a phase 1 clinical trial
11.1.4 reporting to the fda

The conduct of the study will comply with all FDA safety reporting requirements. PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER FROM
REPORTING REQUIREMENTS FOR HRPO/QASMC. It is the responsibility of the Washington University principal investigator to report to the FDA as follows:
- Report any unexpected fatal or life-threatening suspected adverse reaction (refer to Appendix A for definitions) no later than 7 **calendar days** after initial receipt of the information.  
- Report a suspected adverse reaction that is both serious and unexpected
(SUSAR, refer to Appendix A) no later than **15 calendar days** after it is determined that the information qualifies for reporting. Report an adverse event
(refer to Appendix A) as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the drug and the adverse event, such as o A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure o One or more occurrences of an event that is not commonly associated with drug exposure but is otherwise uncommon in the population exposed to the drug
o An aggregate analysis of specific events observed in a clinical trial that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group
- Report any findings from epidemiological studies, pooled analysis of multiple studies, or clinical studies that suggest a significant risk in humans exposed to the drug no later than **15 calendar days** after it is determined that the information qualifies for reporting.  
- Report any findings from animal or in vitro testing that suggest significant risk in humans exposed to the drug no later than 15 calendar days after it is determined that the information qualifies for reporting.  
- Report any clinically important increase in the rate of a serious suspected adverse reaction of that listed in the protocol or IB within 15 calendar days after it is determined that the information qualifies for reporting.  
Submit each report as an IND safety report in a narrative format or on FDA Form 3500A or in an electronic format that FDA can process, review, and archive. Study teams must notify the Siteman Cancer Center Protocol Development team of each potentially reportable event within 1 business day after initial receipt of the information, and must bring the signed 1571 and FDA Form 3500A to the Siteman Cancer Center Protocol Development team no later than 1 business day prior to the due date for reporting to the FDA. Each notification to FDA must bear prominent identification of its contents ("IND Safety Report") and must be transmitted to the review division in the Center for Drug Evaluation and Research (CDER) or in the Center for Biologics Evaluation and Research (CBER)
that has responsibility for review of the IND. Relevant follow-up information to an IND safety report must be submitted as soon as the information is available and must be identified as such ("Follow-up IND Safety Report").
a phase 1 clinical trial
11.1.5 reporting to the institutional

In accordance with institutional policies and NIH guidelines, any unanticipated problems must be reported to the Institutional Biological and Chemical Safety Committee (IBC) at Washington University School of Medicine.  
The Washington University Sponsor-Investigator (or designee) must report the following events to the Biosafety Officer at the time of submission to HRPO:
- Any overt personnel exposure to recombinant DNA-containing material, whether or not that exposure leads to illness
- Any significant spill of recombinant DNA-containing material outside of a biological safety cabinet, where a significant spill is:
o A spill of recombinant risk group 1 agent-containing material which requires remediation by EH&S or other first responders o A spill of recombinant risk group 2 agent-containing material which is greater than 1 liter o Any size spill of risk group 3 agent-containing material or material the IBC
has mandated to be handled using BSL2+ practices and procedures o Any incident which results in the release of recombinant DNA to the environment
In addition, the IBC must be informed of the following events:
- Any serious adverse event which is both unexpected and associated with the use of the gene transfer product The Biosafety Officer may be contacted at ehsibc@wustl.edu.  
When submitting reports to the IBC, the FDA MedWatch form will be used. The Washington University Sponsor-Investigator (or designee) will be responsible for submitting all MedWatch forms from secondary sites to the IBC. WUSM IBC guidelines specify that any study modifications related to the investigational agent as well as the IRB renewal paperwork should be sent to the IBC for approval (if a modification) or acknowledgment (if an annual renewal). The IRB and IBC will review all submissions simultaneously.
a phase 1 clinical trial
11.1.6 reporting to secondary sites

The Washington University Sponsor-Investigator (or designee) will notify the research team at each secondary site of all unanticipated problems involving risks to participants or others that have occurred at other sites within 10 working days of the occurrence of the event or notification of the Sponsor-Investigator (or designee) of the event. This includes events that take place both at Washington University and at other secondary sites, if applicable. Refer to Section 16.0 (Multicenter Management) for more information.
a phase 1 clinical trial
secondary site reporting requirements

The research team at each secondary site is required to promptly notify the Washington University Sponsor-Investigator and designee of all serious adverse events (refer to Appendix A, Section D)
within 1 working day of the occurrence of the event or notification of the secondary site's PI of the event. This notification may take place via email if there is not yet enough information for a formal written report (using FDA Form 3500a (MedWatch) and Washington University's cover sheet
(Appendix C). A formal written report must be sent to the Washington University SponsorInvestigator and designee within 4 calendar days (for fatal or life-threatening suspected adverse reactions) or 11 calendar days (for serious unexpected suspected adverse reactions) of the occurrence of the event or notification of the secondary site's PI of the event.  
The research team at a secondary site is responsible for following its site's guidelines for reporting applicable events to its site's IRB according to its own institutional guidelines. The research team at Washington University is responsible for reporting all applicable events to the FDA, IBC, and Ichor as needed.  
Washington University pre-approval of all protocol exceptions must be obtained prior to implementing the change. Local IRB approval must be obtained as per local guidelines. Washington University IRB approval is not required for protocol exceptions occurring at secondary sites.
a phase 1 clinical trial
exceptions to expedited reporting

Events that do not require expedited reporting as described in Section 11.1 include:  
- planned hospitalizations - hospitalizations <24 hours
- respite care
- events related to disease progression
Events that do not require expedited reporting must still be captured in the EDC.
a phase 1 clinical trial
12 data and safety monitoring

In compliance with the Washington University Institutional Data and Safety Monitoring Plan, an independent Data and Safety Monitoring Board (DSMB) will be specifically convened for this trial to review toxicity data. A DSMB will consist of no fewer than 3 members including 2 clinical investigators and a biostatistician. DSMB members must be employed by Washington University, Barnes-Jewish Hospital, or St. Louis Children's Hospital. Like investigators, DSMB members are subject to the Washington School of Medicine policies regarding standards of conduct. Individuals invited to serve on the DSMB will disclose any potential conflicts of interest to the trial principal investigator and/or appropriate university officials, in accordance with institution policies. Potential conflicts that develop during a trial or a member's tenure on a DSMB must also be disclosed.  
Until such a time as the first secondary site enrolls its first patient, a semi-annual DSM report to be prepared by the study team will be submitted to the Quality Assurance and Safety Monitoring Committee
(QASMC) semi-annually beginning six months after study activation at Washington University (if at least one patient has been enrolled) or one year after study activation (if no patients have been enrolled at the six-month mark).  
The DSM report for the DSMB will be prepared by the study team with assistance from the study statistician, will be reviewed by the DSMB, and will be submitted to the QASM Committee. The DSMB
must meet at least every 6 months beginning after study activation at Washington University, beginning six months after enrollment of the first patient at a secondary site, no more than one month prior to the due date of the DSM report to QASMC. This report will include:
- HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, regulatory coordinator name, and statistician
- Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date of HRPO expiration, date of most recent QA audit, study status, and phase of study
- History of study including summary of substantive amendments; summary of accrual suspensions including start/stop dates and reason; and summary of protocol exceptions, error, or breach of confidentiality including start/stop dates and reason
- Study-wide target accrual and study-wide actual accrual including numbers from participating sites
- Protocol activation date at each participating site
- Average rate of accrual observed in year 1, year 2, and subsequent years at each participating site
- Expected accrual end date and accrual by site - Objectives of protocol with supporting data and list the number of participants who have met each objective  
- Measures of efficacy
- Early stopping rules with supporting data and list the number of participants who have met the early stopping rules
- Summary of toxicities at all participating sites
- Abstract submissions/publications
- Summary of any recent literature that may affect the safety or ethics of the study Further DSMB responsibilities are described in the DSMB charter.
The study principal investigator and coordinator will monitor for serious toxicities on an ongoing basis. Once the principal investigator or coordinator becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according to institutional guidelines (please refer to Section 11). Refer to the Washington University Quality Assurance and Safety Monitoring Committee Policies and Procedures for full details on the responsibilities of the DSMC. This is located on the QASMC website at https://siteman.wustl.edu/research/clinical-research-resources/protocol-office-prmcqasmc/.
a phase 1 clinical trial
nih recombinant dna advisory committee

Appendix M-I-C-1 of the NIH Guidelines for Research Involving Recombinant DNA Molecules specify:
No later than 20 working days after enrollment (see definition of enrollment in Section I-E-7) of the first research participant in a human gene transfer experiment, the Principal Investigator(s) shall submit the following documentation to NIH OBA: (1) a copy of the informed consent document approved by the Institutional Review Board (IRB); (2) a copy of the protocol approved by the Institutional Biosafety Committee (IBC) and IRB; (3) a copy of the final IBC approval from the clinical trial site; (4) a copy of the final IRB approval; (5) a brief written report that includes the following information: (a) how the investigator(s) responded to each of the RAC's recommendations on the protocol (if applicable); and (b) any modifications to the protocol as required by FDA; (6) applicable NIH grant number(s); (7) the FDA Investigational New Drug Application (IND) number; and (8) the date of the initiation of the trial. The purpose of requesting the FDA IND number is for facilitating interagency collaboration in the Federal oversight of human gene transfer research.
a phase 1 clinical trial
12.1.2 annual reports

Appendix M-I-C-3 of the NIH Guidelines for Research Involving Recombinant DNA Molecules specify:
Within 60 days after the one-year anniversary of the date on which the investigational new drug (IND)
application went into effect, and after each subsequent anniversary until the trial is completed, the Principal Investigator (or delegate) shall submit the information set forth in (a), (b), and (c). When multiple studies are conducted under the single IND, the Principal Investigator (or delegate) may choose to submit a single annual report covering all studies, provided that each study is identified by its OBA protocol number.  
(a) Clinical Trial Information. A brief summary of the status of each trial in progress and each trial completed during the previous year. The summary is required to include the following information for each trial: (1) the title and purpose of the trial; (2) clinical site; (3) the Principal Investigator; (4) clinical protocol identifiers, including the NIH OBA protocol number, NIH grant number(s) (if applicable), and the FDA IND application number; (5) participant population (such as disease indication and general age group, e.g., adult or pediatric); (6) the total number of participants planned for inclusion in the trial; the number entered into the trial to date; the number whose participation in the trial was completed; and the number who dropped out of the trial with a brief description of the reasons; (7) the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, or fully completed, and (8) if the trial has been completed, a brief description of any study results. (b) Progress Report and Data Analysis. Information obtained during the previous year's clinical and non-clinical investigations, including: (1) a narrative or tabular summary showing the most frequent and most serious adverse experiences by body system; (2) a summary of all serious adverse events submitted during the past year; (3) a summary of serious adverse events that were expected or considered to have causes not associated with the use of the gene transfer product such as disease progression or concurrent medications; (4) if any deaths have occurred, the number of participants who died during participation in the investigation and causes of death; and (5) a brief description of any information obtained that is pertinent to an understanding of the gene transfer product's actions, including, for example, information about dose-response, information from controlled trials, and information about bioavailability. (c) A copy of the updated clinical protocol including a technical and non-technical abstract.
a phase 1 clinical trial
13 statistical considerations experimental design

This is a phase 1, open-label, trial of a neoantigen DNA vaccine strategy. Twenty patients who have had an R0/R1 surgical resection, and who have completed adjuvant chemotherapy will be enrolled. At our institution, pancreatic cancer patients undergo routine staging during (three months) and after adjuvant chemotherapy. If there is no evidence of disease, patients will be eligible for enrollment. After enrollment, exome sequencing of tumor/normal DNA and cDNA-capture sequencing of the tumor will be performed to identify somatic mutations present in the tumor and confirm expression of these mutations at the mRNA level. Epitope prediction algorithms will then be used to prioritize neoantigens for inclusion in neoantigen DNA vaccines, and the neoantigen DNA vaccines will be designed and manufactured. The neoantigen DNA vaccines will be administered following completion of adjuvant chemotherapy. The neoantigen DNA
vaccines will be administered at six time points, weeks 1, 5, 9, 13, 17, and 21.
a phase 1 clinical trial
13.1.1 sample size and accrual

Development of cancer vaccines is currently an area of intense research interest. The traditional paradigm for phase 1 clinical trials has been heavily influenced by phase 1 clinical trials of chemotherapeutic agents, where dose escalation designs are appropriate given the rather narrow dose versus safety concerns of these agents. 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 [52]. Consistent with recent recommendations published in the statistical literature, the general philosophy of this phase I clinical trial is to facilitate a prompt preliminary evaluation of the safety and immunogenicity of a personalized pancreatic cancer DNA vaccine strategy by testing a fixed dose of vaccine, instead of performing a dose escalation [52]. The sample size (n=15) is chosen to provide a reasonable ability to detect serious adverse events associated with vaccine administration.  
Based on extensive simulations regarding the sample size for pilot or translational studies, Piantadosi [83] recommended that a sample size of 10 to 20 patients would provide a reasonable precision for estimating preliminary information. We therefor expect that, as detailed below, the proposed sample size for this study will be adequate in estimating both safety and preliminary immune efficacy data. The sample size of n=15 will consist of EVALUABLE patients. Patients who screen fail due to sequencing issues such as poor sample quality will be replaced.
a phase 1 clinical trial
13.1.2 sample size calculations for

The primary objective of this study is to evaluate the safety of the neoantigen DNA vaccines. We have chosen to power the study to provide a reasonable ability to detect serious adverse events associated with vaccine administration.  
Sample size calculations for safety are expressed in terms of the ability to detect serious adverse events.  
The ability of the study to identify serious adverse events is best expressed by the maximum true rate of events that would be unlikely to be observed and the minimum true rate of events that would very likely be observed. Table below shows the probabilities of observing 0, or 2 or more serious adverse events given variety of hypothesized "true" AE rates. If the true rate is at least 15%, for example, there is >90%
chance of observing at least 1 serious adverse event among a sample size of n=15 evaluable patients.  
Conversely, there is only 10% chance that we would observe 2 or more serious adverse event among n=15 evaluable patients if the true rate is less than 3.5%. Although we believe that the true event rate is likely to be quite low, this table presents a range of event rates in an attempt to illustrate the sensitivity of this study to identify potential safety problems with the neoantigen DNA vaccines.  
| True Event rate   | Pr(0/15)   | Pr(2+/15)   |
|-------------------|------------|-------------|
| 0.010             | 0.860      | 0.010       |
| 0.035             | 0.586      | 0.100       |
| 0.050             | 0.463      | 0.171       |
| 0.100             | 0.206      | 0.451       |
| 0.150             | 0.087      | 0.681       |
a phase 1 clinical trial
probability of detecting sae for

The secondary objective and primary scientific endpoint is to assess the prevalence of antigen-specific T cells in the peripheral blood of patients pre- and post-vaccination as measured by ELISPOT.. A power analysis was performed using paired t-test for over time differences (e.g., changes in ELISPOT). Assuming a moderate correlation between measures taken from the same individual, the designed sample size (n=15 evaluable patients) allows us 80% power at 1-sided 0.05 alpha level to detect a minimum increase of 0.68*SD, where SD represents the standard deviation of measures for immunogenicity. Our preliminary data showed that antigen-specific T cells can be measured with a coefficient of variability (CV=SD/Mean) of approximately 20%. Therefore, if assuming similar variability in the proposed study, the designed sample size provides 80% power to detect a minimal of 15% change in the average antigen-specific T cells. We expect that more power could be achieved because multiple measurements will be taken from the same patient and this allows borrowing information across different time points.
a phase 1 clinical trial
data analysis

As a phase I trial to evaluate the preliminary data on the safety and immunogenicity of a neoantigen DNA vaccine strategy, the data analysis for this study is descriptive in nature. Demographic and clinical characteristics of the sample, toxicity by grade, as well as response and time to toxicity will be listed and summarized using descriptive statistics.
a phase 1 clinical trial
13.2.1 primary objective safety analysis

Toxicity evaluation is the primary objective of this trial. The data will be descriptive, and standard toxicity definitions and criteria will be used as outlined in the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.  
Since enrollment will be concurrent with the first dose of the personalized pancreatic cancer DNA vaccines, all subjects will have received at least one vaccination, and all subjects will provide at least some safety data.  
The number and percentage of subjects experiencing each type of adverse event will be tabulated by severity, and relationship to treatment. If appropriate, confidence intervals will be used to characterize the precision of the estimate. A complete listing of adverse events will also be tabulated, and will provide details including severity, relationship to treatment, onset, duration, and outcome. Laboratory data measured on a continuous scale will be characterized by summary statistics (mean and standard deviation). Boxplots of laboratory data will be generated for baseline values and for values measured during and after protocol therapy at each specific time point. Each boxplot will show the median, 1st and 3rd quartiles. Outliers will be individually plotted in a separate graph, as appropriate.
a phase 1 clinical trial
13.2.2 secondary and exploratory objectives

Immune response as measured by ELISPOT analysis is the secondary objective of this trial. Immune response as measured by multiparametic flow cytometry is an exploratory objective of this trial. The frequency of antigen-specific T cells at each time will be summarized using means, standard deviations and medians, and the change over time will also be compared using two-ANOVA for repeated measurement data or Friedman rank-sum test as appropriate. The immunogenicity of the neoantigen DNA vaccine will also be analyzed qualitatively by summarizing the phenotypic and functional characteristics of antigen-specific T cells. Responses will be considered positive if the number of T cells after vaccination is greater than two standard deviations above the mean before vaccination [82]. The frequency of positive responses at each time point will be assessed and binomial response rates with 95% confidence interval estimates will be presented. In addition to presenting the binomial response rates, graphical and tabular summaries of the underlying distributions will be made.
a phase 1 clinical trial
13.2.3 additional exploratory objectives

Blood samples will be obtained at multiple time points (prior to vaccination, during, and post-vaccination)
in order to procure PBMC for correlative studies. Functional studies will include ELISPOT, T cell polyfunctionality by intra-cellular cytokine and degranulation analysis using multi-parametric flow cytometry, as detailed in Section 9. Time to disease progression will be evaluated with physical examination and diagnostic imaging as clinically indicated. The time to disease progression will be described using Kaplan-Meier product limited method. The median progression-free survival (PFS), median overall survival (OS), and their 95% CIs will be estimated. The association between immunogenicity and PFS or OS will be explored by comparing the survival curves between immune responders versus non-responders. To determine whether the observed difference is larger than might be expected by chance, a permutation test will be used to compare the observed test statistic to the distribution of test statistics that would be seen if there were no difference between the two studies. Specifically, we will randomly shuffle the status of response and calculate the test statistic from the shuffled data. This procedure will be repeated 10,000 times and the resultant testing statistics will provide an accurate representation of the null distribution. The observed test statistics of between-study differences will be compared to the null distributions. For each outcome, the permuted pvalue will be the fraction of permuted samples that resulted in a small statistic than the original sample
[85].
a phase 1 clinical trial
14 data management

Data collected will be collected using paper case report forms or OnCore electronic data capture forms. Forms must be completed within 28 days of time point.  
| Forms must be completed within 28 days of time point. Case Report Form Submission Schedule Original Consent Form Prior to registration Registration Form Eligibility Form Demographics Form On-Study Form Medical History Form Prior to starting treatment Enrollment Mid chemo End of chemo Week 1 Week 5 Week 9 Week 13 Week 17 Week 21 Week 25 Week 73 Physical Exam Form Week 1 Week 5 Week 9 Week 13 Week 17 Week 21 Vaccine Administration Form Enrollment Mid chemo End of chemo Week 1 Week 5 Week 9 Week 13 Week 17 Week 21 Week 25 Week 73 Immune Monitoring Form Imaging Form Mid chemo End of chemo Week 1 Week 5 Week 9 Week 13 Week 17 Week 21 Week 25 Concomitant Medications Form Continuous through Week 25 Toxicity Form Week 25 Follow Up Form Week 73 Year 2 and annually thereafter MedWatch Form See Section 11.0 for reporting requirements   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Any queries generated by Washington University must be responded to within 28 days of receipt by the participating site. The Washington University research team will conduct a regular review of data status at all secondary sites, with appropriate corrective action to be requested as needed.
a phase 1 clinical trial
adverse event collection in the

All adverse events that occur beginning with start of treatment (minus exceptions defined in Section 11.0) must be captured in the Toxicity Form. Baseline AEs should be captured on the Medical History Form.  
Participant death due to disease progression should be reported on the Toxicity Form as grade 5 disease progression. If death is due to an AE (e.g. cardiac disorders: cardiac arrest), report as a grade 5 event under that AE. Participant death must also be recorded on the Death Form.
a phase 1 clinical trial
15 auditing

As coordinating center of this trial, Washington University (via the Quality Assurance and Safety Monitoring Committee (QASMC) will monitor each participating site to ensure that all protocol requirements are being met; that applicable federal regulations are being followed; and that best practices for patient safety and data collection are being followed per protocol. Participating sites will be asked to send copies of all audit materials, including source documentation. The audit notification will be sent to the Washington University Research Patient Coordinator, who will obtain the audit materials from the participating institution. Notification of an upcoming audit will be sent to the research team one month ahead of the audit. Once accrual numbers are confirmed, and approximately 30 days prior to the audit, a list of the cases selected for review (up to 10 for each site) will be sent to the research team. However, if during the audit the need arises to review cases not initially selected, the research team will be asked to provide the additional charts within two working days.  
Items to be evaluated include:
- Subject screening and enrollment
- Reporting of adverse events
- Maintenance of HIPAA compliance - Completeness of regulatory documentation
- Completeness of participant documentation - Acquisition of informed consent
- IRB documentation
- Issues of protocol adherence Additional details regarding the auditing policies and procedures can be found at https://siteman.wustl.edu/wp-content/uploads/2015/10/QASMC-Policies-and-Procedures-03.31.2015.pdf
a phase 1 clinical trial
16 multicenter regulatory requirements

Washington University requires that each participating site sends its informed consent document to be reviewed and approved by the Washington University Regulatory Coordinator (or designee) prior to IRB/IEC submission. Site activation is defined as when the secondary site has received official written documentation from the coordinating center that the site has been approved to begin enrollment. At a minimum, each participating institution must have the following documents on file at Washington University prior to study activation:
- Documentation of IRB approval of the study in the form of a letter or other official document from the participating institution's IRB. This documentation must show which version of the protocol was approved by the IRB.  
- Documentation of IRB approval of an informed consent form. The consent must include a statement that data will be shared with Washington University, including the Quality Assurance and Safety Monitoring Committee (QASMC), the DSMC (if applicable), and the Washington University study team.  
- Documentation of FWA, signed FDA Form 1572 (if applicable), and the CVs of all participating investigators.  
- Protocol signature page signed and dated by the investigator at each participating site.
The coordinating center Principal Investigator (or designee) is responsible for disseminating to the participating sites all study updates, amendments, reportable adverse events, etc. Protocol/consent modifications and IB updates will be forwarded electronically to the secondary sites within 4 weeks of obtaining Washington University IRB approval. Activated secondary sites are expected to submit protocol/consent/IB modifications to their local IRBs within 4 weeks of receipt unless otherwise noted. Upon the secondary sites obtaining local IRB approval, documentation of such shall be sent to the Washington University study team within 2 weeks of receipt of approval.  
Documentation of participating sites' IRB approval of annual continuing reviews, protocol amendments or revisions, all SAE reports, and all protocol violations/deviations/exceptions must be kept on file at Washington University. The investigator or a designee from each institution must participate in a regular conference call to update and inform regarding the progress of the trial.
a phase 1 clinical trial
17 regulatory and ethical obligations

In accordance with US FDA regulations (21 CFR 50) and guidelines (Federal Register, May 9, 1997, Vol. 62, Number 90 - ICH Good Clinical Practice Consolidated Guideline) it is the investigator's responsibility to ensure that witnessed informed consent is obtained from the subject before participating in an investigational study, after an adequate explanation of the purpose, methods, risks, potential benefits and subject responsibilities of the study. Procedures that are to be performed as part of the practice of medicine and which would be done whether or not study entry was contemplated, such as for diagnosis or treatment of a disease or medical condition, may be performed and the results subsequently used for determining study eligibility without first obtaining consent. On the other hand, informed consent must be obtained prior to initiation of any screening procedures that are performed solely for the purpose of determining eligibility for research. Each subject must be given a copy of the informed consent. The original signed consent must be retained in the institution's records and is subject to review by the sponsor, the HRPO and any other applicable regulatory agencies responsible for the conduct of the institution. All elements listed in the ICH Good Clinical Practice guidelines must be included in the informed consent.  
Informed consent will be obtained by either the principal investigator or by individuals approved by the principal investigator and whose names have been submitted to the IRB. Informed consent will be obtained from the subject after the details of the protocol have been reviewed. The individual responsible for obtaining consent will assure, prior to signing of the informed consent, that the subject has had all questions regarding therapy and the protocol answered.
a phase 1 clinical trial
institutional review board

In accordance with US FDA regulations (21 CFR 56) and guidelines (Federal Register, May 9, 1997 Vol.  
62 Number 90 - ICH Good Clinical Practice Consolidated Guideline) all research involving human subjects must be reviewed and approved by the local IRB. All modifications to the protocol, consent forms, or other study documents must be reviewed and approved by the local IRB. At Washington University School of Medicine, the Human Research Protection Office serves as the local IRB.
a phase 1 clinical trial
subject confidentiality

In order to ensure subject confidentiality, each subject will be assigned a study number. Subject samples and medical information will be de-identified and labeled with the study number. The link between subject identification and study number will be safeguarded in a secure file in a locked room, and access will be restricted to the principal investigator, study coordinator, and other co-investigators as necessary. Collected data will be recorded on case report forms. Case report forms will be safeguarded in a locked cabinet and/or a password-protected secure computer drive and access will be restricted to the principal investigator, study coordinator, and other co-investigators as necessary. Subject medical information related to, or obtained for the purposes of this trial are confidential, and disclosure to third parties is prohibited. The exception is regulatory authorities including the FDA, NIH/OBA, and the local IRB. Data from this study must be available for inspection on request of regulatory authorities including the FDA and the local IRB.
a phase 1 clinical trial
18 administrative and legal obligations

Source documents are original documents, data, and records from which the subject's data are obtained.  
These include but are not limited to hospital records, clinical and office charts, laboratory and pharmacy records, diaries, diagnostic imaging studies, and correspondence.  
The principal investigator and staff are responsible for maintaining a comprehensive file of all studyrelated documents, suitable for inspection at any time by representatives from the PRMC, HRPO, FDA,
and any other applicable regulatory agency. Pertinent documents in the study file include:
(1) The original protocol with all amendments (2) Curriculum vitae of principal investigator and co-investigators (3) Approval notification and any other correspondence with the PRMC, HRPO, NIH RAC and FDA Pertinent documents in each individual subject file include:
(1) Informed consent forms (2) Case report forms
(3) Supporting copies of source documentation All original source documentation must be readily available.
a phase 1 clinical trial
18.1.2 retention of records

The principal investigator must retain records related to this study including protocols; amendments; IRB/IBC approvals; FDA IND records and other correspondence; completed, signed and dated consent forms; patient medical records; case report forms; drug accountability records and any other correspondence related to the conduct of the study. U.S. FDA regulations (21 CFR 312.62[c]) require that all records pertaining to the conduct of this study, must be retained by the responsible investigator for a minimum of 2 years after marketing application approval. If no application is filed, these records must be kept 3 years after the investigation is discontinued and the U.S. FDA and the applicable local health authorities are notified.
a phase 1 clinical trial
policy regarding research-related injuries

Washington University School of Medicine investigators and their staffs will try to reduce, control, and treat any complications from this research.  
Any subjects who believe that they have been injured as a result of participation in this study will be instructed to contact the principal investigator, William E. Gillanders, M.D. at (314) 747-0072. Alternatively, they can contact Dr. Jonathan Green, Chairman of the Human Research Protection Office, at (800) 438-0445.  
Decisions about payment for medical treatment for research-related injuries will be made by Washington University School of Medicine. In general, Washington University School of Medicine will provide no long-term medical care or financial compensation for research-related injuries.
a phase 1 clinical trial
study termination

The principal investigator and the Siteman Cancer Center reserve the right to terminate the study. The principal investigator will notify the PRMC and HRPO in writing of the study's completion or early termination.
a phase 1 clinical trial
19 references

1. Siegel, R., et al., *Cancer statistics, 2014.* CA Cancer J Clin, 2014. 64(1): p. 9-29.  
2. Rahib, L., et al., Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res, 2014. 74(11): p. 2913-21.  
3. Conroy, T., et al., *FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.* N Engl J
Med, 2011. 364(19): p. 1817-25.  
4. Von Hoff, D.D., et al., Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med, 2013. 369(18): p. 1691-703.  
5. Jones, S., et al., *Core signaling pathways in human pancreatic cancers revealed by global* genomic analyses. Science, 2008. 321(5897): p. 1801-6.  
6. Clark, C.E., G.L. Beatty, and R.H. Vonderheide, Immunosurveillance of pancreatic adenocarcinoma: insights from genetically engineered mouse models of cancer. Cancer Lett, 2009. 279(1): p. 1-7.  
7. Clark, C.E., et al., Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res, 2007. 67(19): p. 9518-27.  
8. Mahadevan, D. and D.D. Von Hoff, *Tumor-stroma interactions in pancreatic ductal* adenocarcinoma. Mol Cancer Ther, 2007. 6(4): p. 1186-97.  
9. Porembka, M.R., et al., Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. Cancer Immunol Immunother, 2012. 61(9): p. 1373-85.  
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42. Boyer, J.D., et al., SIV DNA vaccine co-administered with IL-12 expression plasmid enhances CD8 SIV cellular immune responses in cynomolgus macaques. J Med Primatol, 2005. 34(5-6): p.  
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43. Chong, S.Y., et al., Comparative ability of plasmid IL-12 and IL-15 to enhance cellular and humoral immune responses elicited by a SIVgag plasmid DNA vaccine and alter disease progression following SHIV(89.6P) challenge in rhesus macaques. Vaccine, 2007. 25(26): p.  
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44. Hirao, L.A., et al., *Combined effects of IL-12 and electroporation enhances the potency of DNA*
vaccination in macaques. Vaccine, 2008. 26(25): p. 3112-20.  
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46. Luckay, A., et al., Effect of plasmid DNA vaccine design and in vivo electroporation on the resulting vaccine-specific immune responses in rhesus macaques. J Virol, 2007. 81(10): p. 525769.  
47. Otten, G., et al., *Enhancement of DNA vaccine potency in rhesus macaques by electroporation.*
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48. Otten, G.R., et al., Potent immunogenicity of an HIV-1 gag-pol fusion DNA vaccine delivered by in vivo electroporation. Vaccine, 2006. 24(21): p. 4503-9.  
49. Schadeck, E.B., et al., *A dose sparing effect by plasmid encoded IL-12 adjuvant on a SIVgagplasmid DNA vaccine in rhesus macaques.* Vaccine, 2006. 24(21): p. 4677-87.  
50. Rice, J., C.H. Ottensmeier, and F.K. Stevenson, *DNA vaccines: precision tools for activating* effective immunity against cancer. Nat Rev Cancer, 2008. 8(2): p. 108-20.  
51. Weiner, D.B., *DNA vaccines: Crossing a line in the sand Introduction to special issue.* Vaccine, 2008.  
52. Simon, R.M., et al., *Clinical trial designs for the early clinical development of therapeutic cancer* vaccines. J Clin Oncol, 2001. 19(6): p. 1848-54.  
53. Bowne, W.B., et al., *Coupling and uncoupling of tumor immunity and autoimmunity.* J Exp Med, 1999. 190(11): p. 1717-22.  
54. Hawkins, W.G., et al., Immunization with DNA coding for gp100 results in CD4 T-cell independent antitumor immunity. Surgery, 2000. 128(2): p. 273-80.  
55. Dunn, G.P., et al., *A critical function for type I interferons in cancer immunoediting.* Nat Immunol, 2005. 6(7): p. 722-9.  
56. Dunn, G.P., C.M. Koebel, and R.D. Schreiber, *Interferons, immunity and cancer immunoediting.*
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57. Dunn, G.P., L.J. Old, and R.D. Schreiber, *The three Es of cancer immunoediting.* Annu Rev Immunol, 2004. 22: p. 329-60.  
58. Shankaran, V., et al., IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature, 2001. 410(6832): p. 1107-11.  
59. Diamond, M.S., et al., Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J Exp Med, 2011. 208(10): p. 1989-2003.  
60. Dunn, G.P., et al., *Cancer immunoediting: from immunosurveillance to tumor escape.* Nat Immunol, 2002. 3(11): p. 991-8.  
61. Vesely, M.D., et al., *Natural innate and adaptive immunity to cancer.* Annu Rev Immunol, 2011.  
29: p. 235-71.  
62. Vesely, M.D. and R.D. Schreiber, *Cancer immunoediting: antigens, mechanisms, and* implications to cancer immunotherapy. Ann N Y Acad Sci, 2013. **1284**: p. 1-5.  
63. Klco, J.M., et al., Functional heterogeneity of genetically defined subclones in acute myeloid leukemia. Cancer Cell, 2014. 25(3): p. 379-92.  
64. Welch, J.S., et al., *The origin and evolution of mutations in acute myeloid leukemia.* Cell, 2012.  
150(2): p. 264-78.  
65. Ding, L., et al., *Genome remodelling in a basal-like breast cancer metastasis and xenograft.*
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67. Peters, B. and A. Sette, Generating quantitative models describing the sequence specificity of biological processes with the stabilized matrix method. BMC Bioinformatics, 2005. 6: p. 132.  
68. Lundegaard, C., et al., NetMHC-3.0: accurate web accessible predictions of human, mouse and monkey MHC class I affinities for peptides of length 8-11. Nucleic Acids Res, 2008. 36(Web Server issue): p. W509-12.  
69. Hoof, I., et al., *NetMHCpan, a method for MHC class I binding prediction beyond humans.*
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a phase 1 clinical trial
20 appendices

| Abbreviations   |                                                                                   |
|-----------------|-----------------------------------------------------------------------------------|
| AE              | Adverse Event                                                                     |
| CBER            | Center for Biologics Evaluation and Research                                      |
| CFR             | Code of Federal Regulations                                                       |
| CPA             | Cooperative Project Assurance                                                     |
| CR              | Complete response                                                                 |
| CRA             | Clinical Research Associate                                                       |
| CRF             | Case Report Form                                                                  |
| CT              | Computed Tomography                                                               |
| CTCAE           | Common Terminology Criteria for Adverse Events                                    |
| CTEP            | Cancer Therapy Evaluation Program                                                 |
| DNA             | Deoxyribonucleic acid                                                             |
| DCTD            | Division of Cancer Treatment and Diagnosis                                        |
| ELISPOT         | Enzyme-linked immunospot assay                                                    |
| ECOG            | Eastern Cooperative Oncology Group                                                |
| FDA             | Food and Drug Administration                                                      |
| FWA             | Federal-wide Assurance                                                            |
| GLP             | Good Laboratory Practice                                                          |
| GMP             | Good Manufacturing Practice                                                       |
| GPC             | Gel permeation chromatography                                                     |
| HIPAA           | Health Insurance Portability and Accountability Act                               |
| HLA             | Human leukocyte antigen                                                           |
| HRPO            | Human Research Protection Office (Institutional Review Board at WUSM)             |
| IBC             | Institutional Biosafety Committee                                                 |
| ICH             | International Conference of Harmonization                                         |
| IDB             | Investigational Drug Branch                                                       |
| IRB             | Institutional Review Board                                                        |
| LD              | Longest diameter                                                                  |
| MPA             | Multiple Project Assurance                                                        |
| MRI             | Magnetic Resonance Imaging                                                        |
| NCI             | National Cancer Institute                                                         |
| NIH             | National Institutes of Health                                                     |
| OBA             | Office of Biotechnology Activities                                                |
| OHRP            | Office for Human Research Protection                                              |
| PBMC            | Peripheral blood mononuclear cell                                                 |
| PD              | Progressive disease                                                               |
| PHI             | Protected Health Information                                                      |
| PR              | Partial response                                                                  |
| RAC             | Recombinant DNA Advisory Committee                                                |
| RECIST          | Response Evaluation Criteria in Solid Tumors                                      |
| QASMC           | Quality Assurance and Safety Monitoring Committee                                 |
| SAE             | Serious Adverse Event                                                             |
| SAS             | Statistical Analysis System; Analytical software from the SAS Institute, Cary, NC |
| SCC             | Siteman Cancer Center                                                             |
| SCIP            | Siteman Cancer Information Portal                                                 |
| SD              | Stable disease                                                                    |
| SD              | Standard Deviation                                                                |
| THF             | Tetrahydrofuran                                                                   |
| UPN             | Universal Product Number                                                          |
| WUSM            | Washington University School of Medicine                                          |
| WUSTL           | Washington University in Saint Louis                                              |
a phase 1 clinical trial
ecog/zubrod performance status scale

| ECOG/Zubrod Score   | Performance Status                                     |
|---------------------|--------------------------------------------------------|
| 0                   | Asymptomatic                                           |
| 1                   | Symptomatic, fully ambulatory                          |
| 2                   | Symptomatic, in bed < 50% of the day                   |
| 3                   | Symptomatic, in bed > 50% of the day but not bedridden |
| 4                   | Bedridden                                              |
| 5                   | Dead                                                   |
a phase 1 clinical trial
national cancer institute common terminology

This study will collect adverse events using the NCI Common Terminology Criteria for Adverse Events v4.0 (CTCAE), if applicable. The CTCAE provides a descriptive terminology that is to be used for adverse event reporting. A grading (severity) scale is also provided in the CTCAE for each adverse event term. An electronic version of the CTCAE may be accessed through the web at http://ctep.cancer.gov. Alternatively, a full copy is available from the principal investigator.
a phase 1 clinical trial
20.4 appendix a definitions for

Definition: any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related.  
Grading: the descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting. A copy of the CTCAE version 5.0 can be downloaded from the CTEP website.  
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms listed that should be used are those provided by the Department of Health and Human Services' Office for Human Research Protections (OHRP). A copy of this guidance can be found on OHRP's website: http://www.hhs.gov/ohrp/policy/advevntguid.html
a phase 1 clinical trial
b. suspected adverse reaction (sar)

As defined in 21 CFR 312.32:
Definition: any adverse event for which there is a reasonable possibility that the drug caused the adverse event. "Reasonable possibility" means there is evidence to suggest a causal relationship between the drug and the adverse event. "Suspected adverse reaction" implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.
a phase 1 clinical trial
c. life-threatening adverse event /

As defined in 21 CFR 312.32:
Definition: any adverse drug event or suspected adverse reaction is considered "life-threatening" if, in the view of the investigator, its occurrence places the patient at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death.
a phase 1 clinical trial
d. serious adverse event (sae)

Definition: an adverse event or suspected adverse reaction is considered "serious" if, in the view of the investigator, it results in any of the following outcomes:
o Death  
o A life-threatening adverse event o Inpatient hospitalization or prolongation of existing hospitalization o A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions o A congenital anomaly/birth defect o Any other important medical event that does not fit the criteria above but, based upon appropriate medical judgment, may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed above E. **Protocol Exceptions**
Definition: A planned change in the conduct of the research for one participant.
a phase 1 clinical trial
f. deviation

Definition: Any alteration or modification to the IRB-approved research without prospective IRB approval.  
The term "research" encompasses all IRB-approved materials and documents including the detailed protocol, IRB application, consent form, recruitment materials, questionnaires/data collection forms, and any other information relating to the research study. A minor or administrative deviation is one that does not have the potential to negatively impact the rights, safety, or welfare of participants or others or the scientific validity of the study. A major deviation is one that does have the potential to negatively impact the rights, safety, or welfare of participants or others or the scientific validity of the study.
a phase 1 clinical trial
20.5 appendix b reporting timelines

| Expedited Reporting Timelines                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                |     |     |                       |
|---------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------|-----|-----|-----------------------|
| Event                                                                           | HRPO                                                                                                                                                                                                                                                                                                                                                                                                                     | QASMC                                                                                                                          | FDA | IBC | Ichor Medical Systems |
| Serious AND  unexpected suspected  adverse reaction                             | Since the TDS-IM device  may be involved with the  occurrence of adverse  events, Ichor Medical  Systems will be included  in the Adverse Event  reporting plan. Reports to  Ichor for SAEs or for  adverse events with  possible relationship to the  device should follow the  timing for reporting to the  WUSM Human Research  Protection Office and  should be directed to  Drew Hannaman at  dhannaman@ichorms.com |                                                                                                                                |     |     |                       |
| Unexpected fatal or  life-threatening  suspected adverse  reaction              | Report no later than 15  calendar days after it is  determined that the  information qualifies for  reporting                                                                                                                                                                                                                                                                                                            | Report at time of  HRPO submission;  IBC will retrieve  information from  myIRB and will  follow up with study  team if needed |     |     |                       |
| Report no later than 7  calendar days after initial  receipt of the information |                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                |     |     |                       |
| Unanticipated  problem involving risk  to participants or  others               | Report within 10 working days.  If the event results in the death  of a participant enrolled at  WU/BJH/SLCH, report within  1 working day.                                                                                                                                                                                                                                                                              | Report via email after  IRB acknowledgment                                                                                     |     |     |                       |
| Major deviation                                                                 | Report within 10 working days.  If the event results in the death  of a participant enrolled at  WU/BJH/SLCH, report within  1 working day.                                                                                                                                                                                                                                                                              |                                                                                                                                |     |     |                       |
| A series of minor                                                               | Report within 10 working days.                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                |     |     |                       |  
| Expedited Reporting Timelines                                                                                             |                                                                                                                                                                                                                                                                                                                     |       |     |     |                       |
|---------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------|-----|-----|-----------------------|
| Event                                                                                                                     | HRPO                                                                                                                                                                                                                                                                                                                | QASMC | FDA | IBC | Ichor Medical Systems |
| deviations that are  being reported as a  continuing  noncompliance Protocol exception                                    | Approval must be obtained  prior to implementing the  change                                                                                                                                                                                                                                                        |       |     |     |                       |
| Clinically important  increase in the rate of  a serious suspected  adverse reaction of  that list in the protocol  or IB | Report no later than 15  calendar days after it is  determined that the  information qualifies for  reporting                                                                                                                                                                                                       |       |     |     |                       |
| Complaints                                                                                                                | If the complaint reveals an  unanticipated problem  involving risks to participants  or others OR noncompliance,  report within 10 working days.  If the event results in the death  of a participant enrolled at  WU/BJH/SLCH, report within  1 working day. Otherwise,  report at the time of continuing  review. |       |     |     |                       |
| Breach of                                                                                                                 | Within 10 working days.                                                                                                                                                                                                                                                                                             |       |     |     |                       |
| confidentiality Incarceration                                                                                             | If withdrawing the participant  poses a safety issue, report  within 10 working days.  If withdrawing the participant  does not represent a safety issue  and the patient will be                                                                                                                                   |       |     |     |                       |  
| Expedited Reporting Timelines                                                                                                      |                                                                                                                                                                                                                                                                                                                 |                                                                                                                    |     |                       |                       |
|------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------|-----|-----------------------|-----------------------|
| Event                                                                                                                              | HRPO                                                                                                                                                                                                                                                                                                            | QASMC                                                                                                              | FDA | IBC                   | Ichor Medical Systems |
| withdrawn, report at continuing  review.                                                                                           | Routine Reporting Timelines                                                                                                                                                                                                                                                                                     |                                                                                                                    |     |                       |                       |
| Event                                                                                                                              | HRPO                                                                                                                                                                                                                                                                                                            | QASMC                                                                                                              | FDA | Ichor Medical Systems |                       |
| Adverse event or SAE  that does not require  expedited reporting                                                                   | The most current  toxicity table from the  DSM report is provided  to the FDA with the  IND's annual report.                                                                                                                                                                                                    |                                                                                                                    |     |                       |                       |
| Minor deviation                                                                                                                    | Report summary information at the time of  continuing review.                                                                                                                                                                                                                                                   |                                                                                                                    |     |                       |                       |
| Complaints                                                                                                                         | If the complaint reveals an unanticipated problem  involving risks to participants or others OR  noncompliance, report within 10 working days. If  the event results in the death of a participant  enrolled at WU/BJH/SLCH, report within 1  working day. Otherwise, report at the time of  continuing review. |                                                                                                                    |     |                       |                       |
| Incarceration                                                                                                                      | If withdrawing the participant poses a safety  issue, report within 10 working days.  If they do not meet the definition of an  unanticipated problem involving risks to  participants or others, report summary  information at the time of continuing review                                                  | Adverse events will be  reported in the toxicity  table in the DSM report  which is typically due  every 6 months. |     |                       |                       |
| If withdrawing the participant does not represent a  safety issue and the patient will be withdrawn,  report at continuing review. |                                                                                                                                                                                                                                                                                                                 |                                                                                                                    |     |                       |                       |  
| Expedited Reporting Timelines for Secondary Sites                               |                                                                                           |                                                                                                                         |     |                       |
|---------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------|-----|-----------------------|
| Event                                                                           | WU (Coordinating Center)                                                                  | Local IRB                                                                                                               | FDA | Ichor Medical Systems |
| Serious AND unexpected                                                          | Report no later than 11 calendar days                                                     |                                                                                                                         |     |                       |
| suspected adverse reaction                                                      | after it is determined that the information  qualifies for reporting.                     | The research team at  Washington University is  responsible for reporting all                                           |     |                       |
| Unexpected fatal or lifethreatening suspected                                                                                 | applicable events to Ichor as  needed.                                                    |                                                                                                                         |     |                       |
| adverse reaction                                                                | Report all applicable  events to local IRB  according to local  institutional guidelines. | The research team at  Washington University is  responsible for reporting all  applicable events to the  FDA as needed. |     |                       |
| Report no later than 4 calendar days after  initial receipt of the information. |                                                                                           |                                                                                                                         |     |                       |
| Unanticipated problem  involving risk to participants  or others                | Report no later than 4 calendar days after  initial receipt of the information.           |                                                                                                                         |     |                       |
| Adverse event or SAE that  does not require expedited  reporting                | As per routine data entry expectations                                                    |                                                                                                                         |     |                       |
| Protocol exception                                                              | Approval must be obtained prior to  implementing the change.                              |                                                                                                                         |     |                       |
a phase 1 clinical trial
20.6 appendix c washington university

SAE COVER SHEET- Secondary Site Assessment  
Washington University HRPO#: Sponsor-Investigator: Subject Initials: Subject ID: Treating MD: Treating Site: EVENT TERM: Admission Date: EVENT GRADE: Date of site's first notification:  
Treating MD Event Assessment:
Is this event **possibly, probably, or definitely** related study treatment?  
yes no If yes, please list which drug (if more than one)______________________________ Explain ______________________________________________________________________  
_________________________ ___________________________ _________________ Physician's Name Physician's Signature Date