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

Tracking Information
First Submitted Date ICMJE	December 21, 2011
First Posted Date ICMJE	December 23, 2011
Last Update Posted Date	April 7, 2017
Study Start Date ICMJE	December 2011
Actual Primary Completion Date	April 2015 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: August 15, 2013)	Groups 1 and 2: Progression-free survival rate [ Time Frame: 6 months post-Day 1 ]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).; Group 2C: Objective Response Rate [ Time Frame: Every 8 weeks from Day 1 through progression or initiation of other anti-cancer therapy ]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.
Original Primary Outcome Measures ICMJE; (submitted: December 22, 2011)	Progression-free survival rate [ Time Frame: 6 months post-Day 1 ]; 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).
Change History	Complete list of historical versions of study NCT01498328 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: August 15, 2013)	Safety and Tolerability [ Time Frame: Until 28 days or initiation of other anti-cancer treatment, whichever is first ]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 ]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.; EGFRvIII-specific immune response [ Time Frame: Several times during the first month of treatment and then approximately every 8 weeks until treatment is stopped. ]Characterize the EGFRvIII specific immune response to rindopepimut.
Original Secondary Outcome Measures ICMJE; (submitted: December 22, 2011)	Safety and Tolerability [ Time Frame: Until 28 days or initiation of other anti-cancer treatment, whichever is first ]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 ]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. ]Characterize the EGFRvIII specific immune response to rindopepimut.
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	A Study of Rindopepimut/GM-CSF in Patients With Relapsed EGFRvIII-Positive Glioblastoma
Official Title ICMJE	A Phase II Study of Rindopepimut/GM-CSF in Patients With Relapsed EGFRvIII-Positive Glioblastoma
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.
Study Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
Condition ICMJE	Glioblastoma; Small Cell Glioblastoma; Giant Cell Glioblastoma; Gliosarcoma; Glioblastoma With Oligodendroglial Component; Recurrent Glioblastoma; Relapsed Glioblastoma
Intervention ICMJE	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.
Study Arms	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 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). Interventions: Drug: Bevacizumab Drug: Rindopepimut (CDX-110) with GM-CSF
Publications *	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. Retraction in: CNS Oncol. 2016;5(2):110.; Retraction in:CNS Oncol. 2016;5(2):110
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: September 30, 2016)	127
Original Estimated Enrollment ICMJE; (submitted: December 22, 2011)	95
Actual Study Completion Date	May 17, 2016
Actual Primary Completion Date	April 2015 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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.
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01498328
Other Study ID Numbers ICMJE	CDX110-06
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Celldex Therapeutics
Study Sponsor ICMJE	Celldex Therapeutics
Collaborators ICMJE	Not Provided
Investigators ICMJE	Not Provided
PRS Account	Celldex Therapeutics
Verification Date	April 2017
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP