Vaccine Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme (ACTIVATe)
A Complementary Trial of an Immunotherapy Vaccine Against Tumor-Specific EGFRvIII
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.
Visão geral do estudo
Status
Condições
Intervenção / Tratamento
Descrição detalhada
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.
Tipo de estudo
Inscrição (Real)
Estágio
- Fase 2
Contactos e Locais
Locais de estudo
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North Carolina
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Durham, North Carolina, Estados Unidos, 27710
- Duke University Medical Center
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Texas
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Houston, Texas, Estados Unidos, 77030-4009
- M. D. Anderson Cancer Center at University of Texas
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-
Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
Aceita Voluntários Saudáveis
Gêneros Elegíveis para o Estudo
Descrição
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).
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Tratamento
- Alocação: Não randomizado
- Modelo Intervencional: Atribuição Paralela
- Mascaramento: Nenhum (rótulo aberto)
Armas e Intervenções
Grupo de Participantes / Braço |
Intervenção / Tratamento |
|---|---|
|
Experimental: Arm I (ACTIVATE)
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.
|
Dado por via intradérmica
Given intradermally
Standard of care chemotherapy
Outros nomes:
|
|
Experimental: Arm II (ACT II 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), 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.
|
Dado por via intradérmica
Given intradermally
Standard of care chemotherapy
Outros nomes:
|
|
Experimental: Arm III (ACT II 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), 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.
|
Dado por via intradérmica
Given intradermally
Standard of care chemotherapy
Outros nomes:
|
O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
|
Humoral and Cellular Immune Response
Prazo: 26 months
|
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)
Prazo: 58 months
|
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
|
Medidas de resultados secundários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
|
Response to Vaccination
Prazo: 26 months
|
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
|
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Toxicity to PEP-3 Vaccine Immunization
Prazo: 26 months
|
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
|
Colaboradores e Investigadores
Patrocinador
Investigadores
- Investigador principal: Gordana Vlahovic, MD, Duke University
Publicações e links úteis
Publicações Gerais
- Schmittling RJ, Archer GE, Mitchell DA, Heimberger A, Pegram C, Herndon JE 2nd, Friedman HS, Bigner DD, Sampson JH. Detection of humoral response in patients with glioblastoma receiving EGFRvIII-KLH vaccines. J Immunol Methods. 2008 Nov 30;339(1):74-81. doi: 10.1016/j.jim.2008.08.004. Epub 2008 Sep 4.
- Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, Gilbert MR, Herndon JE 2nd, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling RJ, Shi W, Vredenburgh JJ, Bigner DD. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010 Nov 1;28(31):4722-9. doi: 10.1200/JCO.2010.28.6963. Epub 2010 Oct 4.
- Sampson JH, Aldape KD, Archer GE, Coan A, Desjardins A, Friedman AH, Friedman HS, Gilbert MR, Herndon JE, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling R, Shi W, Vredenburgh JJ, Bigner DD, Heimberger AB. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol. 2011 Mar;13(3):324-33. doi: 10.1093/neuonc/noq157. Epub 2010 Dec 10.
Datas de registro do estudo
Datas Principais do Estudo
Início do estudo
Conclusão Primária (Real)
Conclusão do estudo (Real)
Datas de inscrição no estudo
Enviado pela primeira vez
Enviado pela primeira vez que atendeu aos critérios de CQ
Primeira postagem (Estimativa)
Atualizações de registro de estudo
Última Atualização Postada (Estimativa)
Última atualização enviada que atendeu aos critérios de controle de qualidade
Última verificação
Mais Informações
Termos relacionados a este estudo
Termos MeSH relevantes adicionais
- Doenças Cerebrais
- Doenças do Sistema Nervoso Central
- Doenças do Sistema Nervoso
- Neoplasias por Tipo Histológico
- Neoplasias por local
- Neoplasias Glandulares e Epiteliais
- Astrocitoma
- Glioma
- Neoplasias Neuroepiteliais
- Tumores Neuroectodérmicos
- Neoplasias, Células Germinativas e Embrionárias
- Neoplasias, Tecido Nervoso
- Neoplasias do Sistema Nervoso Central
- Neoplasias do Sistema Nervoso
- Neoplasias
- Glioblastoma
- Neoplasias Cerebrais
- Efeitos Fisiológicos das Drogas
- Mecanismos Moleculares de Ação Farmacológica
- Agentes Antineoplásicos
- Fatores imunológicos
- Agentes Antineoplásicos Alquilantes
- Agentes Alquilantes
- Temozolomida
- Sargramostim
Outros números de identificação do estudo
- Pro00004040
- P50NS020023 (Concessão/Contrato do NIH dos EUA)
- CDR0000589632 (Outro identificador: National Cancer Institute)
- DUMC-5421 (Identificador de registro: DUMC IRB)
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