A Phase I Study of a Personalized NeoAntigen Cancer Vaccine With Radiotherapy Plus Pembrolizumab/MK-3475 Among Newly Diagnosed Glioblastoma Patients
This research study is studying a new type of vaccine as a possible treatment for patients with glioblastoma. This research study is a Phase I clinical trial, which tests the safety of an investigational intervention and also tries to define the appropriate dose of the intervention to use for further studies. Investigational means that the intervention is being studied and that research doctors are trying to find more about it. It also means that the FDA (U.S. Food and Drug Administration) has not approved the Personalized NeoAntigen Cancer Vaccine for any use in patients, including people with glioblastoma. The purpose of the initial study cohort (Cohort 1) is to determine if it is possible to make and administer safely a vaccine against glioblastoma by using information gained from specific characteristics of the participants tumor. It is known that glioblastomas have mutations (changes in genetic material) that are specific to an individual patient's tumor. These mutations can cause the tumor cells to produce proteins that appear very different from the body's own cells. It is possible that these proteins used in a vaccine may induce strong immune responses, which may help the body fight any tumor cells that could cause the glioblastoma to come back in the future. Three additional cohorts (1a, 1b, \& 1c) were added to the study following completion of accrual to the original study cohort (cohort 1). Each new cohort receives NeoVax and radiation therapy as administered to cohort 1 and will also receive pembrolizumab: cohort 1a patients will start pembrolizumab w/in 2 weeks after start of RT, and continue every 3 weeks for up to 2 years; cohort 1b patients will start pembrolizumab 2-4 weeks after completion of NeoVax priming, and continue every 3 weeks for up to 2 years; cohort 1c patients will receive a single dose of pembrolizumab administered within 2 weeks after start of RT, re-start 2-4 weeks after completion of NeoVax priming, and continue every 3 weeks for up to 2 years. The rationale for adding these new cohorts is: 1) to assess the safety and feasibility of NeoVax when administered with pembrolizumab; and 2) to determine if the timing of anti-PD-1 administration impacts the immunogenicity of NeoVax. An additional sub-study cohort (1d) is being added for patients whose tumor is MGMT-methylated. Cohort 1d will enroll patients with tumors for which the MGMT status is methylated or partially methylated; patients on cohort 1d will receive standard daily temozolomide during radiation and as adjuvant therapy for up to six cycles following completion of radiation therapy. The rationale for adding cohort 1d is to determine the safety and feasibility of NeoVax when administered with pembrolizumab and temozolomide.
∙ Participants must meet the following criteria on screening examination to be eligible to participate in the study (labs/tests/assessments within 14 days prior to initial study registration unless otherwise specified)
• Participant is willing and able to give written informed consent
• Pathologically confirmed WHO grade IV glioblastoma or variants (gliosarcoma, glioblastoma with oligodendroglial features, giant cell glioblastoma) with adequate tumor material for genomic sequencing. Participants will be eligible if the original diagnosis was a lower grade glioma and a subsequent histologic diagnosis of glioblastoma or its variants was made, and patient received no prior therapy other than surgery
‣ Patients with a diagnosis of astrocytoma with molecular features of glioblastoma will be considered eligible for trial.
⁃ In addition, patients with IDH-mutated tumors will also continue to be eligible for trial, despite the release of updated WHO disease classifications in 2021.
• The tumor must be primarily supratentorial in location as determined by diagnostic imaging performed preoperatively
• Radiographic contrast enhancement attributable to residual tumor on post-operative imaging performed within 72 hours of resection must not exceed 1 cm in maximal diameter in biperpendicular plances (greater than 1 cm in one plane but less than 1 cm in other planes will be allowed)
• CT or MRI within 14 days prior to start of study therapy (NOTE: This criterion does not apply to Cohort 1d participants who are registering after having initiated standard of care therapy.)
• Age ≥18 years
• Karnofsky performance status ≥ 70
• Participant is a candidate for, and agrees to receive conventional external beam radiotherapy. (Patients screening for Cohort 1d can be actively receiving - or already completed - their first line conventional external beam radiotherapy.)
• No corticosteroid dosing within 5 days of radiation therapy initiation (Cohorts 1a, 1b, 1c, \& 1d).
• Normal hematologic, renal and hepatic function as defined below:
‣ ANC: greater or equal to 1,000 /mcl
⁃ Platelets: greater than or equal to 100,000 /mcl
⁃ Hemoglobin: greater than or equal to 9 gm/dl or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment)
⁃ International normalized ratio (INR) or prothrombin time: less than or equal to 1.5 times institutional ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
⁃ Activated partial thromboplatin time (aPTT): less than or equal to 1.5 X institutional ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
⁃ Serum creatinine: less than or equal to 1.5 X institutional ULN OR Measured or calculated creatinine clearance ≥60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN
⁃ Total bilirubin: less than or equal to 1.5 X institutional ULN (or less than or equal to 3.0 X institutional ULN for Gilbert's Syndrome) OR Direct bilirubin ≤ institutional ULN for subjects with total bilirubin levels \> 1.5 institutional ULN
⁃ AST (SGOT) and ALT (SGPT): less than or equal to 2.5 X institutional ULN (or less than or equal to 5.0 X institutional ULN for Gilbert's Syndrome)
• MGMT promoter methylation status determined by an institutional CLIA-approved laboratory using a methylation specific PCR assay
• Adequate tumor content as determined by institutional pathologist for nucleic acid extraction and DNA sequence analysis
• Patients unable to undergo magnetic resonance (MR) imaging because of non-compatible devices can be enrolled, provided CT scans are obtained and are of sufficient quality. Patients without non-compatible devices may not have CT scans performed to meet this requirement
• An interval of at least 3 weeks between prior surgical resection to start of study therapy (or one week for stereotactic biopsy to start of study treatment);
• Women of childbearing potential (WOCBP) must have a negative pregnancy test (minimum sensitivity 25 IU/L or equivalent of HCG) before entry onto the trial, because the effects NeoVax on the developing human fetus are unknown
• Participants cannot be breast feeding;
• Female participants enrolled in the study, who are not free from menses for greater than or equal to 2 years, post hysterectomy/oophorectomy, or surgically sterilized, must be willing to use either 2 adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy or to abstain from sexual activity throughout the study, starting with visit 1 through 120 days after the last dose of the study therapy;
• Approved contraceptive methods include for example; intra uterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, or female condom with spermicide. Spermicides alone are not an acceptable method of contraception;
• Male participants must agree to use an adequate method of contraception starting with the first dose of radiation therapy through 120 days after the last dose of study therapy.