Trial Title:
Neoantigen-based Personalized DNA Vaccine With Retifanlimab PD-1 Blockade Therapy in Patients With Newly Diagnosed, Unmethylated Glioblastoma
NCT ID:
NCT05743595
Condition:
Unmethylated Glioblastoma
Conditions: Official terms:
Glioblastoma
Conditions: Keywords:
glioblastoma
neoantigen vaccine
PD-1 blockade
unmethylated MGMT
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
Personalized Neoantigen DNA vaccine
Description:
The sites of immunization may be rotated for each of the immunizations.
Arm group label:
Cohort A: Personalized neoantigen DNA vaccine + retifanlimab
Arm group label:
Cohort B: Personalized neoantigen DNA vaccine + retifanlimab
Intervention type:
Biological
Intervention name:
Retifanlimab
Description:
Retifanlimab will be supplied by Incyte.
Arm group label:
Cohort A: Personalized neoantigen DNA vaccine + retifanlimab
Arm group label:
Cohort B: Personalized neoantigen DNA vaccine + retifanlimab
Other name:
INCMGA00012
Other name:
MGA012
Intervention type:
Device
Intervention name:
TDS-IM v 2.0 electroporation device
Description:
Each DNA vaccination will be 1 mL vaccine administered intramuscularly using an
integrated electroporation administration system
Arm group label:
Cohort A: Personalized neoantigen DNA vaccine + retifanlimab
Arm group label:
Cohort B: Personalized neoantigen DNA vaccine + retifanlimab
Summary:
This is a single institution, open-label, multi-arm, phase I study assessing the safety
and immunogenicity of a personalized neoantigen-based personalized DNA vaccine combined
with PD-1 blockade therapy in subjects with newly diagnosed, MGMT promoter unmethylated
glioblastoma (GBM).
Immune checkpoint blockade, specifically those targeting the PD-1/PD-L1 pathways, has
shown efficacy in multiple solid and hematologic malignancies. Furthermore, as has been
demonstrated in metastatic melanoma, combining PD-1/PD-L1 blockade with other immune
checkpoint inhibitors has shown improved objective response rates, though there is a
significant increase in serious immune-related adverse events. As such, current trials
are exploring different doses, administration schedules, and immune checkpoint agents.
One alternative approach, however, is to introduce a tumor-directed therapy such as a
personalized neoantigen vaccine combined with these immune modulating agents (i.e. immune
checkpoint blocking antibodies) to maximize the tumor-specific response but minimize the
toxicity associated with increasing non-specific systemic immune activation by generating
a potent and focused neoantigen specific immune response.
This study will test the hypothesis that a personalized neoantigen DNA vaccine in
combination with concurrent administration of immune checkpoint blockade therapy will
enhance the magnitude and breadth of neoantigen-specific T cell responses while
maintaining an acceptable safety profile. The overall goal of this study is to identify
the optimal vaccine plus adjuvant platform that can be tested in a subsequent phase II
study to determine the efficacy of a personalized neoantigen vaccine approach in patients
with GBM.
Criteria for eligibility:
Criteria:
Step 1 Inclusion Criteria for Tissue Sequencing:
- Newly diagnosed histologically or molecularly consistent with WHO grade IV high
grade glioma, IDH wildtype.
- Patients who had prior craniotomy with biopsy, subtotal resection, total gross
resection, or re-resection will be permitted.
- Consent to genome sequencing and dbGaP-based data sharing and has provided or will
provide germline (PBMC) and tumor DNA/RNA samples of adequate quality for
sequencing. (Acquisition of specimens for sequencing and the sequencing itself may
be done as part of routine care or another research project.)
- At least 18 years of age.
- Ability to understand and willingness to sign an IRB approved written informed
consent document (or that of legally authorized representative, if applicable).
Step 2 Inclusion Criteria for Treatment Administration:
- Confirmed MGMT promoter unmethylated glioblastoma multiforme. Patients with
secondary glioblastoma, in particular those who are IDH1 or IDH2 mutant, will not be
excluded. High grade gliomas with molecular features of glioblastoma will be
included. MGMT promoter methylation status must be determined by a standard
PCR-based assay.
Note: While tissue sequencing can begin prior to confirmation of MGMT promotor status,
the manufacturing process will not begin until MGMT promotor is confirmed as
unmethylated.
- Personalized neoantigen DNA vaccine manufactured for administration.
- Karnofsky performance status ≥ 60%
- Normal bone marrow and organ function as defined below:
- Absolute neutrophil count ≥ 1,500/mcL
- Platelets ≥ 100,000/mcL
- Total bilirubin ≤ 1.5 x IULN
- AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN
- Creatinine ≤ IULN OR creatinine clearance ≥ 60 mL/min/1.73 m^2 for patients
with creatinine levels above institutional normal
- Systemic corticosteroid therapy is permitted provided dosing is no greater than 2 mg
per day (dexamethasone or equivalent) on the day of vaccine administration.
Participants using topical, ocular, intra-articular, or intranasal/inhaled steroids
may participate. Brief courses of corticosteroids for prophylaxis (eg, contrast dye
allergy) or study treatment-related standard premedication are permitted.
- Bevacizumab will be allowed if given for symptomatic control of vasogenic edema and
to avoid corticosteroid use.
- Women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control, abstinence) prior to study entry and
for the duration of study participation, including at least 5 months (for women of
childbearing potential) and at least 7 months (for men) after last dose of study
drug. Should a woman become pregnant or suspect she is pregnant while participating
in this study, she must inform her treating physician immediately.
- Patients who require additional surgery prior to vaccination (craniotomy with
biopsy, subtotal resection, total gross resection, or laser interstitial thermal
therapy (LITT) laser ablation) will not be considered ineligible.
Step 2 Exclusion Criteria:
- As this study aims to assess the immunogenicity of a personalized neoantigen DNA
vaccine in combination with checkpoint blockade, no prior immunotherapy will be
permitted.
- Inadequate tissue acquisition to allow for neoantigen screening.
- No candidate neoantigen identified during screening.
- A history of other malignancy ≤ 3 years previous with the exception of non-melanoma
skin cancer, any in situ cancer that has been successfully resected and cured,
treated superficial bladder cancer, or any early-stage solid tumor that was
successfully resected without need for adjuvant radiation or chemotherapy.
- Known allergy, or history of serious adverse reaction to, vaccines such as
anaphylaxis, hives, or respiratory difficulty.
- A history of allergic reactions attributed to compounds of similar chemical or
biologic composition to any agents used in the study.
- History of immunodeficiency disorder or autoimmune condition requiring active
immunosuppressive therapy. This includes inflammatory bowel disease, ulcerative
colitis, Crohn's disease, systemic vasculitis, scleroderma, psoriasis, multiple
sclerosis, hemolytic anemia, immune-mediated thrombocytopenia, rheumatoid arthritis,
systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, or other
rheumatologic disease or any other medical condition or use of medication which
might make it difficult for the patient to complete the full course of treatments or
to generate an immune response to vaccines.
- Presence of acute or chronic bleeding or clotting disorder that would contraindicate
IM injections.
- Presence of a cardioverter-defibrillator or pacemaker (to prevent a life-threatening
arrhythmia) that is located ipsilateral to the intended deltoid injection site
(unless deemed acceptable by a Cardiologist).
- Presence of any metal implants or implantable medical device within the
electroporation area.
- Any active uncontrolled neurologic disorder, including seizures and epilepsy.
- Recurrent known vasovagal-related syncopal episodes resulting in loss of
consciousness.
- Individuals in whom skin pinch thickness for all eligible injection sites exceeds 50
mm.
- Individuals in whom the ability to observe possible local reactions at the eligible
injection sites is, in the opinion of the investigator, unacceptably obscured due to
a physical condition or permanent body art.
- History of organ transplant, including allogeneic stem cell transplantation.
- Receiving any other investigational agents within 4 weeks of beginning study
treatment.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection requiring systemic antibiotics or antifungal treatment, symptomatic
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements.
- Evidence of interstitial lung disease, history of interstitial lung disease, or
active, non-infectious pneumonitis.
- Presence of clinically significant increased intracranial pressure (e.g. impending
herniation) or hemorrhage, uncontrolled seizures, or requirement for immediate
palliative treatment.
- Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
pregnancy test within 7 days of first dose of vaccine.
- Has received a live vaccine within 28 days of the planned start of study drug.
Participants may receive the COVID-19 vaccine as long as it is not a live vaccine.
COVID-19 vaccination will be captured in the eCRF as a concomitant medication.
Administration of study treatment may be delayed to ensure vaccination is completed.
- Active HBV or HCV infection that requires treatment. Hepatitis B virus DNA and HCV
RNA must be undetectable upon testing. Participants who have cleared a prior HBV
infection (defined as HBsAg negative, hepatitis B surface antibody positive,
hepatitis B core antibody positive) are eligible for the study.
- Note: For participants with cleared prior HBV infection, HBV prophylaxis should
be considered per the investigator's discretion. Monitor for HBV reactivation
every 3 cycles by performing HBV viral load and HBsAg serology test. Additional
viral serologic testing may be performed at the investigator's discretion.
- Note: Participants with no prior history of HBV infection who have been
vaccinated against HBV and who have a positive test result for antibody to
hepatitis B surface antigen as the only evidence of prior exposure may
participate in the study.
- Note: Hepatitis C antibody-positive participants who received and completed
treatment for hepatitis C that was intended to eradicate the virus may
participate if HCV RNA levels are undetectable.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Washington University School of Medicine
Address:
City:
Saint Louis
Zip:
63110
Country:
United States
Status:
Recruiting
Contact:
Last name:
Tanner M Johanns, M.D., Ph.D.
Phone:
314-273-2723
Email:
tannerjohanns@wustl.edu
Investigator:
Last name:
Tanner M Johanns, M.D., Ph.D.
Email:
Principal Investigator
Investigator:
Last name:
Milan G Chheda, M.D.
Email:
Sub-Investigator
Investigator:
Last name:
Albert Kim, M.D., Ph.D.
Email:
Sub-Investigator
Investigator:
Last name:
Joshua Dowling, M.D.
Email:
Sub-Investigator
Investigator:
Last name:
Eric Leuthardt, M.D.
Email:
Sub-Investigator
Investigator:
Last name:
Gregory J Zipfel, M.D.
Email:
Sub-Investigator
Investigator:
Last name:
Joshua Osbun, M.D.
Email:
Sub-Investigator
Investigator:
Last name:
Christopher Abraham, M.D.
Email:
Sub-Investigator
Investigator:
Last name:
Jiayi Huang, M.D.
Email:
Sub-Investigator
Investigator:
Last name:
Feng Gao, Ph.D.
Email:
Sub-Investigator
Investigator:
Last name:
William E Gillanders, M.D.
Email:
Sub-Investigator
Start date:
October 27, 2023
Completion date:
October 31, 2027
Lead sponsor:
Agency:
Washington University School of Medicine
Agency class:
Other
Collaborator:
Agency:
Incyte Corporation
Agency class:
Industry
Collaborator:
Agency:
PapiVax Biotech, Inc.
Agency class:
Other
Collaborator:
Agency:
The Foundation for Barnes-Jewish Hospital
Agency class:
Other
Source:
Washington University School of Medicine
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05743595
http://www.siteman.wustl.edu
