Glioblastoma
Conditions
Brief summary
This is a single institution, open-label, single arm, study assessing the safety, feasibility, and immunogenicity of a personalized neoantigen-based vaccine in subjects with newly diagnosed, unmethylated glioblastoma.
Interventions
BIOLOGICALPersonalized neoantigen DNA vaccine supplied by Geneos Therapeutics
-The neoantigen DNA vaccines are also known as DNA plasmid vector expressing tumor-specific antigens.
DEVICECELLECTRA®2000 EP Device supplied by Geneos Therapeutics
CELLECTRA® 2000 Device is a system indicated for use to enhance the uptake and expression of plasmid-based biologics in order to enhance vaccine efficacy.
DRUGPlasmid encoded IL-12
The INO-9012 vials will be supplied by Geneos Therapeutics
Sponsors
Washington University School of Medicine
Geneos Therapeutics
The Foundation for Barnes-Jewish Hospital
National Institute of Neurological Disorders and Stroke (NINDS)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Newly diagnosed histologically confirmed MGMT unmethylated glioblastoma multiforme (WHO grade IV). 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 methylation status must be confirmed by standard a PCR-based assay. * 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. * 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) ≤ 3.0 x IULN * Creatinine ≤ IULN OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal * Systemic corticosteroid therapy is permitted provided dosing is no greater than 4 mg per day (dexamethasone or equivalent) on the day of vaccine administration. * Bevacizumab will be allowed if given for symptomatic control of vasogenic edema and to avoid high dose of corticosteroids. * 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. * Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).
Exclusion criteria
* As this study aims to assess the immunogenicity of personalized neoantigen DNA vaccine plus plasmid encoded IL-12 as an adjuvant, 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. * Receiving any other investigational agents within 4 weeks of beginning study treatment. * 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. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * 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 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. * Presence of acute or chronic bleeding or clotting disorder that would contraindicate IM injections * Fewer than 2 acceptable sites available for IM injection and CELLECTRA® 2000 EP considering the deltoid and anterolateral quadriceps muscles: * Tattoos, keloids, or hypertrophic scars located within 2 cm of intended administration site * Implantable-cardioverter-defibrillator (ICD) or pacemaker (to prevent a life-threatening arrhythmia) that is located ipsilateral to the deltoid injection site (unless deemed acceptable by a cardiologist) * Any metal implants or implantable medical device within the intended treatment site (i.e. electroporation area).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility of Generating a Personalized Neoantigen DNA Vaccine for Patients With Newly Diagnosed, Unmethylated GBM as Measured by the Number of Participants Who Had Candidate Tumor-specific Neoantigens Identified | 4 weeks post-completion of radiotherapy (day 1 of cycle 1) | The number of enrolled participants where at least one candidate tumor-specific neoantigen was identified for vaccine inclusion. Candidate neoantigen identification was done through tumor sequencing and in silico prediction algorithms prioritizing expressed (inferred by RNAseq) and presented (patient specific HLA class 1 molecule-restricted) peptides. |
| Feasibility of Generating a Personalized Neoantigen DNA Vaccine for Patients With Newly Diagnosed, Unmethylated GBM as Measured by the Number of Participants With a Manufactured Neoantigen-based DNA Vaccine | 4 weeks post-completion of radiotherapy (day 1 of cycle 1) | The number of enrolled participants with identifiable candidate tumor-specific neoantigen(s) who had a personalized DNA vaccine successfully manufactured. |
| Feasibility of Generating a Personalized Neoantigen DNA Vaccine for Patients With Newly Diagnosed, Unmethylated GBM as Measured by the Number of Participants Who Had the First Vaccine Administered at 4 Weeks Post-completion of Radiotherapy | 4 weeks post-completion of radiotherapy (estimated to be day 1 of cycle 1) | The number of enrolled participants with identifiable candidate tumor-specific neoantigen(s) who had a personalized DNA vaccine successfully manufactured and administered by 4 weeks post-completion of radiation therapy. |
| Safety and Tolerability of a Personalized Neoantigen DNA Vaccine as Measured by Number of Participants With Dose-limiting Toxicities (DLTs) | Up to 30 days | A DLT will be defined as any grade 3 toxicity or greater according to CTCAE v5 considered at least possibly related to study treatment. The DLT observation period begins with Cycle 1 Day 1 (date of first vaccine administration) and continues for 30 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immunogenicity of a Personalized Neoantigen DNA Vaccine as Measured by the Number of Individual Neoantigens Per Number of Neoantigens Vaccinated Against, With Which a Measurable CD8 T Cell-specific Response is Identified | Week 10 following vaccination on day 1 of cycle 1 | CD8 T cells will be isolated from peripheral blood samples and will be stimulated with individual peptides corresponding to the patient-specific neoantigen candidates included in the respective DNA vaccine. Response will be measured by IFN gamma production via ELISPOT assay. |
| Number of High Quality Candidates Neoantigens Present in Participants With Newly Diagnosed GBM | 4 weeks post-completion of radiotherapy (day 1 of cycle 1) | -High quality neoantigens will be defined as those that meet criteria for inclusion in a vaccine |
| The Percentage of Participants Who Did Not Progress or Expire by 6 Months From Time of Diagnosis | 6 months | -Progression is defined as any of the following * ≥ 25% increase in sum products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement obtained either at baseline or best response, on stable or increasing doses of corticosteroids\*. The absolute increase in any dimension must be at least 5mm when calculating the products. * Significant increase in T2/FLAIR nonenhancing lesion on stable/increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy\* not caused by comorbid events * New measurable lesion. * Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. seizures, medication adverse effects, complications of therapy, cerebrovascular events, infection, and so on) or changes in corticosteroid dose. |
| The Percentage of Participants Who Did Not Expire by 12 Months From Time of Diagnosis | 12 months | — |
| Immunogenicity of a Personalized Neoantigen DNA Vaccine as Measured by the Number of Participants That Had the T-cell Phenotype, Myeloid Derived Suppressor Cell Frequency by Flow Cytometry Analysis Performed | Up to week 24 post-vaccination (day 1 of cycle 1) | — |
| Immunogenicity of a Personalized Neoantigen DNA Vaccine as Measured by the Number of Participants That Had the Diversity of Clonality From T Cell Receptor Sequencing Analysis Performed | Up to week 24 post-vaccination (day 1 of cycle 1) | Measured by the number of patients that the analysis was able to be performed. |
| Immunogenicity of a Personalized Neoantigen DNA Vaccine as Measured by Putative Antigen Specificity From T Cell Receptor Sequencing | Up to week 24 post-vaccination (day 1 of cycle 1) | — |
| Immunogenicity of a Personalized Neoantigen DNA Vaccine as Measured by the Number of Participants With a Measurable Neoantigen-specific CD8 T Cell Response | Week 10 following vaccination on day 1 of cycle 1 | CD8 T cells will be isolated from peripheral blood samples and will be stimulated with pooled peptides corresponding to the patient-specific neoantigen candidates included in the respective DNA vaccine. Response will be measured by IFN gamma production via ELISPOT assay. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORTanner M Johanns, M.D., Ph.D.
Washington University School of Medicine
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 62 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 9 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 8 / 9 |
| other Total, other adverse events | 9 / 9 |
| serious Total, serious adverse events | 6 / 9 |
Outcome results
None listed