- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02366728
DC Migration Study for Newly-Diagnosed GBM (ELEVATE)
Evaluation of Overcoming Limited Migration and Enhancing Cytomegalovirus-specific Dendritic Cell Vaccines With Adjuvant TEtanus Pre-conditioning in Patients With Newly-diagnosed Glioblastoma
Study Overview
Status
Detailed Description
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at time of first vaccination, are unable to tolerate TMZ, or whose DCs or PBLs fail to meet release criteria will be withdrawn from the study and replaced and will not undergo repeat leukapheresis.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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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North Carolina
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Durham, North Carolina, United States, 27710
- Duke University Medical Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Group I: Unpulsed DC pre-conditioning
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.
|
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.
Other Names:
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.
Other Names:
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.
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.
Other Names:
0.4mL of saline given in the opposite groin 1 day before the fourth vaccine in all groups
|
Experimental: Group II: Tetanus pre-conditioning
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.
|
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.
Other Names:
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.
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.
Other Names:
0.4mL of saline given in the opposite groin 1 day before the fourth vaccine in all groups
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.
Other Names:
|
Experimental: Group III: Basiliximab and Tetanus pre-conditioning
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.
|
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.
Other Names:
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.
Other Names:
0.4mL of saline given in the opposite groin 1 day before the fourth vaccine in all groups
Group III will receive basiliximab infusions (20 mg I.V) 1 week before the first vaccine and 1 week before the second vaccine.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Median Overall Survival
Time Frame: Up to 72 months (from the time of randomization of the first patient until approximately 31 months after randomization of the last patient)
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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.
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Up to 72 months (from the time of randomization of the first patient until approximately 31 months after randomization of the last patient)
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Percentage of 111In-labeled Dendritic Cells Migrating to the Inguinal Lymph Nodes
Time Frame: For each patient, migration studies will occur after vaccination #4 which occurs approximately 7 months after study consent.
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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.
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For each patient, migration studies will occur after vaccination #4 which occurs approximately 7 months after study consent.
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Median Overall Survival in CMV Positive Participants
Time Frame: Up to 72 months (from the time of randomization of the first patient until approximately 31 months after randomization of the last patient)
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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.
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Up to 72 months (from the time of randomization of the first patient until approximately 31 months after randomization of the last patient)
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Median Overall Survival in CMV Negative Participants
Time Frame: Up to 72 months (from the time of randomization of the first patient until approximately 31 months after randomization of the last patient)
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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.
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Up to 72 months (from the time of randomization of the first patient until approximately 31 months after randomization of the last patient)
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Median Progression-free Survival
Time Frame: Up to 72 months (from the time of randomization of the first patient until approximately 31 months after randomization of the last patient)
|
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)
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Median Progression-free Survival in CMV Positive Participants
Time Frame: 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 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)
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Median Progression-free Survival in CMV Negative Participants
Time Frame: 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 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)
|
Collaborators and Investigators
Investigators
- Principal Investigator: Dina Randazzo, DO, Duke University
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms, Glandular and Epithelial
- Glioma
- Neoplasms, Neuroepithelial
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Glioblastoma
- Astrocytoma
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Temozolomide
- Basiliximab
Other Study ID Numbers
- Pro00054740
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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