Neoantigen-Based Personalized Vaccine and Nivolumab with or without Ipilimumab in Treating Patients with Newly Diagnosed Unmethylated Glioblastoma
This phase I pilot trial studies the side effects of a neoantigen-based glioblastoma vaccine (neoantigen-based personalized vaccine) given with nivolumab with or without ipilimumab and to see how well they work in treating patients with newly diagnosed unmethylated glioblastoma. Vaccines, such as neoantigen-based personalized vaccine, are made from personalized peptides that may help the body build an effective immune response to kill tumor cells that express mutations specific to each person’s tumor that are discovered during genetic testing. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving a neoantigen-based personalized vaccine, nivolumab, and ipilimumab may work better in treating patients with unmethylated glioblastoma.
Inclusion Criteria
- Newly diagnosed histologically confirmed unmethylated glioblastoma multiforme (World Health Organization [WHO] grade IV). Patients with secondary glioblastoma, in particular those who are IDH1 or IDH2 mutant, will not be excluded. Unmethylated MGMT must be confirmed by a polymerase chain reaction (PCR)-based assay.
- Patients who had craniotomy with biopsy, subtotal resection, total gross resection, or re-resection will be permitted.
- Consented to genome sequencing and the database of genotypes and phenotypes (dbGaP)-based data sharing and has provided or will provide germline (PBMC) and tumor DNA/ribonucleic acid (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%
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Total bilirubin =< 1.5 x institutional upper limit of normal (IULN)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 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 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 Institutional Review Board (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 various vaccine plus adjuvant combinations, 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 poly-ICLC or other 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 pre-existing immunodeficiency disorder or autoimmune condition requiring 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, Sjogren’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.
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03422094.
PRIMARY OBJECTIVES:
I. To determine the safety and tolerability of a personalized neoantigen peptide vaccine plus poly-ICLC (neoantigen-based glioblastoma vaccine) with or without anti-CTLA-4 (ipilimumab) and/or anti-PD-1 (nivolumab) therapy in patients with newly diagnosed, unmethylated glioblastoma (GBM).
II. To determine the feasibility of generating a personalized neoantigen peptide vaccine for patients with newly diagnosed, unmethylated GBM.
SECONDARY OBJECTIVES:
I. To assess the immunogenicity of a personalized neoantigen peptide vaccine plus polyICLC with or without anti-CTLA-4 and/or anti-PD-1 therapy in patients with newly diagnosed, unmethylated GBM.
II. To determine the number of high quality candidate neoantigens present in patients with newly diagnosed GBM.
III. To evaluate preliminary efficacy by determining the 6 month progression-free survival rate (PFS-6) and 12 month overall survival rate (OS-12).
EXPLORATORY OBJECTIVES:
I. To characterize tumor-infiltrating lymphocytes (TIL) derived from tissue specimens from patients who have received a personalized neoantigen peptide vaccine before and after vaccination.
II. To identify pre- and post-vaccination biomarkers associated with response to personalized neoantigen vaccine.
III. To perform gene expression analysis of TIL and peripheral blood mononuclear cell (PBMC) to determine activation states before and after vaccination compared to unvaccinated controls.
IV. To evaluate antigen-specific cellular and humoral immune responses in the peripheral blood against non-immunized tumor-associated antigens (i.e., epitope spreading).
V. To characterize recurrent tumor samples and cell-free circulating tumor deoxyribonucleic acid (DNA) to assess for antigenic maintenance or loss before, during, and after treatment.
OUTLINE: Patients are assigned to 1 of 5 cohorts based on when they enroll.
COHORT A: Patients receive neoantigen-based glioblastoma vaccine subcutaneously (SC) over four injections on days 1, 8, 15, and 22 of cycle 1 and then on day 1 for every cycle thereafter. Patients also receive nivolumab intravenously (IV) over 60 minutes beginning at time of disease progression and then every 4 weeks thereafter. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
COHORT B: Patients receive neoantigen-based glioblastoma vaccine as in cohort A. Patients also receive nivolumab IV over 60 minutes on day 1 of each cycle beginning on cycle 2. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
COHORT C: Patients receive neoantigen-based glioblastoma vaccine as in cohort A. Patients also receive nivolumab IV over 60 minutes beginning on day 1 of cycle 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
COHORT D: Patients receive neoantigen-based glioblastoma vaccine as in cohort A. Patients also receive ipilimumab IV over 30 minutes on days 1 and 22 of cycle 1 and nivolumab over 60 minutes on day 1 of each cycle beginning on cycle 3. Cycles with neoantigen-based glioblastoma vaccine and nivolumab repeat every 28 days in the absence of disease progression or unacceptable toxicity.
COHORT E: Patients receive neoantigen-based glioblastoma vaccine as in cohort A. Patients also receive nivolumab IV over 60 minutes every 2 weeks and ipilimumab IV over 30 minutes every 6 weeks beginning on day 1 of cycle 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then periodically for up to 24 months.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationSiteman Cancer Center at Washington University
Principal InvestigatorTanner M. Johanns
- Primary ID201804195
- Secondary IDsNCI-2018-00917
- ClinicalTrials.gov IDNCT03422094