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

NCT03688178 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: Pro00082570
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

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 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.

Conditions

Glioblastoma

Keywords

Glioblastoma; Dendritic cells; Temozolomide; Duke University; Varlilumab; Desjardins

Outcome Measures

Primary Outcomes (3)

• Median Overall Survival (OS) of Subjects Receiving Td pre-conditioning

  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

  5 years

• 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

  Percentage of patients with unacceptable toxicity (all Groups)

  5 years

• 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+).

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

  50 days

Secondary Outcomes (3)

• Median Overall Survival (OS) of Subjects Receiving DC vaccines, varlilumab, and Td pre-conditioning

  5 years

• Median Progression-free Survival (PFS)

  5 years

• Median Chemokine (C-C motif) ligand 3 (CCL3) Levels in Serum at 24, 48, and 72 hours after Pre-conditioning

  2 days

Study Arms (3)

Gr1: DC vaccine (DC pre-conditioning)

EXPERIMENTAL

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.

Biological: Human CMV pp65-LAMP mRNA-pulsed autologous DCs; Drug: Temozolomide; Biological: Unpulsed DCs

Gr2: DC Vaccine (Td pre-conditioning)

EXPERIMENTAL

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.

Biological: Human CMV pp65-LAMP mRNA-pulsed autologous DCs; Drug: Temozolomide; Biological: Td

Gr3:DC Vaccine+varlilumab(Td pre-conditioning)

EXPERIMENTAL

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.

Biological: Human CMV pp65-LAMP mRNA-pulsed autologous DCs; Drug: Temozolomide; Biological: Varlilumab; Biological: Td

Interventions

Human CMV pp65-LAMP mRNA-pulsed autologous DCs BIOLOGICAL

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.

Gr1: DC vaccine (DC pre-conditioning); Gr2: DC Vaccine (Td pre-conditioning); Gr3:DC Vaccine+varlilumab(Td pre-conditioning)

Temozolomide DRUG

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)

Also known as: Temodar, TMZ, Temodal

Gr1: DC vaccine (DC pre-conditioning); Gr2: DC Vaccine (Td pre-conditioning); Gr3:DC Vaccine+varlilumab(Td pre-conditioning)

Varlilumab BIOLOGICAL

Varlilumab is an agonist anti-CD27 monoclonal antibody

Also known as: anti-CD27

Gr3:DC Vaccine+varlilumab(Td pre-conditioning)

Td BIOLOGICAL

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

Also known as: Tetanus-diphtheria (Td) toxoid, Td pre-conditioning

Gr2: DC Vaccine (Td pre-conditioning); Gr3:DC Vaccine+varlilumab(Td pre-conditioning)

Unpulsed DCs BIOLOGICAL

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.

Also known as: Unpulsed DCs pre-conditioning

Gr1: DC vaccine (DC pre-conditioning)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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 other than corticosteroids.

Sponsors & Collaborators

• Annick Desjardins, MD: lead
• Celldex Therapeutics: collaborator

Study Sites (1)

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Related Links

• Preston Robert Tisch Brain Tumor Center

MeSH Terms

Conditions

Glioblastoma

Interventions

Temozolomide; varlilumab; Toxoids

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Vaccines; Biological Products; Complex Mixtures

Study Officials

• Annick Desjardins, MD, FRCPC

  Duke University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Neurosurgery

Study Record Dates

• First Submitted: September 26, 2018
• First Posted: September 28, 2018
• Study Start: August 26, 2020
• Primary Completion: March 1, 2026
• Study Completion: March 1, 2026
• Last Updated: April 15, 2025

Record last verified: 2025-04

Locations

US (1)