Vaccine Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

Study Overview
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Brief Summary
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RATIONALE: Vaccines made from a peptide may help the body build an effective immune response to kill tumor cells. Colony-stimulating factors, such as GM-CSF, increase the number of white blood cells and platelets found in bone marrow or peripheral blood. Giving vaccine therapy after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial is studying how well vaccine therapy works in treating patients with newly diagnosed glioblastoma multiforme.

Detailed Description
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OBJECTIVES: Primary To assess humoral and cellular immune responses to adjuvant PEP-3-KLH conjugate vaccine in patients with newly diagnosed glioblastoma multiforme (GBM). To assess the clinical efficacy of the PEP-3-KLH conjugate vaccine, in terms of progression-free survival, in patients with newly diagnosed GBM. Secondary To determine whether patients with GBM, who are known to be at least mildly immunosuppressed, can respond to standard and proven vaccine strategies. To assess for any potential toxicity to the PEP-3-KLH conjugate vaccine in patients with newly diagnosed GBM. OUTLINE: This is a multicenter study. Patients are stratified according to participating center. At the time the study was initiated, standard of care temozolomide was not established, therefore, Arm I (ACTIVATE)was given without monthly cycles of temozolomide. At the point of interim analysis, monthly cycles of temozolomide had become standard of care. Arm II was then given the standard of care 5-day cycles of monthly temozolomide and during this time, dose-intensified temozolomide was in trials to compare with the 5-day temozolomide. Therefore, Arm III was initiated to determine the immunologic effects of 21-day monthly cycles of temozolomide with vaccine. Arm I (ACTIVATE): Patients receive PEP-3-KLH conjugate vaccine and sargramostim (GM-CSF) intradermally on days 1, 15, and 29 and then monthly in the absence of disease progression or unacceptable toxicity. Arm II (ACT II Standard (STD)): Patients first receive 3 initial vaccinations of an epidermal growth factor receptor variant III (EGRRvIII)- specific peptide (PEP-3) keyhole limpet hemocyanin (KLH) conjugate vaccine and sargramostim (GM-CSF) biweekly starting within 6 weeks of completing radiation. Additional vaccinations are given until clinical or radiographic evidence of progression or death. Patients subsequently receive temozolomide at a targeted dose of 200 mg/m2 for the first 5 days of a 28 day cycle. Arm III (ACT II Dose-intensified (DI)): Patients first receive 3 initial vaccinations of an epidermal growth factor receptor variant III (EGRRvIII)- specific peptide (PEP-3) keyhole limpet hemocyanin (KLH) conjugate vaccine and sargramostim (GM-CSF) biweekly starting within 6 weeks of completing radiation. Additional vaccinations are given until clinical or radiographic evidence of progression or death. Patients subsequently receive temozolomide at a targeted dose of 100 mg/m2 for the first 21 days of a 28 day cycle. Patients undergo delayed-type hypersensitivity (DTH) skin testing* at baseline, after the third vaccination, and then monthly thereafter. Patients also undergo leukapheresis to obtain sufficient peripheral blood lymphocytes for immunologic monitoring at baseline, after the third vaccination, and then, if applicable, at the time of positive DTH response, disease progression, or after the sixth course of post-radiotherapy temozolomide. Methods used for immunologic monitoring include Enzyme-linked Immunospot(ELISPOT) assays, cytotoxicity assays, fluorescence activated cell sorting (FACS), and ELISA. NOTE: *Patients with positive DTH skin testing, also undergo skin punch biopsies. After completion of study therapy, patients are followed periodically.

Official Title
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A Complementary Trial of an Immunotherapy Vaccine Against Tumor-Specific EGFRvIII

Conditions
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Malignant Neoplasms of Brain

Intervention / Treatment
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* Biological: PEP-3 vaccine
* Biological: sargramostim
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed newly diagnosed glioblastoma multiforme Has undergone prior gross total resection (GTR) followed by conformal radiotherapy* with or without concurrent chemotherapy GTR is defined as ≥ 95% volumetric resection of the contrast-enhancing component on the preoperative MRI Residual radiographic contrast enhancement on post-resection CT scan or MRI must be ≤ 1 cm in maximal diameter in any two perpendicular axial planes No evidence of disease progression after completion of radiotherapy* NOTE: *Patients may enroll in part 2 of the study within 2 weeks after surgery; these patients will receive radiotherapy with concurrent chemotherapy during the study EGFRvIII-positive tumor by immunohistochemistry, polymerase chain reaction, or related molecular techniques Karnofsky performance status 80-100% Curran group status I-IV Signed informed consent form Exclusion Criteria: Absolute Neutrophil Count (ANC) < 1,000/mm³ Platelet count < 50,000/mm³ Prothrombin Time/Partial Thromboplastin Time (PT/PTT) > 1.5 times normal Positive hepatitis B (HB) surface antigen (HbsAg), antibody to hepatitis B surface antigen (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc) Pregnant or nursing Positive pregnancy test Active infection requiring treatment Unexplained febrile illness (T max > 101.5 F) Inflammatory bowel disease, lupus erythematosus, rheumatoid arthritis, or other autoimmune disease Known immunosuppressive disease Known HIV infection Diffuse leptomeningeal disease Unstable or severe concurrent medical condition, such as severe heart and lung disease or active hepatitis Demonstrated allergy to temozolomide or inability to tolerate temozolomide for reasons other than lymphopenia Concurrent corticosteroids (except for nasal or inhaled steroids) at a dose above physiologic levels (> 2 mg of dexamethasone/day).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (ACTIVATE)<br>Patients first receive 3 initial vaccinations of an epidermal growth factor receptor variant III (EGRRvIII)-specific peptide (PEP-3) keyhole limpet hemocyanin (KLH) conjugate vaccine and sargramostim (GM-CSF), referred to as PEP-3 vaccine, every 2 weeks starting 4 weeks after the completion of radiation. Subsequent vaccinations were given once a month until clinical or radiographic evidence of progression or death. | Biological: PEP-3 vaccine<br>* Given intradermally<br>Biological: sargramostim<br>* Given intradermally<br>Drug: Temozolomide<br>* Standard of care chemotherapy<br>* Other names: Temodar;|
| Experimental: Arm II (ACT II STD)<br>Patients first receive 3 initial vaccinations of an epidermal growth factor receptor variant III (EGRRvIII)- specific peptide (PEP-3) keyhole limpet hemocyanin (KLH) conjugate vaccine and sargramostim (GM-CSF), referred to as PEP-3 vaccine, biweekly starting within 6 weeks of completing radiation. Additional vaccinations were given until clinical or radiographic evidence of progression or death. Patients subsequently receive temozolomide at a targeted dose of 200 mg/m2 for the first 5 days of a 28 day cycle. | Biological: PEP-3 vaccine<br>* Given intradermally<br>Biological: sargramostim<br>* Given intradermally<br>Drug: Temozolomide<br>* Standard of care chemotherapy<br>* Other names: Temodar;|
| Experimental: Arm III (ACT II DI)<br>Patients first receive 3 initial vaccinations of an epidermal growth factor receptor variant III (EGRRvIII)- specific peptide (PEP-3) keyhole limpet hemocyanin (KLH) conjugate vaccine and sargramostim (GM-CSF), referred to as PEP-3 vaccine, biweekly starting within 6 weeks of completing radiation. Additional vaccinations were given until clinical or radiographic evidence of progression or death. Patients subsequently receive temozolomide at a targeted dose of 100 mg/m2 for the first 21 days of a 28 day cycle. | Biological: PEP-3 vaccine<br>* Given intradermally<br>Biological: sargramostim<br>* Given intradermally<br>Drug: Temozolomide<br>* Standard of care chemotherapy<br>* Other names: Temodar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Humoral and Cellular Immune Response | Number of patients that developed a delayed-type hypersensitivity (DTH) response at following vaccination. Any skin reaction in response to the intradermal injection of the antigen was measured and recorded. A positive skin test was defined as > 5 mm induration (swelling). | 26 months | 
| Clinical Efficacy of Vaccination, in Terms of Progression-free Survival (PFS) | Time in months 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. Macdonald criteria are standard criteria in neuro-oncology. Tumor assessment was made according to the adapted MacDonald criteria based on the combined evaluation of: 1) assessment of the MRI scan for measurable, evaluable, and new lesions (made by the independent external expert too), 2) overall assessment of neurological performance (made by the investigator), 3) concomitant steroid use (as reported by the investigator). | 58 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to Vaccination | The objective is to assess the duration of immunosuppressive cytokine secretion and to identify a receptive interval for active immunotherapy. Immunosuppression will determined by monitoring a panel of immunosuppressive serum/plasma cytokines longitudinally and by determining the response of each patient to Recombivax Hepatitis B (HB) vaccination. Response is defined as seropositive or seronegative to the Hepatitis B surface antigen. | 26 months | 
| Toxicity to PEP-3 Vaccine Immunization | To assess for any potential toxicity to the PEP-3 vaccine immunization in patients with newly diagnosed glioblastoma, Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used to tabulate any toxicities attributable to PEP-3. The number of patients with toxicity attributable to vaccine while on study are tabulated. | 26 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult giant cell glioblastoma, adult gliosarcoma, adult glioblastoma