A Pilot Study to Assess the Safety, Feasibility, and Preliminary Efficacy of a Neoepitope-based Personalized Vaccine Approach in Patients With Newly Diagnosed Glioblastoma
The early clinical development paradigm for chemotherapeutic agents has significantly influenced the development of therapeutic cancer vaccines. However, there are major differences between these two classes of therapeutics that have important implications for early clinical development. Specifically, the phase 1 concept of dose escalation to find a maximum-tolerated dose does not apply to most therapeutic cancer vaccines. Most therapeutic cancer vaccines are associated with minimal toxicity at a range that is feasible to manufacture or administer, and there is little reason to believe that the maximum-tolerated dose is the most effective dose. In a recent article from the biostatistics literature, Simon et al. write that the initial clinical trial of many new vaccines will not be a toxicity or dose-ranging trial but rather will involve administration of a fixed dose of vaccine ... in most cases the dose selected will be based on preclinical findings or practical considerations. Using several dose levels in the initial study to find the minimal active dose or to characterize the dose-activity relationship is generally not realistic. Consistent with these recommendations, the general philosophy of the phase 1 clinical trial is to facilitate a prompt preliminary evaluation of the safety and immunogenicity of the personalized synthetic long peptide vaccine strategy. The proposed clinical trial will test a fixed dose of vaccine. There is considerable experience with the synthetic long peptide vaccine platform. The synthetic long peptide vaccine platform has an excellent safety profile, and the optimal dose appears to be based on practical considerations (solubility of the peptide). The dose to be tested in the proposed clinical trial is consistent with other similar cancer vaccine trials that have been recently completed or are currently ongoing. The sample size (n=10) will provide a reasonably reliable estimate of the safety and immunogenicity of the vaccine.
• Newly diagnosed histologically confirmed glioblastoma multiforme (WHO grade IV). Patients with secondary glioblastoma, in particular those who are IDH1 or IDH2 mutant, will not be excluded.
• Patients who had craniotomy with biopsy, subtotal resection, total gross resection, or re-resection will be permitted.
• Consented 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 under this study or 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. 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).