A Study of Rindopepimut/GM-CSF in Patients With Relapsed EGFRvIII-Positive Glioblastoma

Study Overview
=================
Brief Summary
-----------------
The purpose of this research study is to find out whether adding an experimental vaccine called rindopepimut (also known as CDX-110) to the commonly used drug bevacizumab can improve progression free survival (slowing the growth of tumors) of patients with relapsed EGFRvIII positive glioblastoma.

Detailed Description
-----------------
This Phase II study will enroll patients into three groups. Group 1 are patients who have never been treated with bevacizumab. These patients will be randomly assigned to receive either rindopepimut/GM-CSF or KLH, each along with bevacizumab. Treatment assignment for Group 1 will be blinded. Group 2 and Group 2C patients are those who are refractory to bevacizumab (experienced recurrence or progression of glioblastoma while on bevacizumab or within 2 months of discontinuing bevacizumab). These patients will all receive rindopepimut/GM-CSF along with bevacizumab. Patients will be treated until disease progression or intolerance and all patients will be followed for survival. Patients may be treated with other therapies that are not part of the study after discontinuing treatment with the study vaccine.

Official Title
-----------------
A Phase II Study of Rindopepimut/GM-CSF in Patients With Relapsed EGFRvIII-Positive Glioblastoma

Conditions
-----------------
Gliosarcoma, Glioblastoma, Small Cell Glioblastoma, Giant Cell Glioblastoma, Glioblastoma With Oligodendroglial Component, Recurrent Glioblastoma, Relapsed Glioblastoma

Intervention / Treatment
-----------------
* Drug: Bevacizumab
* Drug: Rindopepimut (CDX-110) with GM-CSF
* Drug: KLH


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Among other criteria, patients must meet the following conditions to be eligible for the study: Age ≥18 years of age. Histologic diagnosis of glioblastoma (WHO Grade IV). Documented EGFRvlll positive tumor status (central lab confirmation). First or second relapse of de novo glioblastoma or first diagnosis or first relapse of secondary glioblastoma. Previous treatment must include surgery, conventional radiation therapy and temozolomide (TMZ). Screening MRI must be obtained at least 4 weeks after any salvage surgery, and at least 12 weeks after radiation therapy. KPS of ≥ 70%. If applicable, systemic corticosteroid therapy must be at a dose of ≤ 4 mg of dexamethasone or equivalent per day during the week prior to Day 1. Evaluable disease in Groups 1 and 2; measurable disease in Group 2C Life expectancy > 12 weeks. Patients in Group 2 and 2C must have had disease progression while receiving bevacizumab or within 2 months of treatment with bevacizumab. Exclusion Criteria: Among other criteria, patients who meet the following conditions are NOT eligible for the study: Subjects unable to undergo an MRI with contrast. History, presence, or suspicion of metastatic disease Prior receipt of vaccination against EGFRvIII. Any known contraindications to receipt of study drugs, including known allergy or hypersensitivity to keyhole limpet hemocyanin (KLH), GM-CSF (sargramostim; LEUKINE®), polysorbate 80 or yeast derived products, or a history of anaphylactic reactions to shellfish proteins. Use of non-protein based investigational therapy within 14 days prior to Day 1 or use of antibody-based investigational therapy within 28 days prior to Day 1. Clinically significant increased intracranial pressure (e.g., impending herniation), uncontrolled seizures, or requirement for immediate palliative treatment Evidence of recent hemorrhage on screening MRI of the brain Evidence of current drug or alcohol abuse. Patients in Group 1 must not have received prior treatment with bevacizumab.

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: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1a: Bevacizumab Naïve with Bevacizumab + rindopepimut.<br>About half of the patients who have never received treatment with bevacizumab will receive rindopepimut/GM-CSF in a blinded fashion in combination with bevacizumab. | Drug: Bevacizumab<br>* A vascular endothelial growth factor (VEGF)-specific humanized monoclonal antibody angiogenesis inhibitor. Infusions of 10 mg/kg of bevacizumab will begin on day 1 and will be administered every two weeks until progression of disease or intolerance during the treatment period.<br>* Other names: Avastin;Drug: Rindopepimut (CDX-110) with GM-CSF<br>* Rindopepimut/GM-CSF will initially be given three times, two weeks apart, followed by monthly injections until tumor progression or intolerance. Each dose will be 0.8 mL containing approximately 500 mcg CDX-110 and 150 mcg GM-CSF.<br>|
| Experimental: Group 1b: Bevacizumab Naïve with Bevacizumab + KLH control<br>About half of the patients who have never received treatment with bevacizumab will receive KLH in a blinded fashion in combination with bevacizumab. | Drug: Bevacizumab<br>* A vascular endothelial growth factor (VEGF)-specific humanized monoclonal antibody angiogenesis inhibitor. Infusions of 10 mg/kg of bevacizumab will begin on day 1 and will be administered every two weeks until progression of disease or intolerance during the treatment period.<br>* Other names: Avastin;Drug: KLH<br>* KLH will initially be given three times, two weeks apart, followed by monthly injections until tumor progression or intolerance. Each dose will be 0.8 mL containing approximately 100 mcg of KLH.<br>|
| Experimental: Group 2 and 2C: Refractory to Bevacizumab<br>Patients with progressive disease while currently on or within two months after discontinuing bevacizumab will be administered rindopepimut/GM-CSF while continuing (or restarting if they had stopped bevacizumab). | Drug: Bevacizumab<br>* A vascular endothelial growth factor (VEGF)-specific humanized monoclonal antibody angiogenesis inhibitor. Infusions of 10 mg/kg of bevacizumab will begin on day 1 and will be administered every two weeks until progression of disease or intolerance during the treatment period.<br>* Other names: Avastin;Drug: Rindopepimut (CDX-110) with GM-CSF<br>* Rindopepimut/GM-CSF will initially be given three times, two weeks apart, followed by monthly injections until tumor progression or intolerance. Each dose will be 0.8 mL containing approximately 500 mcg CDX-110 and 150 mcg GM-CSF.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Groups 1 and 2: Progression-free survival rate | Evaluate the antitumor activity of rindopepimut in adult patients with relapsed glioblastoma, as measured by the progression-free survival rate at 6 months post-Day 1 (PFS 6). | 6 months post-Day 1 | 
| Group 2C: Objective Response Rate | Evaluate the anti-tumor activity of rindopepimut in adult patients with relapsed glioblastoma, as measured by the objective response rate (ORR) for patients with measurable disease at study entry. | Every 8 weeks from Day 1 through progression or initiation of other anti-cancer therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability | Safety and tolerability will be evaluated by comparing the treatment regimens in regards to vital sign measurements, physical and neurological examinations, adverse events reporting, and Karnofsky performance status | Until 28 days or initiation of other anti-cancer treatment, whichever is first | 
| Anti-tumor activity | Evaluated by comparing the treatment regimens for anti-tumor activity, including objective response rate, overall progression free survival (PFS), and overall survival (OS) for Groups 1 and 2; and PFS6, overall PFS, and OS for Group 2C. | During treatment and every 8 weeks through follow up | 
| EGFRvIII-specific immune response | Characterize the EGFRvIII specific immune response to rindopepimut. | Several times during the first month of treatment and then approximately every 8 weeks until treatment is stopped. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
EGFRvIII, Glioblastoma, Rindopepimut, CDX-110, Small cell, Giant cell, Brain Cancer, Brain Tumor, Gliosarcoma, oligodendroglial, radiotherapy, chemoradiation, Tumor, Bevacizumab, Relapsed, Returned, Recurrent, EGFR variant III