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Phase II Trial of Erlotinib Plus Sirolimus for Patients With Recurrent Malignant Glioma Multiforme

Phase 2
18 Years
Not Enrolling
Glioblastoma, Gliosarcoma

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Trial Information

Phase II Trial of Erlotinib Plus Sirolimus for Patients With Recurrent Malignant Glioma Multiforme

The primary objective of this study will be to determine the 6-month progression free
survival of patients with recurrent GBM treated with Erlotinib plus Sirolimus.

This is an exploratory, single-arm, phase II study designed to assess the anti-tumor
activity of a combinatorial regimen consisting of Erlotinib plus Sirolimus among patients
with recurrent GBM. The combinatorial regimen of Erlotinib plus Sirolimus is rationally
designed to simultaneously inhibit upstream (EGFR) and downstream (mTOR) mediators of
Phosphatidylinositide 3-kinase/Protein Kinase B (PI3/AKT) signaling. In a recently completed
phase I study, we determined that an EGFR inhibitor (Gefitinib) can be safely combined with
Sirolimus at dose levels that are routinely used in the monotherapy setting. Therefore, the
primary endpoint of this study is the probability of progression-free survival at 6 months
among recurrent GBM patients treated with standard doses of Erlotinib plus Sirolimus. An
important secondary objective is to further assess the safety of Erlotinib and Sirolimus for
patients with recurrent GBM.

Inclusion Criteria:

- Pts have confirmed diagnosis of recurrent primary WHO grade IV malignant glioma (MG).
Pts w recurrent disease whose diagnostic pathology confirmed GBM will not need
re-biopsy. Pts w prior low-gr glioma / anaplastic glioma are eligible if histologic
assessment demonstrates transformation to GBM

- Age >18 yrs

- Interval of >2 wk between prior surgical resection

- Interval of >12 wks between prior external-beam radiation therapy (XRT) unless there
is either: histopathologic confirmation of recurrent tumor; new enhancement on MRI
outside of XRT treatment field; / progressive radiographic changes after XRT/temo as
well as after adjuvant, post-XRT temo

- Interval of >4 wks between chemo & enrollment on protocol unless: unequivocal
evidence of tumor progression; & pt has recovered fully from all toxicity associated
w prior surgery, XRT/chemo. Pts treated w chemo agents such as VP-16 who would
normally be retreated after shorter intervals may be treated at usual starting time
even if <4 wks from last prior dose chemo

- Karnofsky performance score >= 70 percent

- Hematocrit >29 percent, absolute neutrophil count (ANC) >1,500 cells/microliter,
platelets >100,000 cells/microliter

- Serum creatinine <1.5 mg/dl, serum glutamic oxaloacetic transaminase (SGOT) &
bilirubin <1.5 x upper limit of normal (ULN); fasting plasma triglyceride &
cholesterol < gr1

- For pts on corticosteroids, dose should not be increasing for >7 days prior to
baseline Gd-MRI of brain if medically appropriate

- Pts in enzyme inducing antiepileptic drug cohort must be on stable dose of
p450-inducing EIAED for >2 wks. Pts in non-EIAED cohort must not receive any
p450-EIAED for >2 wks prior to & during participation in trial

- Signed informed consent approved by Institutional Review Board (IRB) prior to pt

- If sexually active, pts will take contraceptive measures for duration of treatments &
for 3 months following discontinuation of Erlotinib

- Pts who have had prior bevacizumab are eligible however interval of >6 weeks must
have elapsed since their last dose

Exclusion Criteria:

- Prior mammalian target of rapamycin (mTOR) directed therapy

- Prior epidermal growth factor receptor (EGFR)-directed therapy

- Female pts are pregnant/breast feeding, or adults of reproductive potential not
employing effective method of birth control. Women of childbearing potential must
have negative serum pregnancy test <72 hours prior to administration of Erlotinib

- Co-medication that may interfere w study results

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection requiring IV antibiotics, symptomatic congestive heart failure, unstable
angina pectoris, cardiac arrhythmia, hyperlipidemia not controlled w medication,
psychiatric illness/social situations that would limit compliance w study
requirements,/disorders associated w significant immunocompromise

- Acute/chronic liver disease

- Impairment of GI function/GI disease that may significantly alter absorption of

- Pts who have received investigational drugs <4 wks prior to entry on study or who
have not recovered from toxic effects of such therapy

- Pts who have received biologic, immunotherapeutic/cytostatic agents <1 wk prior to
entry on study/have not recovered from toxic effects of such therapy

- Pt is <5 yrs free of another primary malignancy except: if other primary malignancy
is not currently clinically significant/requiring active intervention,/if other
primary malignancy is basal cell skin cancer/cervical carcinoma in situ. Existence of
any other malignant disease is not allowed

- Pts have had any surgery other than resection of brain tumor <2 wks prior to entry on
study/have not recovered from side effects of such therapy

- Pts unwilling to/unable to comply w protocol

- Pts w acute/chronic renal insufficiency/those w acute renal insufficiency of any
severity due to hepato-renal syndrome/in peri-operative liver transplantation period

Type of Study:


Study Design:

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

Outcome Measure:

6-month Progression-free Survival (PFS)

Outcome Description:

Percentage of participants surviving six months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to the Macdonald criteria, or death due to any cause. Progression based on Macdonald criteria is defined as a ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration.

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

David Reardon, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University Health System


United States: Institutional Review Board

Study ID:




Start Date:

April 2007

Completion Date:

March 2010

Related Keywords:

  • Glioblastoma
  • Gliosarcoma
  • GBM
  • Brain tumor
  • Erlotinib
  • Sirolimus
  • Glioblastoma multiforme
  • Glioblastoma
  • Gliosarcoma3
  • Tarceva
  • Rapamune
  • Glioblastoma
  • Gliosarcoma
  • Glioma



Duke University Health System Durham, North Carolina  27705