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Ph II Erlotinib + Sirolimus for Pts w Recurrent Malignant Glioma Multiforme

Primary Purpose

Glioblastoma, Gliosarcoma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Erlotinib + sirolimus
Sponsored by
Duke University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma focused on measuring GBM, Brain tumor, Erlotinib, Sirolimus, Glioblastoma multiforme, Glioblastoma, Gliosarcoma3, Tarceva, Rapamune

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 entry
  • 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 Erlotinib
  • 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

Sites / Locations

  • Duke University Health System

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Erlotinib + Sirolimus

Arm Description

Erlotinib & sirolimus on a daily dosing schedule on a 28-day cycle. Dosing was 150 mg of erlotinib and 5mg of sirolimus for patients not on concurrent Cytochrome P450, family 3 (CY3PA)-inducing anti-epileptics (EIAEDS) and 400 mg of erlotinib and 10 mg of sirolimus for patients on concurrent EIAEDS.

Outcomes

Primary Outcome Measures

6-month Progression-free Survival (PFS)
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.

Secondary Outcome Measures

Median Progression Free Survival (PFS)
Time in weeks from the start of study treatment to the date of first progression according to Macdonald criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve. 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.
Median Overall Survival (OS)
Time in weeks from the start of study treatment to date of death due to any cause. Patients alive at last follow-up are censored as of that follow-up date. Median OS was estimated using a Kaplan-Meier curve.
Best Radiographic Response
Best radiographic response per modified Macdonald criteria. Complete response: disappearance of all enhancing tumor, no new lesions, and no steroids or only maintenance doses. Partial response: ≥ 50% reduction in the products of the perpendicular diameters of all enhancing lesions, no new lesions, & steroids must be at a stable/decreasing dose. Stable disease: does not qualify for complete or partial response or progression & is stable clinically. Progression: ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, any new lesion or clinical deterioration.
Number of Participants Experiencing a ≥ Grade 3, Treatment-related, Non-hematologic Toxicity.
Number of participants experiencing a ≥ grade 3, treatment-related, non-hematologic toxicity.

Full Information

First Posted
January 29, 2008
Last Updated
August 2, 2013
Sponsor
Duke University
Collaborators
Genentech, Inc., OSI Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT00672243
Brief Title
Ph II Erlotinib + Sirolimus for Pts w Recurrent Malignant Glioma Multiforme
Official Title
Phase II Trial of Erlotinib Plus Sirolimus for Patients With Recurrent Malignant Glioma Multiforme
Study Type
Interventional

2. Study Status

Record Verification Date
July 2013
Overall Recruitment Status
Completed
Study Start Date
April 2007 (undefined)
Primary Completion Date
September 2008 (Actual)
Study Completion Date
December 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Duke University
Collaborators
Genentech, Inc., OSI Pharmaceuticals

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Primary objective: To determine the 6-month progression free survival of patients with recurrent glioblastoma multiforme (GBM) treated with Erlotinib plus Sirolimus. Secondary objectives: To further define the safety and tolerability of Erlotinib plus Sirolimus when administered to patients with recurrent GBM; and to evaluate progression free survival, radiographic response and overall survival of patients with recurrent GBM treated with Erlotinib plus Sirolimus.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma, Gliosarcoma
Keywords
GBM, Brain tumor, Erlotinib, Sirolimus, Glioblastoma multiforme, Glioblastoma, Gliosarcoma3, Tarceva, Rapamune

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Erlotinib + Sirolimus
Arm Type
Experimental
Arm Description
Erlotinib & sirolimus on a daily dosing schedule on a 28-day cycle. Dosing was 150 mg of erlotinib and 5mg of sirolimus for patients not on concurrent Cytochrome P450, family 3 (CY3PA)-inducing anti-epileptics (EIAEDS) and 400 mg of erlotinib and 10 mg of sirolimus for patients on concurrent EIAEDS.
Intervention Type
Drug
Intervention Name(s)
Erlotinib + sirolimus
Other Intervention Name(s)
sirolimus - Rapamune, erlotinib - Tarceva - OSI-774
Intervention Description
Erlotinib & sirolimus on a daily dosing schedule on a 28-day cycle. Dosing was 150 mg of oral erlotinib and 5mg of oral sirolimus for patients not on concurrent CY3PA-inducing anti-epileptics (EIAEDS) and 400 mg of oral erlotinib and 10 mg of oral sirolimus for patients on concurrent EIAEDS.
Primary Outcome Measure Information:
Title
6-month Progression-free Survival (PFS)
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.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Median Progression Free Survival (PFS)
Description
Time in weeks from the start of study treatment to the date of first progression according to Macdonald criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve. 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.
Time Frame
2 years
Title
Median Overall Survival (OS)
Description
Time in weeks from the start of study treatment to date of death due to any cause. Patients alive at last follow-up are censored as of that follow-up date. Median OS was estimated using a Kaplan-Meier curve.
Time Frame
2 years
Title
Best Radiographic Response
Description
Best radiographic response per modified Macdonald criteria. Complete response: disappearance of all enhancing tumor, no new lesions, and no steroids or only maintenance doses. Partial response: ≥ 50% reduction in the products of the perpendicular diameters of all enhancing lesions, no new lesions, & steroids must be at a stable/decreasing dose. Stable disease: does not qualify for complete or partial response or progression & is stable clinically. Progression: ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, any new lesion or clinical deterioration.
Time Frame
2 years
Title
Number of Participants Experiencing a ≥ Grade 3, Treatment-related, Non-hematologic Toxicity.
Description
Number of participants experiencing a ≥ grade 3, treatment-related, non-hematologic toxicity.
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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 entry 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 Erlotinib 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Reardon, MD
Organizational Affiliation
Duke Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
Duke University Health System
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
19562254
Citation
Reardon DA, Desjardins A, Vredenburgh JJ, Gururangan S, Friedman AH, Herndon JE 2nd, Marcello J, Norfleet JA, McLendon RE, Sampson JH, Friedman HS. Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma. J Neurooncol. 2010 Jan;96(2):219-30. doi: 10.1007/s11060-009-9950-0. Epub 2009 Jun 28.
Results Reference
result
Links:
URL
http://www.cancer.duke.edu/btc/
Description
The Preston Robert Tisch Brain Tumor Center at DUKE

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Ph II Erlotinib + Sirolimus for Pts w Recurrent Malignant Glioma Multiforme

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