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Neuroectodermal Tumors, Primitive

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Neoplasms, Glandular and Epithelial

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Vaccines

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Antineoplastic Agents, Alkylating

Alkylating Agents

This single-arm phase II study will assess the impact of tetanus pre-conditioning and adjuvant GM-CSF on overall survival of newly diagnosed glioblastoma (GBM) patients who have undergone definitive resection, are unmethylated, and completed standard temozolomide and radiation treatment. All enrolled patients will undergo a leukapheresis for the generation of DCs. Patients will then receive approximately 6 weeks of standard of care radiation therapy (RT) and concurrent TMZ. A single post-RT cycle of dose intensified TMZ (100 mg/m2/day for 21 days) will then be given. On day 23 (± 2 days) of the cycle, patients will receive the first of 3 pp65 DC vaccines every 2 weeks. All patients will receive up to a total of 10 DC vaccines

2x10\^7 human CMV pp65-LAMP mRNA-pulsed autologous DCs are given intradermally and bilaterally at the groin site (divided equally to both inguinal regions). Patients will receive up to a total of 10 DC vaccines.

Human CMV pp65-LAMP mRNA-pulsed autologous DCs containing GM CSF

Temozolomide is a chemotherapy drug given to all enrolled patients at the post-RT clinic visit as dose-intensified TMZ (100 mg/m2/day for 21 days).

Before the first DC vaccination, patients will receive 0.5 mL of Td (tetanus and diphtheria toxoids adsorbed) intramuscularly into the deltoid muscle to ensure adequate immunity to the tetanus antigen. Prior to pp65 DC vaccination #4,(3±1) weeks after leukapheresis 2 the vaccine site will receive a pre-conditioning intradermal injection of Td (1 flocculation unit (Lf), in 0.3 mL of saline for a total of 0.4 mL).

Tetanus-Diphtheria Toxoid (Td)

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a sterile, white, preservative-free lyophilized powder in a vial containing 250 mcg that will be reconstituted in 0.5 mL of sterile water for injection and used as an adjuvant with the DC vaccine.

GM-CSF

111-In-labeled DCs are 2 x 10\^7 pp65-LAMP mRNA loaded mature DCs labeled with 111-In (50 μCi / 5 x 10\^7 DCs) and given i.d. as the fourth vaccine. In up to 16 patients, the fourth vaccine will be labeled with 111-In (50 μCi / 5 x 10\^7 DCs) prior to injection.

111-Indium-labeling of Cells for in vivo Trafficking Studies

Mustafa Khasraw, MBChB, MD, FRCP, FRACP

This single-arm phase II study will assess the impact of tetanus pre-conditioning and adjuvant Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) on overall survival of patients newly diagnosed with World Health Organization (WHO) Grade IV glioblastoma who have undergone definitive tumor resection, are cytomegalovirus (CMV) positive and unmethylated, and completed standard temozolomide (TMZ) and radiation treatment. After completion of the standard of care radiotherapy with concurrent TMZ, patients will receive 1 cycle of dose-intensified TMZ followed by pp65-loaded dendritic cell (DC) vaccination beginning on day 23.

Approximately 64 patients with resected, newly-diagnosed WHO Grade IV glioma who are CMV positive and in which the Methylguanine Methyltransferase (MGMT) is not methylated will be accrued to this study before standard of care radiation therapy (RT) and concurrent TMZ, with the goal of treating 48 patients with dose-intensified temozolomide and pp65 loaded dendritic cell vaccine after completion of standard RT and TMZ.

All enrolled patients will undergo a leukapheresis for the generation of DCs. Patients will then receive approximately 6 weeks of the standard of care radiation therapy (RT) and concurrent TMZ at a standard targeted dose of 75 mg/m2/day. For patients whose initial leukapheresis yields less than 3 vaccines, repeat leukapheresis may be obtained. At the post-RT clinic visit, a single post-RT cycle of dose-intensified TMZ (100 mg/m2/day for 21 days) will be given. On day 23 (± 2 days) of the cycle, patients will receive the first of 3 pp65 DC vaccines. Vaccines #1-3 will be given every two weeks (± 2 days). All patients will receive up to a total of 10 DC vaccines, with vaccines administered every 35 days (± 7 days) after the third vaccine, given bilaterally at the groin site unless progression occurs with no further cycles of TMZ. DC vaccines will be given intradermally (i.d.) and divided equally to both inguinal regions. Before the first DC vaccination, patients will receive 0.5 mL of Td (tetanus and diphtheria toxoids adsorbed) intramuscularly into the deltoid muscle to ensure adequate immunity to the tetanus antigen. Patients will undergo leukapheresis again for immunologic monitoring with a specific assessment of baseline antigen-specific cellular and humoral immune responses if needed for further DC generations 14 (± 2) days after vaccine #3. Prior to pp65 DC vaccination #4,(3±1) weeks after leukapheresis 2, the vaccine site will receive a pre-conditioning intradermal injection of Td. Up to 16 patients will receive 111-Indium labeled DCs at the 4th vaccine followed by SPECT/CT imaging immediately, and at 1 and 2 days after injections.

Newly-diagnosed WHO Grade IV glioma patients with their tumor resected and found to be MGMT unmethylated will be accrued to this study before the standard of care chemoradiation with the goal of treating with dose-intensified TMZ and pp65 loaded dendritic cell vaccine after completion of the standard of care chemoradiation.

Immunotherapy Targeted Against Cytomegalovirus in Patients With Newly-Diagnosed WHO Grade IV Unmethylated Glioma

I-ATTAC: Improved Anti-Tumor Immunotherapy Targeted Against Cytomegalovirus in Patients With Newly-Diagnosed WHO Grade IV Unmethylated Glioma

Time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up has OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve.

The Cox proportional hazards model will assess the impact of migration on survival after vaccine #4. Migration is defined as the maximum percentage of 111In-labeled dendritic cells (DCs) reaching inguinal nodes during the 48 hours after the 4th vaccination. The hazard ratio associated with a 1-unit change in migration will be estimated with 95% confidence intervals.CSF to site-draining inguinal lymph nodes after Td pre-conditioning and survival after vaccine # 4.

The Cox proportional hazards model will assess the impact of CCL3 on survival post-vaccine 4. The hazard ratio associate with a 1-unit increase in CCL3 will be estimated with 95% confidence intervals

Cox proportional hazards model will assess the association between fold change increase between baseline and the leukapheresis 2 in the frequency of pp65 antigen-specific CD8+ T cells producing three or more cytokines (IFNγ, CCL3, IL-2, TNFα, CD107a), and survival post-vaccine 4. The hazard ratio associate with a 1-unit fold change in polyfunctionality will be estimated with 95% confidence intervals.

The mean difference in TRegs between vaccine 1 and the maximum measured level post-vaccine 1 will be reported.

An unacceptable toxicity is defined as any grade 3 or greater toxicity that is possibly, probably, or definitely attributed to the pre-conditioning agent Td or pp65 DC vaccine that does not resolve to baseline within 3 weeks; any Grade 3 hypersensitivity reactions or autoimmune toxicity requiring steroids or hormone replacement; , and is not due to progressive disease, or any life-threatening event not attributable to concomitant medication, co-morbid event, or disease progression. Toxicities will be graded according to the National Cancer Institute Common Toxicity Criteria of Adverse Events (NCI CTCAE) version 5 criteria.

Professor of Neurosurgery

Human CMV pp65-LAMP mRNA-pulsed autologous DCs (dendritic cells) containing GM CSF: 2x10\^7 human CMV pp65-LAMP mRNA-pulsed autologous DCs are given intradermally and bilaterally at the groin site (divided equally to both inguinal regions). Patients will receive up to a total of 10 DC vaccines.

Temozolomide: Temozolomide is a chemotherapy drug given to all enrolled patients at the post-RT clinic visit as dose-intensified TMZ (100 mg/m2/day for 21 days).

Tetanus-Diphtheria Toxoid (Td): Before the first DC vaccination, patients will receive 0.5 mL of Td (tetanus and diphtheria toxoids adsorbed) intramuscularly into the deltoid muscle to ensure adequate immunity to the tetanus antigen. Prior to pp65 DC vaccination #4,(3±1) weeks after leukapheresis 2 the vaccine site will receive a pre-conditioning intradermal injection of Td (1 flocculation unit (Lf), in 0.3 mL of saline for a total of 0.4 mL).

GM-CSF: Granulocyte macrophage-colony stimulating factor (GM-CSF) is a sterile, white, preservative-free lyophilized powder in a vial containing 250 mcg that will be reconstituted in 0.5 mL of sterile water for injection and used as an adjuvant with the DC vaccine.

111-Indium-labeling of Cells for in vivo Trafficking Studies: 111-In-labeled DCs are 2 x 10\^7 pp65-LAMP mRNA loaded mature DCs labeled with 111-In (50 μCi / 5 x 10\^7 DCs) and given i.d. as the fourth vaccine. In up to 16 patients, the fourth vaccine will be labeled with 111-In (50 μCi / 5 x 10\^7 DCs) prior to injection.

DC Vaccination With Td Preconditioning and GM CSF

Human CMV pp65-LAMP mRNA-pulsed autologous DCs containing GM CSF: 2x10\^7 human CMV pp65-LAMP mRNA-pulsed autologous DCs are given intradermally and bilaterally at the groin site (divided equally to both inguinal regions). Patients will receive up to a total of 10 DC vaccines.

Temozolomide: Temozolomide is a chemotherapy drug given to all enrolled patients at the post-RT clinic visit as dose-intensified TMZ (100 mg/m2/day for 21 days).

Tetanus-Diphtheria Toxoid (Td): Before the first DC vaccination, patients will receive 0.5 mL of Td (tetanus and diphtheria toxoids adsorbed) intramuscularly into the deltoid muscle to ensure adequate immunity to the tetanus antigen. Prior to pp65 DC vaccination #4,(3±1) weeks after leukapheresis 2 the vaccine site will receive a pre-conditioning intradermal injection of Td (1 flocculation unit (Lf), in 0.3 mL of saline for a total of 0.4 mL).

GM-CSF: Granulocyte macrophage-colony stimulating factor (GM-CSF) is a sterile, white, preservative-free lyophilized powder in a vial containing 250 mcg that will be reconstituted in 0.5 mL of sterile water for injection and used as an adjuvant with the DC vaccine.

111-Indium-labeling of Cells for in vivo Trafficking Studies: 111-In-labeled DCs are 2 x 10\^7 pp65-LAMP mRNA loaded mature DCs labeled with 111-In (50 μCi / 5 x 10\^7 DCs) and given i.d. as the fourth vaccine. In up to 16 patients, the fourth vaccine will be labeled with 111-In (50 μCi / 5 x 10\^7 DCs) prior to injection.

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Mustafa Khasraw, MD

Median Overall Survival (OS) of Subjects Receiving Td Pre-conditioning With GM-CSF

Migration and Survival From Vaccine 4

Chemokine (C-C Motif) Ligand 3 (CCL3) and Survival From Vaccine 4

Polyfunctionality and Survival From Vaccine 4

Maximum Peak Increase From Vaccine 1 in Percent Regulatory T Cells (TReg) of CD4+ T Cells

Number of Participants With Unacceptable Toxicity

Overall Study

Recurrence

Lipid Regulating Agents

Anti-Infective Agents

Amino Acids

Evolocumab

PCSK9 Inhibitors

Anticholesteremic Agents

Hypolipidemic Agents

Antimetabolites

Protease Inhibitors

Serine Proteinase Inhibitors

HIV Protease Inhibitors

Enzyme Inhibitors

Serine

420 mg of evolocumab subcutaneous injection 7-14 days before scheduled surgery for malignant glioma

Erin Severance, BA

This Phase 0 surgical window of opportunity trial seeks to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) properties of an FDA-approved proprotein convertase/ kexin type 9 serine protease inhibitor (PCSK9i) in patients with primary and recurrent World Health Organization (WHO) grade IV malignant glioma. The investigators intend to evaluate whether a clinically licensed PCSK9i called evolocumab (also known as Repatha) can be repurposed as a potential immunotherapeutic for high grade glioma by testing its ability to access the intracranial space. The primary objective is to evaluate whether evolocumab crosses the blood brain barrier (BBB) and is measurable in the resected tumor specimens of patients with primary and recurrent high grade glioma or glioblastoma.

A maximum of 10 participants will receive 420 mg (the maximum single dose) of evolocumab subcutaneously into their thigh, abdomen or upper arm 7-14 days prior to surgical de-bulking of their tumor. After de-bulking, leftover tissue not required for histological analysis will be collected, and the level of evolocumab will be quantified. At two time points, prior to injection of evolocumab and at time of their surgery, participants will have peripheral blood drawn to analyze serum levels of the drug (for comparison to levels found in their leftover tissue). The investigators will follow-up with participants about 2 weeks after surgery at their post-operative visit.

A matched cohort of resected tumor specimens from patients who were not treated with evolocumab from the Duke Brain Tumor Center Biorepository will be used as a comparison for the primary objective and 2 of the 3 secondary objectives of this study comparing brain tumor tissue specimens of patients who did and did not receive evolocumab with respect to lipid metabolism and tumor cells expressing MHC-I.

The PCSK9i Inhibitor Evolocumab - a Surgical Trial of Pharamcodynamics and Kinetics Evaluation

PEskE: A Phase 0/Surgical Window-of-opportunity Study to Evaluate the Pharmacokinetics and Pharmacodynamics of Evolocumab in Patients With Recurrent High-grade Glioma or Glioblastoma

Determined by fluorescence-activated cell sorting (FACS)

Using serum taken before receiving evolocumab (7-14 days before surgery) and serum taken at the time of surgery

Duke University

Poly ICLC

BIRC5 protein, human

Interferons

The study vaccine is comprised of three different peptides (small proteins) mixed with Hiltonol®. The three peptides that make up the study vaccine are called pp65, EphA2, and survivin.

Vaccine that includes 3 peptides (EphA2 linked to P30 peptide, pp65 linked to P30 peptide, and Survivin linked to P30 peptide)

Tumor Associated Antigen Peptide Vaccine P30-EPS Vaccine

Hiltonol® is made up of synthetic (manmade) RNA (ribonucleic acid) and is used as an adjuvant to the vaccine, meaning it is used with the vaccine to stimulate or enhance the activation of your immune system.

Hiltonol

Stevie Threatt

This is a phase 1b study of P30-linked EphA2, CMV pp65, and survivin vaccination (collectively called the P30-EPS vaccine) in HLA-A\*0201 positive patients with a newly diagnosed, unmethylated, and untreated World Health Organization (WHO) grade IV malignant glioma.

This is a phase 1b study of P30-linked EphA2, CMV pp65, and survivin vaccination (collectively called the P30-EPS vaccine) in HLA-A\*0201 positive patients with a newly diagnosed, unmethylated, and untreated World Health Organization (WHO) grade IV malignant glioma at the Preston Robert Tisch Brain Tumor Center (PRTBTC) at Duke, is planned to address the following primary objective: Evaluate the safety profile of a cancer vaccine comprised of P30-linked EphA2, CMV pp65, and survivin peptides.

A maximum of 36 patients with a newly diagnosed, previously untreated WHO grade IV malignant glioma that is MGMT promoter unmethylated will be treated in this study after undergoing standard of care surgical resection followed by 6 weeks of radiation therapy (XRT) with concomitant temozolomide (TMZ) and providing informed consent. Patients will receive seven P30 linked-EphA2, -CMV pp65, and -survivin (P30-EPS) peptide vaccines over two phases. The first 5 will be given during the Priming Phase (day 1 through day 22). The final 2 will be given during the Booster Phase (day 84 \[± 2 days\] and day 140 \[± 2 days\]). During the Booster Phase on Day 84, patients will also be given 20ug/kg Hiltonol® injections to administer at home every 2 weeks until they return on Day 140. Blood will be drawn throughout the study to investigate the immune response to P30-EPS vaccination. The study will enroll two patient strata: patients who are CMV seronegative and patients who are CMV seropositive. Within each stratum, cohorts of 3 patients will initially be accrued to the study to assess the toxicity associated with the vaccine. The starting dose of P30-EPS is 300 μg/peptide/dose, and the dose will be escalated to 400 μg/peptide/dose. In the event of unacceptable dose-limiting toxicity, the dose will be de-escalated to 200 μg/peptide/dose (dose level minus one). Acute toxicity monitoring will focus on dose-limiting toxicities, as defined in Section 9.1.2 of the protocol, occurring between vaccine 1 and 30 days after vaccine 5. The most common side effects of peptide vaccines are redness or swelling at the injection site, local changes to the texture of your skin (hardening) at the injection site, itching, allergic reactions, and a potentially serious side effect called cytokine release syndrome. The most common side effects of Hiltonol® are reactions at the injection site and flu-like symptoms.

ETAPA I: Peptide-based Tumor Associated Antigen Vaccine in GBM

ETAPA I: Evaluation of Tumor Associated P30-Peptide Antigen I; A Pilot Trial of Peptide-based Tumor Associated Antigen Vaccines in Newly Diagnosed, Unmethylated, and Untreated Glioblastoma (GBM)

Percentage of patients who experience dose-limiting toxicity within each stratum at each dose level

Stratified between CMV seropositive and seronegative patients

National Cancer Institute (NCI)

The first 20 patients accrued to this study will be assayed to validate the performance of the assays developed by Personalis. This pilot sub-study will be analyzed in a "blinded" manner without clinical information.

The remaining 80 patients accrued to this study (after the initial 20 patients accrue to the "Pilot" cohort).

The purpose of this study is to better define longitudinal genomic alterations in patients with glioblastoma (GBM), and to determine if plasma circulating tumor DNA (ctDNA) or cell free DNA (cfDNA) is associated with disease recurrence, survival, tumor characteristics, and/or peripheral immunosuppression.

Tumor (archival) specimens will be obtained from the surgical resection and diagnosis of GBM and before initiation of radiotherapy. It is anticipated that a certain proportion of patients will need to undergo further tumor debulking after radiotherapy. In such instances, these post-radiotherapy re-resected tumor specimens will also be collected for later sequencing.

GRETeL: Tumor Response to Standard Radiotherapy and TMZ Patients With GBM

A Study for Patients Newly Diagnosed With Glioblastoma Being Treated With Standard Radiotherapy and Temozolomide (TMZ) to Evaluate Tumor Response Via Liquid Biopsies (GRETeL)

Median number of ctDNA fragments obtained from tumor tissue, pre-radiation serum specimen, and post-radiation serum specimen, and healthy controls.

Assess the association between degree and frequency of ctDNA shedding and clinical characteristics, such as molecular findings, histopathological characteristics, corticosteroid use, and bevacizumab use.

Quantify the level of immune infiltration in the tumor, and assess its association with progression-free survival (PFS), overall survival (OS), and ctDNA detection.

Assess the prognostic value of chromosomal instability/CAN burden, and assess its association with ctDNA from plasma.

Determine if peripheral T cell function and stemness or autoantibodies are association with ctDNA levels, or TME composition.

Identify and describe changes in the cell free DNA (cfDNA) sequencing profiles of patients diagnosed with GBM in pre- versus post-radiation therapy samples, and to assess the association between these changes and clinical outcome, including progression free and overall survival

Identify and describe changes over time after radiotherapy in the cfDNA sequencing profiles of patients diagnosed with GBM, and to assess the association between these longitudinal changes in cfDNA and clinical outcome, including progression free and overall survival

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Immunotherapy Targeted Against Cytomegalovirus in Patients With Newly-Diagnosed WHO Grade IV Unmethylated Glioma	NCT03927222	Glioblastoma	Human CMV pp65-... Temozolomide Tetanus-Diphthe... GM-CSF 111-Indium-labe...	18 Years -	Duke University
Immunotherapy Targeted Against Cytomegalovirus in Patients With Newly-Diagnosed WHO Grade IV Unmethylated Glioma	NCT03927222	Glioblastoma	Human CMV pp65-... Temozolomide Tetanus-Diphthe... GM-CSF 111-Indium-labe...	18 Years -	Duke University
The PCSK9i Inhibitor Evolocumab - a Surgical Trial of Pharamcodynamics and Kinetics Evaluation	NCT04937413	Malignant Gliom... Glioblastoma	Evolocumab	18 Years -	Duke University
ETAPA I: Peptide-based Tumor Associated Antigen Vaccine in GBM	NCT05283109	Glioma, Maligna...	Tumor Associate... Hiltonol	18 Years -	Duke University
GRETeL: Tumor Response to Standard Radiotherapy and TMZ Patients With GBM	NCT05695976	Glioblastoma Glioma, Maligna...		18 Years -	Duke University

Spots Global Cancer Trial Database for khasraw

Every month we try and update this database with for khasraw cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for khasraw

Every month we try and update this database with for khasraw cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for khasraw cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.