3, these patients will be replaced . Patients who are determined at the time of surgery to have transformed from Pro00054746: RESIST Study Version: 20171011 PT-PhI-II v05.22.12 Duke Cancer Institute Page 43 CONFIDENTIAL Grade II to a higher grade will receive TMZ and radiation therapy per standar d of care and monthly vaccines and will be included in the final analysis of the primary objective. 15.4.3 Handling of missing values, censoring, and discontinuations If a patient does not receive any vaccine treatment, they will be excluded from all analyses . 15.5 Secondary Objective An important secondary goal of this study is t o assess the immunogenicity of the PEP IDH1M vaccine alone and in combination with adjuvant TMZ using ELISpot . Levels of immune response will be examined after 3 vaccinations ( i.e., pre-surgery) as well as after 3 additional post -surgery vaccinations . In previous research, the mean (± SD) number of SFC per 106 lymphocytes for cells cultured with no peptide in previous qualified assays has been 4.5 ± 3.6 . The mean (± SD) response for cells cul tured with an irrelevant peptide ( i.e., actin) has been determined to be 4.2 ± 6.3. Values for cells cultured with IDH1 peptide, after subtraction of counts from cells cultured with no peptide, will be determined. A response will be considered positive if this value is greater than 20 SFC per 106 lymphocytes after determining the level of detection in the IDH ELISpot . With 20 patients, there is 80% power to detect a difference of 4.17 SFC per 106 lymphocytes between response for cells cultured in IDH1 pepti de and those cultured without any peptide . This power calculation conservatively assumes the response to IDH1 peptide and no peptide to be independent, and did not adjust for multiplicity. 15.6 Exploratory Objectives Exploratory objectives include: (1) e stimation of overall survival and progression- free survival , (2) examination of the effect of ELISpot results on subsequent OS or PFS , (3) estimation of the radiographic response rate, (4) d etermination of whether tumors are IDH1 negative at surgery, (5) characterization of immunologic cell infiltrate, ( 6) determination of whether IDH R132H can be detected in plasma and whether the study treatment will affect the levels detected, ( 7) determination of whether IDH 2HG can be detected in plasma and whether the study treatment will affect levels detected, ( 8) genomic and proteomic analyses , and ( 9) an assessment of metabolic imaging. 1. The Kaplan- Meier estimator will describe the survival , PFS from vaccine #1, and PFS post -resection of patients treated with PEP IDH1M vaccine. Survival is defined as the time between first vaccine and death, or last follow -up if the patient remains alive. PFS from vaccine #1 is defined as the time between vaccine #1 and initial progression or death, or date of last follow -up if the patient remains alive without disease progression . PFS post-resection is similarly defined but starting at resection. The proportion of patients alive without progression 6 months after resection will be estimated from the Kaplan -Meier estimator. 2. Cox proportional hazards model will be used to explore the association between ELISpot outcome and subsequent OS or PFS. The radiographic response rate (complete response + partial response) will be estimated with a 95% confidence interval . 3. The proportion of tumors that are IDH1 negative at the time of surgery will be estimated, with a 95% confidence interval. 4. Means and standard deviations, as well as quantiles, will be used to describe the distribution of immunologic cell infiltrates found in tumors at the time of surgery. 5. Descriptive statistics will be used to describe the changes over time in the level of IDH R132H as measured from tumor -specific circulating DNA . 6. In a similar manner , changes over time in levels of the 2- HG metabolite as measured by mass spectrometry will be described. 7. Genomic and proteomic analyses of the pre- treatment pathologic specimen and the post -vaccination surgical sample will be conducted. Changes in geneti c alterations, differential protein expressions and PTMs will be described. If statistical tests are conducted, appropriate adjustment for multiplicity will be considered. 8. Measures of metabolism in IDH1+ gliomas will be assessed at several time point s. Paired comparison (e.g. paired t -tests) will be used to assess whether same- day measures on a patient are the same. Assuming repeatability, changes over time in levels of metabolism will be described. Pro00054746: RESIST Study Version: 20171011 PT-PhI-II v05.22.12 Duke Cancer Institute Page 44 CONFIDENTIAL Additional exploratory analyses may be conducted . Among these additional exploratory analyses will be an examination of the relationship among changes in metabolism, genomic expression, 2- HG metabolite, and pathologic expression of IDH . 15.7 Interim Analysis Efficacy : No interim efficacy analysis is planned. Safety : See section 15.4.2. 15.8 Sample Size Calculation See section 15.4.2 . 16 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS 16.1 Regulatory and Ethical Compliance This protocol was designed and will be conducted and reported in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, the Declaration of Helsinki, and applicable federal, state, and local regulations. 16.2 DUHS Institutional Review Board and DCI Cancer Protocol Committee The protocol, informed consent form, advertising material, and additional protocol -related documents must be submitted to the DUHS IRB and DCI CPC for review . The study may be initiated only after the Principal Investigator has received written and dated approval from the CPC and IRB. The Principal Investigator must submit and obtain approval from the IRB for all subsequent protocol amendments and changes to the informed consent form . The CPC should be informed about any protocol amendments that potentially affect research design or data analysis ( i.e., amendments affecting subject population, inclusion/exclusion criteria, agent administration, statistical analysis, etc.). The Principal Investigator must obtain protocol re- approval from the IRB within 1 year of the most recent IRB approval . The Principal Investigator must also obtain protocol re- approval from the CPC within 1 year of the most recent IRB approval, for as long as the protocol remains open to subject enrollment. 16.3 Informed Consent The informed consent form must be written in a manner that is understandable to the subject population. Prior to its use, the informed consent form must be approved by the IRB. The Principal Investigator or authorized key personnel will discuss with the potential subject the purpose of the research, methods, potential risks and benefits, subject concerns, and other study -related matters . This di scussion will occur in a location that ensures subject privacy and in a manner that minimizes the possibility of coercion . Appropriate accommodations will be made available for potential subjects who cannot read or understand English or are visually impair ed. Potential subjects will have the opportunity to contact the Principal investigator or authorized key personnel with questions, and will be given as much time as needed to make an informed decision about participation in the study. Before conducting any study -specific procedures, the Principal Investigator must obtain written informed consent from the subject . The original informed consent form will be stored with the subject’s study records, and a copy of the informed consent form will be provided to th e subject . The Principal Investigator is responsible for asking the subject whether the subject wishes to notify his/her primary care physician about participation in the study . If the subject agrees to such notification, the Principal Investigator will in form the subject’s primary care physician about the subject’s participation in the clinical study. The prospective participant will have as much time as he/she may need to make an informed decision about the study and all treatment related questions will b e answered. Prospective participants will be consented in an exam room where it is just the research staff, the patient and his/her family, if so desired by the patient . Before, during, and after the consent is signed, the research team and investigators will be available in person and by phone to answer any questions the participants may have . Any and all other available treatment options are offered to the patient in order to avoid undue influence. Participants are not offered compensation for this study in order to avoid any monetary coercion/influence. Pro00054746: RESIST Study Version: 20171011 PT-PhI-II v05.22.12 Duke Cancer Institute Page 45 CONFIDENTIAL For those who cannot read or are blind, the consenter will read the consent form verbatim to those who are illiterate or to those who are blind in the presence of a witness . If the subject decides to part icipate, they will sign the consent form, or if they are unable to sign, make another kind of mark (like an X) to indicate consent . The person obtaining consent will document at the bottom of the consent form that the consent form was read out loud to the patient by (name of person obtaining consent) . If an X or mark is used instead of a signature, the person obtaining consent will note on the consent form that the subject wrote a mark or X instead of a signature. The witness will sign the consent form. Subjects who do not read/understand English may be potentially enrolled following DUHS HRPP policy, including obtaining IRB approval of either a short form or long form consent translation. All of the potential subjects are patients of the PI and the PRTBTC . Patients will be recruited for this study as follows : Upon determination that a patient’s tumor histology and radiographic findings are compatible with the eligibility criteria of this protocol, the clinical study will be briefly explained to the patient by the principal investigator (PI) or colleague. If the patient indicates interest in study participation, patient education sheets and possibly the protocol consent form will be provided to the patient as these provide the most comprehensive explanation of the study in lay terms. If the patient shows continued interest, the PI or designee will thoroughly explain the required elements of informed consent and all aspects of the study to the subject including inclusion/exclusion criteria, risks, benefits and alternatives to study participation. 16.4 Privacy, Confidentiality, and Data Storage The Principal Investigator will ensure that subject privacy and confidentiality of the subject’s data will be maintained. RDSPs will be approved by the appropriate institutional Site Based Research group. To protect privacy, every reasonable effort will be made to prevent undue access to subjects during the course of the study . Prospective participants will be consented in an exam room where it is just the research staff, the patient and his family, if desired. For all future visits, interactions with research staff (study doctor and study coordinators) regarding research activities will take place in a private exam room. All research related interactions with the participant will be conducted by qualified research staff who are directly involved in the conduct of the research study. To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock and key accessible only by the research staff. Subjects will be identified only by a unique study number and subject initials . Electronic records of subject data will be maintained using an electronic database housed by the DCI . Access to electronic databases will be limited to protocol personnel. Data stored on portable memory devices will be de- identified . The security and viability of the IT infrastructure will be managed by the DCI and/or Duke Medicine. Upon completion of the study, research records will be archived and handled per DUHS HRPP policy . Subject names or identifiers will not be used in reports, presentations at scientific meetings, or publications in scientific journals. 16.5 Data and Safety Monitoring Data and Safety Monitoring will be performed in accordance with the DCI Data and Safety Monitoring Plan. The Principal Investigator, CPC and DUHS IRB assess the adequacy of proposed Data and Safety Monitoring Plans during initial and ongoing review and ensure inclusion of adverse event reporting guidelines in each protocol. The sponsor -inves tigator is responsible for reporting all applicable events to the appropriate regulatory agencies as described in the protocol. Protocols sponsored by the NCI Cooperative Group Program (e.g., ECOG, GOG, NSABP, ADOSOG, SWOG, RTOG, and CTSU) are monitored by established centralized data and safety monitoring programs within each cooperative group. Phase III and IV protocols (e.g., NIH -supported, large- scale, multi -site phase III therapeutic intervention protocols which involve significant risk) are outside th e scope of this monitoring and safety review system. Independent DSMBs for such studies should be established by the sponsor -investigator. NIH -supported phase III clinical protocols which involve only low risk (e.g. behavioral and nutritional interventions ) will be reviewed by CPC on a case -by- case basis, as their sample size may be too large to be practically monitored by this system. Pro00054746: RESIST Study Version: 20171011 PT-PhI-II v05.22.12 Duke Cancer Institute Page 46 CONFIDENTIAL It is recognized that protocols with corporate sponsors and protocols sponsored by NCI cooperative groups are continually audited for compliance and assessed for scientific progress. DUHS sponsor - investigator protocols without outside sponsorship however, are not, and are the focus of this monitoring plan. Safety Oversight Committee Protocol Review The Safety Oversight Comm ittee conducts annual data and safety monitoring for DUHS sponsor - investigator phase I and II, therapeutic interventional studies that do not have an independent DSMB . Annual safety reviews include review of safety data, enrollment status, stopping rules i f applicable, accrual, toxicities, reference literature, and interim analyses as provided by the sponsor -investigator. Studies are rated satisfactory when adequate accrual with lack of excessive toxicity is present. The sponsor -investigator submits a Safet y Oversight Committee Safety Report to the Safety Oversight Committee annually, upon request, or the data may be submitted simultaneously with required reporting, e.g., FDA annual report. Attachments (e.g., accrual tables, toxicities and reference literature) are also acceptable for Safety Oversight Committee review . The sponsor -investigator is notified in writing if additional information is needed and if protocol or operational changes are required. The Safety Oversight Committee will notify the sponsor -investigator and DUHS IRB when significant safety concerns are identified. The Safety Oversight Committee Chair has the authority to temporarily suspend accrual to the study pending acceptable changes. Any recommendation for temporary or permanent suspension of an NIH-funded clinical protocol will be reported by the sponsor -investigator via written communication to the responsible NCI grant program director. DCI Monitoring Team The DCI Monitoring Team is comprised of individuals who do not have a direct wor king relationship with the sponsor -investigator or research team. This independence of DCI Monitoring Team composition is intended to prevent conflicts of interest and breaches of confidentiality during monitoring visits. The DCI Monitoring Team conducts m onitoring visits as defined by CPC, on DUHS sponsor - investigator therapeutic intervention and prevention intervention studies that do not have an external monitoring plan, ensuring subject safety and that the protocol is conducted, recorded and reported in accordance with the protocol, SOPs, GCP, and applicable regulatory requirements. The Monitoring Team also provides ongoing education and resources to investigators and study teams to enhance the quality. Standard monitoring for therapeutic intervention an d prevention intervention studies is routine monitoring after the third subject is enrolled, followed by annual monitoring of 1-3 subjects until the study is closed to enrollment and subjects are no longer receiving study interventions that are more than m inimal risk. At the time of CPC review, the CPC may assign monitoring requirements in addition to the standard monitoring plan, as summarized in Table 1 on the next page. Also, additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of serious and/or unexpected toxicities, or other concerns and may be initiated upon request of DUHS and DCI Leadership, CPC, Safety Oversight Committee, a sponsor, an investigator or the IRB. SOC members serve as an expert resource and back -up for the DCI Monitoring Team. The DCI Monitoring Team reviews the adequacy of informed consent, enrollment of appropriate patients, implementation of protocol -specifie d procedures and treatment, adequacy of data collection, and appropriateness of adverse event monitoring and reporting . 16.6 Protocol Amendments All protocol amendments must be initiated by the Principal Investigator and approved by the IRB prior to implementat ion. IRB approval is not required for protocol changes that occur to protect the safety of a subject from an immediate hazard. However, the Principal Investigator must inform the IRB and all other applicable regulatory agencies of such action immediately. Though not yet required, th e CPC should be informed about any protocol amendments that potentially affect research design or data analysis (i.e. , amendments affecting subject population, inclusion/exclusion criteria, agent administration, etc.). 16.7 Records Retention The Principal Investigator will maintain study -related records for the longer of a period of: Pro00054746: RESIST Study Version: 20171011 PT-PhI-II v05.22.12 Duke Cancer Institute Page 47 CONFIDENTIAL • at least two years after the date on which a New Drug Application is approved by the FDA • at least two years after formal withdrawal of the IND associat ed with this protocol • at least six years after study completion (Duke policy) 16.8 Conflict of Interest The Principal Investigator and Sub- Investigators must comply with applicable federal, state, and local regulations regarding reporting and disclosure of conf lict of interest . Conflicts of interest may arise from situations in which financial or other personal considerations have the potential to compromise or bias professional judgment and objectivity .