrophil Count >= 1500/mm^3

- Platelets >= 100,000/mm^3

- Creatinine =< 1.7mg/dl

- Total Bilirubin within normal institutional limits

- Transaminases =< 2.5 times above the upper limits of the institutional norm

- PT, PTT ≤ institutional norm

- Patients must be able to provide written informed consent

- Patients with the potential for pregnancy or impregnating their partner must agree to
follow acceptable birth control methods to avoid conception; women of childbearing
potential must have a negative serum pregnancy test; (the anti-proliferative activity
of this experimental drug may be harmful to the developing fetus or nursing infant)

- Patients must have a Mini Mental State Exam score >= 15

Exclusion Criteria:

- Patients with serious concurrent infection or medical illness which would jeopardize
the ability of the patient to receive the treatment outlined in this protocol with
reasonable safety; (examples of medical illnesses are [but not limited to] the
following: uncontrolled hypertension, symptomatic congestive heart failure, unstable
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that
would limit compliance with study requirements)

- Patients with uncontrolled hypertension; hypertension with systolic blood pressure of
> 140 mmHg or diastolic pressure > 90 mmHg; however, patients with well-controlled
hypertension are eligible

- Patients who are pregnant or breast-feeding (the anti-proliferative activity of this
experimental drug may be harmful to the developing fetus or nursing infant)

- Patients who have received more than two prior treatments

- Patients who have had prior therapy with erlotinib or sorafenib or any other agent
targeting EGFR

- Patients receiving concurrent therapy for their tumor (with the exception of

- Patients undergoing major surgery or sustaining a significant traumatic injury within
21 days prior to treatment are ineligible

- Patients with a concurrent malignancy are ineligible unless they are patients with
curatively treated carcinoma-in-situ or basal cell carcinoma of the skin; patients
with a prior malignancy are ineligible unless they have been free of disease for >=
five years

- Patients must not have any evidence of bleeding diathesis or coagulopathy

- Patients with PT INR > 1.5 are excluded, unless the patient is on full dose warfarin

- Patients on full-dose anticoagulants (e.g., warfarin) are eligible provided that both
of the following criteria are met:

- The patient has an in-range INR (usually between 2 and 3) on a stable dose of
oral anticoagulant or on a stable dose of low molecular weight heparin

- The patient has no active bleeding or pathological condition that carries a high
risk of bleeding (e.g., tumor involving major vessels or known varices)

- NOTE: Patients on a full dose of anticoagulants will a different schedule for
PT/INR evaluations

- Prophylactic anticoagulation (i.e. low dose warfarin) are eligible provided their
coagulation parameter levels are as follows: prothrombin time (INR; International
Normalized Ratio of prothrombin time) < 1.1 x institutional upper limit of normal

- Patients with known abnormalities of the cornea based on history (e.g., dry eye
syndrome, Sjogren's syndrome), congenital abnormality (e.g., Fuch's dystrophy),
abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal Rose),
and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production
test) are excluded

- Patients with any condition (e.g., gastrointestinal tract disease resulting in an
inability to take oral medication or a requirement for IV alimentation, prior
surgical procedures affecting absorption, or active peptic ulcer disease) that
impairs their ability to swallow pills are excluded

- Patients cannot be receiving cytochrome P450-inducing anticonvulsants (EIAEDs; e.g.,
phenytoin, carbamazepine, phenobarbital, primidone, oxcarbazepine) and must not have
taken them for at least 10 days

- Patients may not have allergies to or a history of allergic reactions attributed to
erlotinib and/or sorafenib

- Eligibility of patients receiving any other medications or substances known to affect
or with the potential to affect the activity or pharmacokinetics of erlotinib or
sorafenib will be determined following review of their case by the Principal

- HIV patients receiving combination anti-retroviral therapy will be excluded

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall failure rate

Outcome Description:

The overall failure rate will be estimated by dividing the number of events (death) with the total exposure time in the study cohort. 95% confidence intervals and median time of survival will be calculated using standard methods.

Outcome Time Frame:

Time of first day of the treatment to death, assessed up to 3 years

Safety Issue:


Principal Investigator

David Peereboom

Investigator Role:

Principal Investigator

Investigator Affiliation:

New Approaches to Brain Tumor Therapy Consortium


United States: Food and Drug Administration

Study ID:




Start Date:

January 2007

Completion Date:

Related Keywords:

  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Recurrent Adult Brain Tumor
  • Brain Neoplasms
  • Glioblastoma
  • Gliosarcoma



New Approaches to Brain Tumor Therapy ConsortiumBaltimore, Maryland  21231-1000