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=10-20) will provide a reasonably reliable estimate of the safety and
immunogenicity of the vaccine.
It is anticipated that most potential participants will be consented following standard of
care surgical procedure (biopsy, resection). Consenting and eligible patients will have
sequencing data accessed to evaluate for candidate neoantigens (sequencing may take place
under the auspices of this project, as part of the participant's standard of care, or under
a tumor bank or other research project). Shortly before the vaccine is ready for
administration, participants will be re-screened using the criteria below to confirm
eligibility.
Inclusion Criteria:
- Any patient, regardless of current age, who was diagnosed between the ages of 0-21
years with a pediatric brain tumor of any histologic subtype, who has now developed
recurrent or refractory disease.
- Availability of tissue for sequencing to determine presence of targetable neoantigen.
This may be fresh tissue collected as part of routine care, another research project
or archived tissue from a previous craniotomy with biopsy, subtotal resection, total
gross resection, or re-resection.
- Karnofsky/Lansky 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 institutional upper limit of normal (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 minimal based on age
0.1mg/kg/day with a max of 4mg daily (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 at the discretion of the treating physician.
- 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).
Exclusion Criteria:
- As this is a safety and feasibility study, prior immunotherapy will be permitted.
However, any prior immunotherapy must be discontinued at least 2 weeks before peptide
vaccine administration. Non-immunologic therapy may be continued.
- 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.
- Currently receiving any other investigational agents.
- 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, autoimmune condition requiring
immunosuppressive therapy, or chronic infection (i.e. hepatitis B, hepatitis C, HIV).
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.
