DC Migration Study for Newly-Diagnosed GBM

Study Overview
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Brief Summary
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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.

Detailed Description
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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at time of first vaccination, are unable to tolerate TMZ, or whose DCs or PBLs fail to meet release criteria will be withdrawn from the study and replaced and will not undergo repeat leukapheresis.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.

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

Conditions
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Glioblastoma, Astrocytoma, Grade IV, Giant Cell Glioblastoma, Glioblastoma Multiforme

Intervention / Treatment
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* Biological: Unpulsed DCs
* Biological: Td
* Biological: Human CMV pp65-LAMP mRNA-pulsed autologous DCs
* Biological: 111In-labeled DCs
* Drug: Temozolomide
* Drug: Saline
* Drug: Basiliximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years of age WHO Grade IV Glioma with definitive resection prior to enrollment, with residual radiographic contrast enhancing disease on the post-operative CT or Magnetic Resonance Imaging (MRI) of <1 cm in maximal diameter in any axial plane MRI post radiation therapy (RT) does not show progressive disease at time of randomization Karnofsky Performance Status of > 80%. Hemoglobin ≥ 9.0 g/dl, Absolute Neutrophil Count ≥ 1,500 cells/µl, platelets ≥ 125,000 cells/µl Serum creatinine ≤ 1.5 mg/dl, Serum Glutamic Oxaloacetic Transaminase & bilirubin ≤ 1.5 times upper limit of normal Signed informed consent approved by the Institutional Review Board Female patients must not be pregnant or breast-feeding. Female patients of childbearing potential (defined as < 2 years after last menstruation or not surgically sterile) must use a highly effective contraceptive method (allowed methods of birth control, [i.e. with a failure rate of < 1% per year] are implants, injectables, combined oral contraceptives, intra-uterine device [IUDs; only hormonal], sexual abstinence or vasectomized partner) during the trial & for a period of > 6 months following the last administration of trial drug(s). Female patients with an intact uterus (unless amenorrhea for the last 24 months) must have negative serum pregnancy test within 48 hours prior to first study procedure (leukapheresis). Fertile male patients must agree to use a highly effective contraceptive method (allowed methods of birth control [i.e. with a failure rate of < 1% per year] include a female partner using implants, injectables, combined oral contraceptives, IUDs [only hormonal], sexual abstinence or prior vasectomy) during the trial & for a period of > 6 months following the last administration of trial drugs Exclusion Criteria: Pregnant or breast-feeding Women of childbearing potential & men who are sexually active and not willing/able to use medically acceptable forms of contraception Patients with known potentially anaphylactic allergic reactions to gadolinium-Diethylenetriaminepentaacetic Acid Patients who cannot undergo MRI or SPECT due to obesity or to having certain metal in their bodies (specifically pacemakers, infusion pumps, metal aneurysm clips, metal prostheses, joints, rods, or plates) Patients with evidence of tumor in the brainstem, cerebellum, or spinal cord, radiological evidence of multifocal disease, or leptomeningeal disease Severe, active comorbidity, including any of the following Unstable angina and/or congestive heart failure requiring hospitalization Transmural myocardial infarction within the last 6 months Acute bacterial or fungal infection requiring intravenous antibiotics at the time of study initiation Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy Known hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; Known Human Immunodeficiency Virus positive status Major medical illnesses or psychiatric impairments that, in the investigator's opinion, will prevent administration or completion of protocol therapy Active connective tissue disorders, such as lupus or scleroderma that, in the opinion of the treating physician, may put the patient at high risk for radiation toxicity Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids; Prior, unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin; Patients are not permitted to have had any other conventional therapeutic intervention other than steroids prior to enrollment outside of standard of care chemotherapy & radiation therapy. Patients who receive previous inguinal lymph node dissection, radiosurgery, brachytherapy, or radiolabeled monoclonal antibodies will be excluded Current, recent (within 4 weeks of the administration of this study agent), or planned participation in an experimental drug study Known history of autoimmune disease (with the exceptions of medically-controlled hypothyroidism and Type I Diabetes Mellitus)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I: Unpulsed DC pre-conditioning<br>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. | Biological: Unpulsed DCs<br>* 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.<br>* Other names: Unpulsed DCs pre-conditioning;Biological: Human CMV pp65-LAMP mRNA-pulsed autologous DCs<br>* 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.<br>* Other names: DCs;Biological: 111In-labeled DCs<br>* 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.<br>Drug: Temozolomide<br>* 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.<br>* Other names: TMZ;Drug: Saline<br>* 0.4mL of saline given in the opposite groin 1 day before the fourth vaccine in all groups<br>|
| Experimental: Group II: Tetanus pre-conditioning<br>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. | Biological: Td<br>* 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.<br>* Other names: Td pre-conditioning;Biological: Human CMV pp65-LAMP mRNA-pulsed autologous DCs<br>* 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.<br>* Other names: DCs;Biological: 111In-labeled DCs<br>* 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.<br>Drug: Temozolomide<br>* 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.<br>* Other names: TMZ;Drug: Saline<br>* 0.4mL of saline given in the opposite groin 1 day before the fourth vaccine in all groups<br>|
| Experimental: Group III: Basiliximab and Tetanus pre-conditioning<br>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. | Biological: Human CMV pp65-LAMP mRNA-pulsed autologous DCs<br>* 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.<br>* Other names: DCs;Drug: Temozolomide<br>* 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.<br>* Other names: TMZ;Drug: Saline<br>* 0.4mL of saline given in the opposite groin 1 day before the fourth vaccine in all groups<br>Drug: Basiliximab<br>* Group III will receive basiliximab infusions (20 mg I.V) 1 week before the first vaccine and 1 week before the second vaccine.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Overall Survival | 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. | Up to 72 months (from the time of randomization of the first patient until approximately 31 months after randomization of the last patient) | 
| Percentage of 111In-labeled Dendritic Cells Migrating to the Inguinal Lymph Nodes | 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. | For each patient, migration studies will occur after vaccination #4 which occurs approximately 7 months after study consent. | 
| Median Overall Survival in CMV Positive Participants | 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. | Up to 72 months (from the time of randomization of the first patient until approximately 31 months after randomization of the last patient) | 
| Median Overall Survival in CMV Negative Participants | 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. | Up to 72 months (from the time of randomization of the first patient until approximately 31 months after randomization of the last patient) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-free 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. | Up to 72 months (from the time of randomization of the first patient until approximately 31 months after randomization of the last patient) | 
| Median Progression-free Survival in CMV Positive Participants | 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. | Up to 72 months (from the time of randomization of the first patient until approximately 31 months after randomization of the last patient) | 
| Median Progression-free Survival in CMV Negative Participants | 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. | Up to 72 months (from the time of randomization of the first patient until approximately 31 months after randomization of the last patient) |