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

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

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.

Study Overview

• Status: Completed
• Conditions: Glioblastoma; Gliosarcoma; Recurrent Glioblastoma; Small Cell Glioblastoma; Giant Cell Glioblastoma; Glioblastoma With Oligodendroglial Component; Relapsed Glioblastoma
• Intervention / Treatment: Drug: Bevacizumab; Drug: Rindopepimut (CDX-110) with GM-CSF; Drug: KLH

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.

• Study Type: Interventional
• Enrollment (Actual): 127
• Phase: Phase 2

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • St. Joseph's Hospital and Medical Center / Barrow Neurological Institute
  • California
    • Los Angeles, California, United States, 90027
      • Kaiser Permanente Los Angeles Medical Center
    • Los Angeles, California, United States, 90089
      • University of Southern California (USC) Norris Comprehensive Cancer Center
    • Orange, California, United States, 92868
      • UC Irvine Chao Family Comprehensive Cancer Center
    • San Francisco, California, United States, 94143
      • University of California San Francisco
    • Stanford, California, United States, 94305
      • Stanford Cancer Institute, Stanford University
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado, Denver
  • Florida
    • Hollywood, Florida, United States, 33021
      • Memorial Cancer Institute
    • Orlando, Florida, United States, 32806
      • Orlando Health, Inc.
    • Tampa, Florida, United States, 33606
      • Tampa General Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30309
      • Piedmont Atlanta Hospital
    • Atlanta, Georgia, United States, 30342
      • Atlanta Cancer Care
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago
    • Evanston, Illinois, United States, 60201
      • NorthShore University Health System
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • The Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute and Mass General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
    • Lansing, Michigan, United States, 48912
      • Sparrow Cancer Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • John Nasseff Neuroscience Institute, Abbott Northwestern Hospital, 800 e. 28th Str. MR
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Jersey
    • Edison, New Jersey, United States, 08818
      • New Jersey Neuroscience Institute JFK Medical Center
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • Amherst, New York, United States, 14226
      • Dent Neurologic Institute, 3980 Sheridan Dr, 3rd Flr Clinical Rsch
    • Commack, New York, United States, 11725
      • The Long Island Brain Tumor Center at Neurology Surgery, P.C.
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
    • Stony Brook, New York, United States, 11794-8121
      • Stony Brook University Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • The Preston Robert Tisch Brain Tumor Center; Duke University Medical Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Health
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Cancer Institute
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center
    • Cleveland, Ohio, United States, 44106
      • Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97232
      • Legacy Research Institute
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Lehigh Valley Hospital-John and Dorothy Morgan Cancer Center
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Austin, Texas, United States, 78705
      • Texas Oncology Midtown
    • Dallas, Texas, United States, 75246
      • Baylor Research Institute
    • Houston, Texas, United States, 77030
      • UT Health Science Center, Houston Memorial Hermann Hospital, 6400 Fannin Street, #2800
  • Utah
    • Salt Lake City, Utah, United States, 84116
      • Utah Cancer Specialists
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center
    • Seattle, Washington, United States, 98122
      • Swedish Neuroscience Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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. Documented EGFRvlll positive tumor status (central lab confirmation).
4. First or second relapse of de novo glioblastoma or first diagnosis or first relapse of secondary glioblastoma.
5. Previous treatment must include surgery, conventional radiation therapy and temozolomide (TMZ).
6. Screening MRI must be obtained at least 4 weeks after any salvage surgery, and at least 12 weeks after radiation therapy.
7. KPS of ≥ 70%.
8. 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.
9. Evaluable disease in Groups 1 and 2; measurable disease in Group 2C
10. Life expectancy > 12 weeks.
11. 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:

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.
9. Patients in Group 1 must not have received prior treatment with bevacizumab.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	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 Names: 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.
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.	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 Names: Avastin; 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 2 and 2C: 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).	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 Names: 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.

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.

Collaborators and Investigators

• Sponsor: Celldex Therapeutics

Publications and helpful links

General Publications

• Reardon DA, Desjardins A, Vredenburgh JJ, O'Rourke DM, Tran DD, Fink KL, Nabors LB, Li G, Bota DA, Lukas RV, Ashby LS, Duic JP, Mrugala MM, Cruickshank S, Vitale L, He Y, Green JA, Yellin MJ, Turner CD, Keler T, Davis TA, Sampson JH; ReACT trial investigators. Rindopepimut with Bevacizumab for Patients with Relapsed EGFRvIII-Expressing Glioblastoma (ReACT): Results of a Double-Blind Randomized Phase II Trial. Clin Cancer Res. 2020 Apr 1;26(7):1586-1594. doi: 10.1158/1078-0432.CCR-18-1140. Epub 2020 Feb 7.
• Gatson NT, Weathers SP, de Groot JF. ReACT Phase II trial: a critical evaluation of the use of rindopepimut plus bevacizumab to treat EGFRvIII-positive recurrent glioblastoma. CNS Oncol. 2016;5(1):11-26. doi: 10.2217/cns.15.38. Epub 2015 Dec 15.

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (Actual): April 1, 2015
• Study Completion (Actual): May 17, 2016

Study Registration Dates

• First Submitted: December 21, 2011
• First Submitted That Met QC Criteria: December 22, 2011
• First Posted (Estimate): December 23, 2011

Study Record Updates

• Last Update Posted (Actual): February 17, 2020
• Last Update Submitted That Met QC Criteria: February 12, 2020
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: radiotherapy; Brain Tumor; Bevacizumab; Relapsed; Gliosarcoma; Glioblastoma; Brain Cancer; chemoradiation; Recurrent; EGFRvIII; Rindopepimut; CDX-110; Small cell; Giant cell; oligodendroglial; Tumor; Returned; EGFR variant III
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Gliosarcoma; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab; Rindopepimut
• Other Study ID Numbers: CDX110-06

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No