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

• Safety and Tolerability [ Time Frame: Until 28 days or initiation of other anti-cancer treatment, whichever is first ] [ Designated as safety issue: No ]
  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
• Anti-tumor activity [ Time Frame: During treatment and every 8 weeks through follow up ] [ Designated as safety issue: No ]
  Evaluated by comparing the treatment regimens for anti-tumor activity, including objective response rate, overall progression free survival, and overall survival (OS).
• EGFRvIII-specific immune response [ Time Frame: Several times during the first month of treatment and then approximately every 8 weeks until treatment is stopped. ] [ Designated as safety issue: No ]
  Characterize the EGFRvIII specific immune response to rindopepimut.

• Safety and Tolerability [ Time Frame: Until 28 days or initiation of other anti-cancer treatment, whichever is first ] [ Designated as safety issue: Yes ]
  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
• Anti-tumor activity [ Time Frame: During treatment and every 8 weeks through follow up ] [ Designated as safety issue: No ]
  Evaluated by comparing the treatment regimens for anti-tumor activity, including objective response rate, overall progression free survival, and overall survival (OS).
• EGFRvIII-specific immune response [ Time Frame: Several times during the first month of treatment and then approximately every 8 weeks until treatment is stopped. ] [ Designated as safety issue: No ]
  Characterize the EGFRvIII specific immune response to rindopepimut.

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.

This Phase II study will enroll patients into two 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 patients are those who are refractory to bevacizumab (experienced recurrence or progression of glioblastoma while on 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.

• Glioblastoma
• Small Cell Glioblastoma
• Giant Cell Glioblastoma
• Gliosarcoma
• Glioblastoma With Oligodendroglial Component
• Recurrent Glioblastoma
• Relapsed Glioblastoma

• Drug: Bevacizumab
  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.
  Other Name: Avastin
• Drug: Rindopepimut (CDX-110) with GM-CSF
  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.
• Drug: KLH
  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.

• Experimental: Group 1a: Bevacizumab Naïve with Bevacizumab + rindopepimut.
  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.
  Interventions:

  • Drug: Bevacizumab
  • Drug: Rindopepimut (CDX-110) with GM-CSF
• Experimental: Group 1b: Bevacizumab Naïve with Bevacizumab + KLH control
  About half of the patients who have never received treatment with bevacizumab will receive KLH in a blinded fashion in combination with bevacizumab.
  Interventions:

  • Drug: Bevacizumab
  • Drug: KLH
• Experimental: Group 2: Refractory to Bevacizumab
  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).
  Interventions:

  • Drug: Bevacizumab
  • Drug: Rindopepimut (CDX-110) with GM-CSF

Inclusion Criteria:

Among other criteria, patients must meet the following conditions to be eligible for the study:

1. Age ≥18 years of age.
2. Histologic diagnosis of glioblastoma (WHO Grade IV).
3. Previous treatment for glioblastoma must include surgery,conventional radiation therapy and temozolomide (TMZ).
4. First or second relapse of de novo glioblastoma.
5. Screening MRI must be obtained at least 4 weeks after any salvage surgery, and at least 12 weeks after radiation therapy.
6. KPS of ≥ 70%.
7. Life expectancy > 12 weeks.
8. Documented EGFRvIII positive tumor status by a Sponsor designated laboratory.
9. 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.
10. Evaluable disease

Exclusion Criteria:

Among other criteria, patients who meet the following conditions are NOT eligible for the study:

1. Subjects unable to undergo an MRI with contrast.
2. History, presence, or suspicion of metastatic disease
3. Prior receipt of vaccination against EGFRvIII.
4. 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.
5. 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.
6. Clinically significant increased intracranial pressure (e.g., impending herniation), uncontrolled seizures, or requirement for immediate palliative treatment
7. Evidence of recent hemorrhage on screening MRI of the brain
8. Evidence of current drug or alcohol abuse.