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

Study Overview
=================
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.

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

Conditions
-----------------
Glioblastoma, Gliosarcoma

Intervention / Treatment
-----------------
* Drug: Erlotinib + sirolimus


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Erlotinib + Sirolimus<br>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. | Drug: Erlotinib + sirolimus<br>* 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.<br>* Other names: erlotinib - Tarceva - OSI-774;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 2 years | 
| 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. | 2 years | 
| 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. | 2 years | 
| Number of Participants Experiencing a ≥ Grade 3, Treatment-related, Non-hematologic Toxicity. | Number of participants experiencing a ≥ grade 3, treatment-related, non-hematologic toxicity. | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Tarceva, GBM, Brain tumor, Erlotinib, Sirolimus, Glioblastoma multiforme, Glioblastoma, Gliosarcoma3, Rapamune