Neoplasms

All Conditions

Rare Diseases

Glioblastoma

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Vaccines

Temozolomide

Immunoglobulins

Antineoplastic Agents, Alkylating

Alkylating Agents

Patients will receive TMZ at a target dose of 150-200 mg/m\^2/d for 5 days every 4 (+2) weeks for up to 12 cycles. DC vaccines will be administered in equal amounts to both inguinal regions. DC vaccines #1-3 occur every 2 weeks and all subsequent vaccines (up to 10) occur monthly. Group 1 patients will receive autologous unpulsed DC vaccines administered to a single side of the groin and saline administered to the contralateral side the day prior to the 4th DC vaccine as pre-conditioning.

Patients will receive TMZ at a target dose of 150-200 mg/m\^2/d for 5 days every 4 (+2) weeks for up to 12 cycles. DC vaccines will be administered in equal amounts to both inguinal regions. DC vaccines #1-3 occur every 2 weeks and all subsequent vaccines (up to 10) occur monthly. Group 2 patients will receive a single dose of Td toxoid administered to a single side of the groin and saline administered to the contralateral side the day prior to the 4th DC vaccine, which is always given bilaterally at the groin site.

Patients will receive TMZ at a target dose of 150-200 mg/m\^2/d for 5 days every 4 (+2) weeks for up to 12 cycles. DC vaccines will be administered in equal amounts to both inguinal regions. DC vaccines #1-3 occur every 2 weeks and all subsequent vaccines (up to 10) occur monthly. Group 3 patients will receive the first 3 DC vaccines every 2 weeks, same as Groups 1 and 2, but they will also receive varlilumab intraveneously (IV) 7 days before vaccine #1 and again at the same visit as vaccine #1, as well as 7 days before every DC vaccine except vaccine #2. Prior to the 4th vaccine, patients will receive a single dose of Td toxoid administered to a single side of the groin and saline administered to the contralateral side.

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

Temozolomide is a standard chemotherapy given to all enrolled patients at a targeted dose of 150-200mg/m2/d for 5 days every 4 (+ 2) weeks for up to 12 cycles (patients with unmethylated MGMT gene promoter will receive only cycle 1)

Varlilumab is an agonist anti-CD27 monoclonal antibody

Varlilumab

A single dose of Td toxoid (1 flocculation unit, Lf, in 0.4 mLs) administered to a single side of the groin given intradermally

Patients in Group I will receive 1 x 10\^6 autologous unpulsed DCs in saline administered to a single side of the groin intradermally 1 day before the fourth vaccine.

Unpulsed DCs

Annick Desjardins, MD, FRCPC

Patients with newly diagnosed glioblastoma will be consented following tumor resection then undergo leukapheresis for harvest of peripheral blood leukocytes for generation of dendritic cells. Subjects will then receive standard of care (planned 6 weeks) radiation therapy (RT) and concurrent temozolomide (TMZ) at a standard targeted dose of 75 mg/m2/day.

The study cycle of TMZ comprises a targeted dose of 150-200mg/m2/day for 5 days every 4 (+2) weeks for up to 12 cycles (patients with unmethylated MGMT gene promoter will receive only cycle 1). All patients will receive up to a total of 10 DC vaccines called pp65 CMV dendritic cells (DC). Dendritic Cell (DC) vaccines #1-3 will be given every two weeks, thus delaying the initiation of TMZ cycle 2 for patients receiving TMZ. All remaining TMZ/vaccine cycles will be 4 (+2) weeks in length.

After the first 3 DC vaccines given during Cycle 1 of TMZ, the remaining DC vaccine injections are given on Day 21 (+/- 2 days) of each TMZ cycle. Subjects with unmethylated MGMT will only receive one cycle of adjuvant TMZ; however, their vaccine schedule will follow the same 4 (+ 2) week TMZ cycle schedule.

Following RT, patients will be randomized into 1 of 3 groups. Groups 1 and 2 will be blinded. The groups differ in the type of pre-conditioning received prior to DC vaccine #4; additionally, Group 3 will be receiving infusions of varlilumab 7 days prior to and with vaccine #1 and 7 days prior to vaccine #3+. The pre-conditioning for each group is as follows: Group 1: Unpulsed DC pre-conditioning prior to DC vaccine #4; Group 2: Tetanus-diphtheria (Td) pre-conditioning prior to DC vaccine #4; Group 3: Td pre-conditioning prior to DC vaccine #4 and varlilumab infusion at 7 days prior to each DC vaccine (except DC vaccine #2) with Td pre-conditioning prior to vaccine #4.

Human cytomegalovirus (CMV) is a common endemic β-Herpesvirus, and over half of adults have been infected with CMV. CMV does not usually cause significant clinical disease but can cause health problems for people with weakened immune systems. Expression of proteins unique to human CMV has been reported within a large proportion of malignant gliomas (MGs), including detection of the human CMV immunodominant protein pp65-LAMP (pp65-lysosomal-associated membrane protein). Human CMV antigens were not detected in surrounding normal brain samples. The presence of highly-immunogenic human CMV antigens within MGs affords a unique opportunity to target these tumors immunologically.

Dendritic cells (DCs) are antigen-presenting cells in the immune system. DCs are activated then migrate to the lymph nodes to interact with T cells and B cells, which initiates the adaptive immune response. This study generates autologous DCs from peripheral blood leukocytes obtained from the subject during leukapheresis. RNA transfection is the method used in this study for loading antigens onto DCs. DCs are pulsed with human CMV pp65-LAMP mRNA.

Tetanus-diphtheria (Td) toxoid is used for active immunization in children and adults against infection with the bacteria Clostridium tetani and Corynebacterium diphtheria. It is thought that Td toxoid induces an inflammatory milieu within the intradermal vaccine site, thereby promoting the migration of injected tumor-specific DCs. Additionally, in the context of vaccinating the host with tumor-derived peptides, conditioning the vaccine site with Td toxoid has demonstrated enhanced immunogenicity with these peptides. Previous trials have suggested that giving the Td prior to immunotherapy may help improve the effectiveness of the DC vaccine by activating the immune response. This study will further examine whether Td helps activate the immune response by comparing subjects who receive Td pre-conditioning to subjects who receive autologous unpulsed DCs as pre-conditioning.

Varlilumab is a fully human monoclonal antibody (mAb) that targets CD27, a critical molecule in the activation pathway of lymphocytes. Varlilumab is an agonist anti-CD27 mAb that has been shown to activate human T cells in the context of T cell receptor stimulation. In pre-clinical models, varlilumab has been shown to mediate anti-tumor effects and may be particularly effective in combination with other immunotherapies. Anti-CD27 mAb has emerged as a novel costimulatory immune modulator that depletes TRegs without impairing activated effector T cells to improve antitumor immunity. We hypothesize that TReg inhibition through Varlilumab may increase polyfunctional immune responses to CMV.

Assignment to Groups 1 and 2 is blinded, and neither the study team nor the subject knows which pre-conditioning regimen is given. Assignment to Group 3 is not blinded, and the subject and study team know that Td preconditioning and Varlilumab is given.

DC Migration Study to Evaluate TReg Depletion In GBM Patients With and Without Varlilumab

OS is defined as the time in months between randomization and death, or last follow-up if alive (Groups 1 and 2). Kaplan-Meier methods will be used to estimate median OS

Percentage of patients with unacceptable toxicity (all Groups)

Change between baseline and nadir before the 2nd cycle of TMZ (Combined Groups 1 and 2, Group 3)

OS is defined as the time in months between randomization and death, or last follow-up if alive (Group 3). Kaplan-Meier methods will be used to estimate median OS

PFS is defined as the time between randomization and initial failure (disease progression or death) (all Groups). If the patient remains alive without disease progression, PFS will be censored at the time of last follow-up. Kaplan-Meier methods will be used to estimate median PFS

CCL3 levels in serum 24, 48, and 72 hours after pre-conditioning by multiplex. The median CCL3 level will be presented

Celldex Therapeutics

Annick Desjardins, MD

Assistant Professor of Neurosurgery

Infections

Nervous System Diseases

Nutritional and Metabolic Diseases

Symptoms and General Pathology

Tetanus

Tetany

Basiliximab

Immunologic Factors

Immunosuppressive Agents

0.4 mLs of 1 x 10\^6 autologous unpulsed DCs in saline will be administered to a single side of the groin, and 0.4 mLs of saline administered to the contralateral side 1 day prior to the 4th human CMV pp65-LAMP mRNA-pulsed autologous DCs vaccine. pp65 DC Vaccine #4 is 111In-labeled DCs for migration studies.

Tetanus diptheria toxoid (Td) (1 flocculation unit) will be administered to a single side of the groin, and 0.4 mLs of saline administered to the contralateral side 1 day prior to the 4th human CMV pp65-LAMP mRNA-pulsed autologous DCs vaccine. pp65 DC Vaccine #4 is 111In-labeled DCs for migration studies.

Basiliximab infusions prior to human CMV pp65-LAMP mRNA-pulsed autologous DCs vaccines #1 and #2 with Td pre-conditioning (1 flocculation unit) will be administered to a single side of the groin, and 0.4 mLs of saline administered to the contralateral side 1 day prior to the 4th human CMV pp65-LAMP mRNA-pulsed autologous DCs vaccine.

Patients in Groups II and III will receive a single dose of Td toxoid (1 flocculation unit, Lf, in 0.4 mLs) administered to a single side of the groin given intradermally 1 day before the fourth vaccine.

111In-labeled DCs are 2 x 10\^7 pp65-LAMP mRNA loaded mature DCs will be labeled with 111In (50 μCi / 5 x 10\^7 DCs) and given i.d. as fourth vaccine for Groups I and II only.

111In-labeled DCs

Temozolomide is a standard chemotherapy given to all enrolled patients at a targeted dose of 150-200mg/m2/d for 5 days every 5 (± 1) weeks for a total of 6 to 12 cycles at the discretion of the treating oncologist.

0.4mL of saline given in the opposite groin 1 day before the fourth vaccine in all groups

Saline

Group III will receive basiliximab infusions (20 mg I.V) 1 week before the first vaccine and 1 week before the second vaccine.

Dina Randazzo, DO

This randomized phase II study will assess the impact of pre-conditioning on migration and survival among newly diagnosed glioblastoma (GBM) patients who have undergone definitive resection and completed standard temozolomide (TMZ) and radiation treatment, as well as the impact of tetanus pre-conditioning and basiliximab together on survival. After completing standard of care radiotherapy with concurrent TMZ, patients will be randomized to 1 of 3 treatment arms: 1). receive cytomegalovirus (CMV)-specific dendritic cell (DC) vaccines with unpulsed (not loaded) DC pre-conditioning prior to the 4th vaccine; 2). receive CMV-specific DC vaccines with Tetanus-Diphtheria Toxoid (Td) pre-conditioning prior to the 4th vaccine; 3). receive basiliximab infusions prior to the 1st and 2nd DC vaccines along with Td pre-conditioning prior to the 4th vaccine. A permuted block randomization algorithm using a 1:1:1 allocation ratio will be used to assign patients to a treatment arm. Randomization will be stratified by CMV status (positive, negative), with the assignment to arms I and II being double-blinded. Effective March 2017, randomization to Group III has been terminated.

A maximum of 100 patients with resected, newly-diagnosed World Health Organization (WHO) Grade IV GBM will be enrolled in this study with the expectation that approximately 79 patients will be randomized to subsequent treatment after completion of radiation treatment with concurrent temozolomide. Effective March 2017, randomization to Group III has been terminated. All consented patients will undergo a leukapheresis after resection for harvest of Peripheral Blood Lymphocytes (PBLs) for generation of DCs. Patients will then receive Radiation Therapy (RT) and concurrent TMZ at a standard targeted dose of 75 mg/m\^2/d. Patients should start RT within approximately 6 weeks of surgery. Patients who experience progressive disease during radiation, are dependent on steroid supplements above physiologic levels at time of first vaccination, are unable to tolerate TMZ, or whose DCs or PBLs fail to meet release criteria will be withdrawn from the study and replaced and will not undergo repeat leukapheresis. For patients whose initial leukapheresis yields less than 3 vaccines, repeat leukapheresis may be obtained a minimum of 2 weeks from the previous leukapheresis (and may be repeated as needed) if pre-pheresis blood work is within the Apheresis Center's parameters and as long as this does not cause a significant delay in treatment for the patient.

After RT and concurrent TMZ, patients will then be randomized and begin the initial cycle of TMZ at a standard targeted dose of 150-200mg/m\^2/d for 5 days at the discretion of the treating oncologist 4 (± 2) weeks after completing RT. The study cycle of TMZ comprises a targeted dose of 150-200mg/m\^2/d for 5 days every 5 (± 1) weeks. All patients will receive up to a total of 10 DC vaccines given bilaterally at the groin site unless progression occurs. DC vaccines will be given intradermally (i.d.) and divided equally to both inguinal regions. DC vaccines #1-3 will be given every two weeks, thus delaying the initiation of TMZ cycle 2. Patients will then be vaccinated in conjunction with subsequent TMZ cycles every 5 (± 1) weeks for a total of 6 to 12 cycles after RT at the discretion of the treating oncologist. DCs will be given on day 21 ± 2 days of each TMZ cycle. DC vaccinations will continue during TMZ cycles up to a total of 10 unless progression occurs.

Before the first DC vaccination, all patients will receive immunization with 0.5 mL of Td intramuscularly into the deltoid muscle to ensure adequate immunity to the tetanus antigen. Those assigned to Group III will receive basiliximab 20 mg infusions 1 week before the 1st and 1 week before the 2nd vaccine. At the time of the fourth DC vaccine, patients will receive pre-conditioning per the assigned group (Group I-unpulsed DCs i.d.; Group II- Td i.d.; Group III-Td i.d.). A single dose of Td toxoid (1 flocculation unit, in 0.3 milliliters (mLs) of saline for a total volume of 0.4 mLs) or 0.4 mLs of 1 x 10\^6 autologous unpulsed DCs in saline will be administered to a single side of the groin, and 0.4 mLs of saline administered to the contralateral side 12-24 hours prior to the fourth DC vaccine, which is always given bilaterally at the groin site. Patients in Groups I and II will then receive 111In-labeled DCs to compare the effects of different skin preparations on DC migration followed by Single-Photon Emission Computed Tomography and Computed Tomography (SPECT/CT) imaging immediately and at 1 and 2 days after injection. Group III will not undergo migration studies. Groups I and II will be double blinded. Group III will not be blinded.

All patients will undergo leukapheresis again for immunologic monitoring with specific assessment of baseline antigen-specific cellular and humoral immune responses and further DC generations 4 (± 2) weeks after vaccine #3. Patients will be imaged bimonthly without receiving any other prescribed anti-tumor therapy. Patients will undergo an additional leukapheresis for generation of DCs if needed to continue vaccinations.

As part of standard care for these patients, upon tumor progression, participants may undergo stereotactic biopsy or resection. As this is not a research procedure consent will be obtained separately. However, if tissue is obtained, it will be used to confirm tumor progression histologically and to assess immunologic cell infiltration and pp65 antigen escape at the tumor site.

DC Migration Study for Newly-Diagnosed GBM

Evaluation of Overcoming Limited Migration and Enhancing Cytomegalovirus-specific Dendritic Cell Vaccines With Adjuvant TEtanus Pre-conditioning in Patients With Newly-diagnosed Glioblastoma

Overall survival will be defined as the time in months between randomization and death, or last follow-up if alive. Kaplan-Meier methods will be used to estimate overall survival.

Within Groups I and II only, the percentage of 111In-labeled DCs migrating to the inguinal lymph nodes from the initial injection sites in the left and right groin at 48 hours post-vaccination #4 will be calculated.

Median overall survival will be estimated in the subset of participants that are CMV positive. Overall survival will be defined as the time in months between randomization and death, or last follow-up if alive. Kaplan-Meier methods will be used to estimate overall survival.

Median overall survival will be estimated in the subset of participants that are CMV negative. Overall survival will be defined as the time in months between randomization and death, or last follow-up if alive. Kaplan-Meier methods will be used to estimate overall survival.

Progression-free survival will be defined as the time in months between randomization and disease progression or death. Participants alive without disease progression will be censored at the time of their last follow-up. Kaplan-Meier methods will be used to estimate progression-free survival.

Median progression-free survival will be estimated in the subset of participants that are CMV positive. Progression-free survival will be defined as the time in months between randomization and disease progression or death. Participants alive without disease progression will be censored at the time of their last follow-up. Kaplan-Meier methods will be used to estimate progression-free survival.

Median progression-free survival will be estimated in the subset of participants that are CMV negative. Progression-free survival will be defined as the time in months between randomization and disease progression or death. Participants alive without disease progression will be censored at the time of their last follow-up. Kaplan-Meier methods will be used to estimate progression-free survival.

Mustafa Khasraw, MBChB, MD, FRCP, FRACP

Professor

Group I: Unpulsed DC Pre-conditioning

Group II: Tetanus Pre-conditioning

Group III: Basiliximab and Tetanus Pre-conditioning

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Participants who received at least one ppp65 vaccine.

Mustafa Khasraw, M.D.

Median Overall Survival

Data not collected on the Basiliximab and Tetanus pre-conditioning group.

Percentage of 111In-labeled Dendritic Cells Migrating to the Inguinal Lymph Nodes

Participants who are CMV positive. Data not collected on the Basiliximab and Tetanus pre-conditioning group.

Median Overall Survival in CMV Positive Participants

Participants who are CMV negative. Data not collected on the Basiliximab and Tetanus pre-conditioning group.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
DC Migration Study to Evaluate TReg Depletion In GBM Patients With and Without Varlilumab	NCT03688178	Glioblastoma	Human CMV pp65-... Temozolomide Varlilumab Td Unpulsed DCs	18 Years -	Duke University
DC Migration Study for Newly-Diagnosed GBM	NCT02366728	Glioblastoma Astrocytoma, Gr... Giant Cell Glio... Glioblastoma Mu...	Unpulsed DCs Td Human CMV pp65-... 111In-labeled D... Temozolomide Saline Basiliximab	18 Years - 80 Years	Duke University

Spots Global Cancer Trial Database for unpulsed dcs

Every month we try and update this database with for unpulsed dcs 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.