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

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ClinicalTrials.gov Identifier: NCT03688178
Recruitment Status : Suspended (Pending new testing requirements from the FDA)
First Posted : September 28, 2018
Last Update Posted : August 26, 2019
Sponsor:
Collaborator:
Celldex Therapeutics
Information provided by (Responsible Party):
Gary Archer Ph.D., Duke University

Tracking Information
First Submitted Date  ICMJE September 26, 2018
First Posted Date  ICMJE September 28, 2018
Last Update Posted Date August 26, 2019
Actual Study Start Date  ICMJE July 22, 2019
Estimated Primary Completion Date March 1, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 27, 2018)
  • Median Overall Survival (OS) of Subjects Receiving Td pre-conditioning [ Time Frame: 5 years ]
    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
  • Safety of administering Varlilumab to GBM patients receiving temozolomide and dendritic cell vaccines ± Td pre-conditioning as measured by the percentage of patients with unacceptable toxicity regardless of attribution [ Time Frame: 5 years ]
    Percentage of patients with unacceptable toxicity (all Groups)
  • Median percent change between baseline, assessed on day 14, and nadir levels of Treg before the time that the second cycle of adjuvant TMZ would be administered. Treg determined by flow cytometry (CD3+ CD4+ CD25+ Foxp3+). [ Time Frame: 50 days ]
    Change between baseline and nadir before the 2nd cycle of TMZ (Combined Groups 1 and 2, Group 3)
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03688178 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 27, 2018)
  • Median Overall Survival (OS) of Subjects Receiving DC vaccines, varlilumab, and Td pre-conditioning [ Time Frame: 5 years ]
    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
  • Median Progression-free Survival (PFS) [ Time Frame: 5 years ]
    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
  • Median Percentage of 111In-labeled DCs Reaching Inguinal Nodes [ Time Frame: 2 days ]
    The percentage of 111In-labeled DCs reaching inguinal nodes calculated from the initial signal at the injections site in the groin at 1 and 2 days after the 4th vaccination base upon SPECT/CT. The median percentage at each time point will be presented
  • Median Chemokine (C-C motif) ligand 3 (CCL3) Levels in Serum at 24, 48, and 72 hours after Pre-conditioning [ Time Frame: 2 days ]
    CCL3 levels in serum 24, 48, and 72 hours after pre-conditioning by multiplex. The median CCL3 level will be presented
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE DC Migration Study to Evaluate TReg Depletion In GBM Patients With and Without Varlilumab
Official Title  ICMJE DC Migration Study to Evaluate TReg Depletion In GBM Patients With and Without Varlilumab
Brief Summary

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 20 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.

DCs in vaccine #4 will be labeled with a radioactive substance called 111Indium before injection to allow the study team to track migration using SPECT scans taken at 24 and 48 hours following DC Vaccine #4.

Detailed Description

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.

The in vivo distribution of DCs will be evaluated in Vaccine #4 using 111Indium (111In)-labeled pp65-LAMP mRNA loaded mature DCs. 111In-labeled DCs have been used extensively for evaluation of adoptively transferred tumor infiltrating lymphocytes, natural killer cells, granulocytes, dendritic cells, and whole blood leukocytes, for in vivo localization studies in humans. Subjects will undergo SPECT/CT imaging immediately after Vaccine #4 and then at 1 and 2 days after injection.

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.

To examine the impact of Varlilumab on T cell responses to naïve antigen, pp65-loaded DC Vaccine #1 will also include separate DCs loaded with the full mRNA of HIV Gag protein; responses to HIV-Gag are uncommon and can serve as a naïve antigen in our HIV negative patient population. It has been shown that removal of regulatory T cells (TRegs) can enhance polyfunctional T-cell responses to HIV Gag. We hypothesize that TReg inhibition through Varlilumab may increase polyfunctional immune responses to CMV.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:
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.
Primary Purpose: Treatment
Condition  ICMJE Glioblastoma
Intervention  ICMJE
  • Biological: Human CMV pp65-LAMP mRNA-pulsed autologous DCs
    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 20 DC vaccines.
  • Drug: Temozolomide
    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)
    Other Names:
    • Temodar
    • TMZ
    • Temodal
  • Biological: Varlilumab
    Varlilumab is an agonist anti-CD27 monoclonal antibody
    Other Name: anti-CD27
  • Biological: Td
    A single dose of Td toxoid (1 flocculation unit, Lf, in 0.4 mLs) administered to a single side of the groin given intradermally
    Other Names:
    • Tetanus-diphtheria (Td) toxoid
    • Td pre-conditioning
  • Biological: 111In-labeled DCs
    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
  • Biological: Unpulsed DCs
    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 Name: Unpulsed DCs pre-conditioning
  • Biological: HIV-Gag mRNA-pulsed autologous DCs
    2x10^7 HIV-Gag mRNA-pulsed autologous DCs are given intradermally and bilaterally at the groin site (divided equally to both inguinal regions) only with DC Vaccine #1
Study Arms  ICMJE
  • Experimental: Gr1: DC vaccine (DC 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 20) 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 then receive 111In-labeled DCs as the 4th vaccine to compare the effects of different skin preparations on DC migration followed by SPECT/CT imaging immediately and at 1 and 2 days after injections.
    Interventions:
    • Biological: Human CMV pp65-LAMP mRNA-pulsed autologous DCs
    • Drug: Temozolomide
    • Biological: 111In-labeled DCs
    • Biological: Unpulsed DCs
    • Biological: HIV-Gag mRNA-pulsed autologous DCs
  • Experimental: Gr2: DC Vaccine (Td 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 20) 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 then receive 111In-labeled DCs as the 4th vaccine to compare the effects of different skin preparations on DC migration followed by SPECT/CT imaging immediately and at 1 and 2 days after injection.
    Interventions:
    • Biological: Human CMV pp65-LAMP mRNA-pulsed autologous DCs
    • Drug: Temozolomide
    • Biological: Td
    • Biological: 111In-labeled DCs
    • Biological: HIV-Gag mRNA-pulsed autologous DCs
  • Experimental: Gr3:DC Vaccine+varlilumab(Td 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 20) 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. Patients will then receive 111In-labeled DCs at the 4th vaccine to compare the effects of varlilumab with the different skin preparations on DC migration followed by SPECT/CT imaging immediately and at 1 and 2 days after injection.
    Interventions:
    • Biological: Human CMV pp65-LAMP mRNA-pulsed autologous DCs
    • Drug: Temozolomide
    • Biological: Varlilumab
    • Biological: Td
    • Biological: 111In-labeled DCs
    • Biological: HIV-Gag mRNA-pulsed autologous DCs
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Suspended
Estimated Enrollment  ICMJE
 (submitted: September 27, 2018)
112
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 1, 2025
Estimated Primary Completion Date March 1, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age ≥18 years of age.
  • Glioblastoma with definitive resection prior to enrollment, with residual radiographic contrast enhancing disease on the post-operative CT or MRI of <1 cm in maximal diameter in any axial plane.
  • Enough tumor tissue available for determination of MGMT gene promoter status.
  • CMV Seropositive.
  • KPS of ≥ 80%
  • Hemoglobin ≥ 9.0 g/dl, ANC ≥ 1,500 cells/µl, platelets ≥ 100,000 cells/µl.
  • Serum creatinine ≤ 1.5 mg/dl, serum SGOT and 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 [IUD; only hormonal], sexual abstinence or vasectomized partner) during the trial and 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 a negative serum pregnancy test within 48 hours prior to first study treatment.
  • 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 and for a period of > 6 months following the last administration of trial drugs.

Exclusion Criteria:

  • Pregnant or breast-feeding.
  • Women of childbearing potential and 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-DTPA.
  • 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 HIV and Hepatitis C 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. (Treatment with tamoxifen or aromatase inhibitors or other hormonal therapy that may be indicated in prevention of prior cancer disease recurrence, are not considered current active treatment.)
  • Patients are not permitted to have had any other conventional therapeutic intervention other than steroids prior to enrollment outside of standard of care chemotherapy and 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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03688178
Other Study ID Numbers  ICMJE Pro00082570
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Gary Archer Ph.D., Duke University
Study Sponsor  ICMJE Gary Archer Ph.D.
Collaborators  ICMJE Celldex Therapeutics
Investigators  ICMJE
Principal Investigator: Annick Desjardins, MD, FRCPC Duke University
PRS Account Duke University
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP