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

  • STATUS
    Recruiting
  • End date
    Mar 9, 2025
  • participants needed
    80
  • sponsor
    Gary Archer Ph.D.
Updated on 9 June 2022
MRI
temozolomide
tumour resection
mgmt gene

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 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.

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.

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.

Details
Condition Glioblastoma
Treatment Temozolomide, Unpulsed DCs, Td, Human CMV pp65-LAMP mRNA-pulsed autologous DCs, 111In-labeled DCs, Varlilumab, HIV-Gag mRNA-pulsed autologous DCs
Clinical Study IdentifierNCT03688178
SponsorGary Archer Ph.D.
Last Modified on9 June 2022

Eligibility

Yes No Not Sure

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 plane
Able to receive SOC RT/TMZ for approximately 6 weeks duration and of more than 54GY
MRI post RT does not show progressive disease outside the radiation field
Enough tumor tissue available for determination of MGMT gene promoter status
CMV Seropositive
KPS of ≥ 70%
Hemoglobin ≥ 9.0 g/dl, ANC ≥ 1,000 cells/µl, platelets ≥ 100,000 cells/µl
Serum creatinine ≤3 times institutional upper limit of normal for age, serum SGOT ≤ 3 times institutional upper limit of normal f.or age and bilirubin ≤ 1.5 times upper limit of normal prior to starting TMZ cycle 1 (Exception to bilirubin criteria: Patient has known Gilbert's Syndrome or patient has suspected Gilbert's Syndrome, for which additional lab testing of direct and/or indirect bilirubin supports this diagnosis. In these instances, a total bilirubin of ≤ 3 x ULN is acceptable)
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 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
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.)
other than corticosteroids
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)
Clear my responses

How to participate?

Step 1 Connect with a study center
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer  to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar

Primary Contact

site

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Browse trials for

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note