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Glioblastoma

Brain Neoplasms

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Neuroectodermal Tumors, Primitive

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Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

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Central Nervous System Neoplasms

Nervous System Neoplasms

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Central Nervous System Diseases

Neuroepithelioma

All Drugs and Chemicals

Antineoplastic Agents

Vaccines

Molgramostim

Sargramostim

Temozolomide

Immunomodulating Agents

Mitogens

Keyhole-limpet hemocyanin

Antineoplastic Agents, Alkylating

Alkylating Agents

Immunologic Factors

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.

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.

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.

PEP-3 vaccine

sargramostim

Gordana Vlahovic, MD

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.

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.

Vaccine Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

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

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).

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).

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.

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.

National Institute of Neurological Disorders and Stroke (NINDS)

John Sampson

Professor of Neurology

The adverse events were gathered in Common Terminology Criteria for Adverse Events v.3.0, and have been converted to v.4.0 for entry into ClinicalTrials.gov.

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) 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.

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) 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.

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) 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.

Arm III (ACT II DI)

Total

Age, Continuous

Gender

Dr. John H. Sampson

The test was performed on a subset of patients in each group that were available at vaccine 8, and results posted for those 30 patients who had the tests performed.

Humoral and Cellular Immune Response

Clinical Efficacy of Vaccination, in Terms of Progression-free Survival (PFS)

This objective was not completed, as the test was not performed successfully.

Response to Vaccination

Toxicity to PEP-3 Vaccine Immunization

Overall Study

Blood and Lymph Conditions

Immune System Diseases

Lymphopenia

Patients receive CMV-ALT IV over 45-90 minutes (course 1 only) and CMV pp65-LAMP mRNA-loaded DC (CMV-DC) vaccine intradermally and administered in equal portions to each inguinal region. Vaccination repeats every 1-3 weeks for up to 3 doses in the absence of unacceptable toxicity.

Patients receive CMV-DC vaccine intradermally and administered in equal portions to each inguinal region. Vaccination repeats every 1-3 weeks for up to 3 doses in the absence of unacceptable toxicity.

Within 6 to 24 hours prior to vaccination, patients undergo skin site preparation with unpulsed DCs at the vaccination site in one inguinal region. Patients then receive indium In 111-labeled CMV-DC.

Within 6 to 24 hours prior to vaccination, patients undergo vaccination skin site preparation in the opposite inguinal region with tetanus toxoid. Patients then receive 111 In-labeled CMV-DC.

tetanus toxoid

therapeutic autologous dendritic cells

therapeutic autologous lymphocytes

Katherine Peters, MD, PhD

RATIONALE: Vaccines may help the body build an effective immune response to kill cancer cells. Radiation therapy uses high-energy x-rays to kill cancer cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving vaccine therapy together with radiation therapy and chemotherapy may kill more cancer cells.

PURPOSE: This randomized phase I/II trial is studying how well vaccine therapy works in treating patients with newly diagnosed glioblastoma multiforme recovering from lymphopenia caused by temozolomide.

OBJECTIVES:

Primary

* To evaluate the feasibility and safety of vaccination with cytomegalovirus (CMV) pp65-lysosomal-associated membrane protein (LAMP) mRNA-loaded dendritic cells (DCs) during recovery from therapeutic temozolomide-induced lymphopenia with or without autologous lymphocyte transfer (ALT) in patients with newly diagnosed glioblastoma multiforme and who are seropositive or seronegative for CMV.

Secondary

* To assess humoral and cellular immune responses in these patients to CMV pp65-LAMP mRNA-loaded dendritic cell (CMV-DC) vaccine and to compare the impact of ALT and CMV seropositivity on these parameters.
* To determine if vaccination with or without ALT extends total time to progression or overall survival of these patients when compared to a recent historical cohort.
* To assess the differential ability of indium In\^111-labeled DCs to track to the inguinal lymph nodes under different skin preparative conditions.
* To assess the differential ability of \^111In-labeled DCs to track to lymph nodes on the tumor-bearing and non-tumor-bearing side of the cervical lymph nodes.
* To characterize immunologic cell infiltrate in recurrent tumors and seek evidence of antigen escape in recurrent or progressive tumors.

Patients undergo leukapheresis no more than 4 weeks after surgical resection to obtain peripheral blood lymphocytes (PBLs) for human cytomegalovirus (CMV)-autologous lymphocyte transfer (ALT) and CMV-dendritic cell (DC) generation.

Beginning 2-6 weeks after resection, patients undergo external beam radiotherapy (RT) once daily, 5 days a week, for up to 7 weeks. Beginning on day 1 of RT, patients receive oral temozolomide (TMZ) once daily for up to 49 days. Patients with progressive disease during RT, dependence on steroids above physiologic levels, intolerance to TMZ, or failure to meet cell release criteria for DCs or PBLs are removed from study.

Beginning within 2-4 weeks after completion of concurrent RT and TMZ, patients resume oral TMZ once daily on days 1-5. Treatment repeats every 4-6 weeks for up to 6 courses\* in the absence of disease progression or unacceptable toxicity. Beginning on day 19-23 of course 1, patients also receive an intradermal immunization. Patients are stratified by CMV serology status (positive vs negative) and are randomized to 1 of 2 vaccine treatment arms.

Note: \*Patients may receive additional TMZ treatment at the discretion of the patient and their treating neuro-oncologist.

* Arm I (DC vaccination plus ALT): Patients receive CMV-ALT IV over 45-90 minutes (course 1 only) and 2 x 10\^7 CMV pp65-LAMP mRNA-loaded DC (CMV-DC) vaccine intradermally and administered in equal portions to each inguinal region. Vaccination repeats every 1-3 weeks for up to 3 doses in the absence of unacceptable toxicity.
* Arm II (DC vaccination alone): Patients receive CMV-DC vaccine as in arm I. At approximately 2-6 weeks after the third vaccination, all patients undergo a second leukapheresis to obtain peripheral blood mononuclear cells for immunologic monitoring and additional DCs for continued vaccinations. Patients may undergo an additional leukapheresis if they achieve a positive immunological response to therapy or if they require additional DCs to be generated due to a prolonged progression-free survival. Leukapheresis may be performed monthly, but will likely be performed every 4 months throughout the study to generate enough DCs to continue monthly vaccinations.
* Additional cohort (GM-CSF): Patients receive CMV-DC vaccine as in arm II, except that they will also receive GM-CSF in each vaccine. Vaccines continue for a total of 10 unless tumor progression occurs. Patients in this cohort may be enrolled at any point prior to completion of adjuvant TMZ provided they meet all other eligibility criteria.

Prior to the fourth vaccination, patients in both arms and patients with disease progression determined prior to the first scheduled vaccination are stratified according to side of inguinal injection (left vs right) and vaccination skin site preparation (unpulsed DCs vs tetanus toxoid). Patients are then randomized to 1 of 2 treatment arms.

* Arm I (unpulsed DCs): Within 6 to 24 hours prior to vaccination, patients undergo skin site preparation with 1 x 10\^6 unpulsed DCs at the vaccination site in one inguinal region. Patients then receive indium In\^111-labeled CMV-DC.
* Arm II (tetanus toxoid): Within 6 to 24 hours prior to vaccination, patients undergo vaccination skin site preparation in the opposite inguinal region with tetanus toxoid. Patients then receive indium In\^111-labeled CMV-DC as in arm I.

At the time of progression, patients receive a final intradermal vaccination comprising \^111In-labeled CMV-DCs at the base of the jaw bilaterally and to the inguinal region, as a control. Gamma camera images are then taken at 24 and 48 hours after the vaccination to compare DC migration in the groin to each side of the neck injection sites and to observe migration from the neck injection sites to the deep and superficial cervical lymph nodes.

After completion of TMZ therapy, patients continue receiving DC vaccinations in the absence of disease progression (except GM-CSF cohort - total of 10 vaccinations).

Patients undergo blood sample collection periodically for immunologic studies. Samples are examined for functional CD4 and CD8 immune response of patients by cytokine fluorescent cytometry; enumeration of pp65 antigen-specific CD8+ T cells by tetramer analysis; antigen-induced T-cell proliferation; cytokine secretion and quantitative anti-pp65 antibody concentration in the serum by ELISA; and CMV pp65 quantitation in genomic DNA by reverse transcriptase-polymerase chain reaction. Patients may also undergo stereotactic biopsy or tumor resection to confirm tumor progression histologically and to assess immunologic cell infiltration and pp65 antigen escape at the tumor site by immunohistochemistry and polymerase chain reaction.

Quality of life is assessed by the self-reported Functional Assessment of Cancer Therapy-Brain questionnaire at initial leukapheresis, at the first vaccination, after the third vaccination at the time of post-vaccine leukapheresis, and then with every even-numbered vaccination thereafter. A neuropsychological assessment is also conducted prior to the first vaccine and then with every second vaccination thereafter in order to monitor for any changes in neurocognitive or affective changes.

After completion of study therapy, patients are followed periodically.

Anti-Tumor Immunotherapy Targeted Against Cytomegalovirus in Patients With Newly-Diagnosed Glioblastoma Multiforme During Recovery From Therapeutic Temozolomide-induced Lymphopenia

National Cancer Institute (NCI)

Gary Archer Ph.D.

Assistant Professor Neurosurgery

Basiliximab

Daclizumab

Immunosuppressive Agents

Temozolomide, PEP-3-KLH conjugate vaccine, and daclizumab

Temozolomide, PEP-3-KLH conjugate vaccine, and normal saline

Patients will receive basiliximab 20 mg IV with vaccine # 1 only and continue with PEP-3-KLH, temozolomide.

PEP-3-KLH conjugate vaccine

daclizumab

temozolomide

placebo

Basiliximab 20 mg IV over 30 minutes with PEP-3-KLH vaccine # 1 only.

PEP-3-KLH

Duane Mitchell, MD, PhD

RATIONALE: Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Vaccines may help the body build an effective immune response to kill tumor cells. Monoclonal antibodies, such as basiliximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether giving chemotherapy, radiation therapy, and vaccine therapy together with basiliximab is a more effective treatment for glioblastoma multiforme than chemotherapy, radiation therapy, and vaccine therapy alone.

PURPOSE: This randomized phase I trial is studying the side effects and best way to give chemotherapy and radiation therapy followed by vaccine therapy with basiliximab in treating patients with glioblastoma multiforme that has been removed by surgery.

OBJECTIVES:

Primary

* To determine if basiliximab inhibits the functional and numeric recovery of T-regulatory cells (Tregs) after therapeutic temozolomide (TMZ)-induced lymphopenia in the context of vaccinating adult patients with newly diagnosed glioblastoma multiforme (GBM) using PEPvIII-keyhole limpet hemocyanin (KLH).

Secondary

* To evaluate the safety of basiliximab in the context of vaccinating adult patients with newly diagnosed GBM using PEP-3-KLH conjugate vaccine during recovery from therapeutic TMZ-induced lymphopenia.
* To determine if basiliximab enhances the magnitude or character of PEPvIII-KLH-induced cellular or humoral immune responses, inhibits or enhances activation-induced cell death, or induces immunologic or clinical evidence of autoimmunity.
* To determine if basiliximab enhances the magnitude or character of PEPvIII-KLH-induced cellular or humoral immune responses, inhibits or enhances activation-induced cell death, or induces immunologic or clinical evidence of autoimmunity.
* To determine if basiliximab alters the phenotype (CD56-expression), cytokine secretion profile, or cytotoxicity of CD3-negative CD56-positive natural killer cells.
* To determine if basiliximab, in addition to vaccination, extend progression-free survival compared to historical cohorts.
* To characterize immunologic cell infiltrate in recurrent tumors and seek evidence of antigen escape outgrowth.

OUTLINE:

* Leukapheresis: Patients undergo leukapheresis over 2-4 hours for immunologic monitoring.
* Concurrent standard adjuvant chemoradiotherapy: Patients receive external-beam radiotherapy once daily, 5 days a week, over 6-7 weeks (33 fractions) and concurrent temozolomide by mouth 7 days a week for up to 49 days beginning on the first day and continuing until the last day of radiotherapy.
* Temozolomide and PEP-3-KLH conjugate vaccine: Approximately 3 weeks after completion of radiotherapy, patients receive temozolomide by mouth on days 1-21, or on days 1-5 depending on their treating neuro-oncologist, basiliximab IV over 30 minutes on day 21, and PEP-3-KLH conjugate vaccine intradermally on days 21, 35, and 49.

Patients then receive a second course of temozolomide by mouth on days 1-21 or days 1-5, depending on their treating neuro-oncologist. Treatment with temozolomide repeats every 4 weeks for 5 additional courses. Patients also receive PEP-3-KLH conjugate vaccine on day 21 of each remaining temozolomide course. Patients then receive the vaccine monthly until disease progression.

Patients undergo blood sample collection periodically for laboratory studies.

After completion of study therapy, patients are followed periodically.

Chemotherapy, Radiation Therapy, and Vaccine Therapy With Basiliximab in Treating Patients With Glioblastoma Multiforme That Has Been Removed by Surgery

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Vaccine Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme	NCT00643097	Malignant Neopl...	PEP-3 vaccine sargramostim Temozolomide	18 Years -	Duke University
Vaccine Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme	NCT00639639	Malignant Neopl...	tetanus toxoid therapeutic aut... therapeutic aut...	18 Years -	Duke University
Vaccine Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme	NCT00639639	Malignant Neopl...	tetanus toxoid therapeutic aut... therapeutic aut...	18 Years -	Duke University
Chemotherapy, Radiation Therapy, and Vaccine Therapy With Basiliximab in Treating Patients With Glioblastoma Multiforme That Has Been Removed by Surgery	NCT00626015	Malignant Neopl...	PEP-3-KLH conju... daclizumab temozolomide placebo PEP-3-KLH	18 Years - 120 Years	Duke University

Spots Global Cancer Trial Database for malignant neoplasms of brain