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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. Amanda Cashen, Chair 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.
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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.
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19 references

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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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22. Echchakir, H., et al., A point mutation in the alpha-actinin-4 gene generates an antigenic peptide recognized by autologous cytolytic T lymphocytes on a human lung carcinoma.  
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27. Rammensee, H., et al., *SYFPEITHI: database for MHC ligands and peptide motifs.*
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30. Bijker, M.S., et al., Superior induction of anti-tumor CTL immunity by extended peptide vaccines involves prolonged, DC-focused antigen presentation. Eur J Immunol, 2008.  
38(4): p. 1033-42.  
31. Sabbatini, P., et al., Phase I trial of overlapping long peptides from a tumor self-antigen and poly-ICLC shows rapid induction of integrated immune response in ovarian cancer patients. Clin Cancer Res, 2012. 18(23): p. 6497-508.  
32. 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.  
33. Ott, P.A., et al., An immunogenic personal neoantigen vaccine for patients with melanoma. Nature, 2017. 547(7662): p. 217-221.  
34. Dunn, G.P., et al., *A critical function for type I interferons in cancer immunoediting.* Nat Immunol, 2005. 6(7): p. 722-9.  
35. Dunn, G.P., C.M. Koebel, and R.D. Schreiber, *Interferons, immunity and cancer* immunoediting. Nat Rev Immunol, 2006. 6(11): p. 836-48.  
36. Dunn, G.P., L.J. Old, and R.D. Schreiber, *The three Es of cancer immunoediting.* Annu Rev Immunol, 2004. 22: p. 329-60.  
37. Shankaran, V., et al., *IFNgamma and lymphocytes prevent primary tumour development* and shape tumour immunogenicity. Nature, 2001. 410(6832): p. 1107-11.  
38. 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.  
39. Dunn, G.P., et al., *Cancer immunoediting: from immunosurveillance to tumor escape.*
Nat Immunol, 2002. 3(11): p. 991-8.  
40. Vesely, M.D., et al., *Natural innate and adaptive immunity to cancer.* Annu Rev Immunol, 2011. 29: p. 235-71.  
41. 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.  
42. 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.  
43. 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.  
44. Hoof, I., et al., *NetMHCpan, a method for MHC class I binding prediction beyond* humans. Immunogenetics, 2009. 61(1): p. 1-13.  
45. Nielsen, M., et al., The role of the proteasome in generating cytotoxic T-cell epitopes:
insights obtained from improved predictions of proteasomal cleavage. Immunogenetics, 2005. 57(1-2): p. 33-41.  
46. Jaramillo, A., et al., *Identification of HLA-A3-restricted CD8+ T cell epitopes derived* from mammaglobin-A, a tumor-associated antigen of human breast cancer. Int.J.Cancer, 2002. 102(5): p. 499.  
47. Jaramillo, A., et al., *Recognition of HLA-A2-restricted mammaglobin-A-derived epitopes* by CD8+ cytotoxic T lymphocytes from breast cancer patients. Breast Cancer Res.Treat.,
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48. Manna, P.P., et al., Generation of CD8+ cytotoxic T lymphocytes against breast cancer cells by stimulation with mammaglobin-A-pulsed dendritic cells. Breast Cancer Res.Treat., 2003. 79(1): p. 133.  
49. Narayanan, K., et al., *Response of established human breast tumors to vaccination with* mammaglobin-A cDNA. J.Natl.Cancer Inst., 2004. 96(18): p. 1388.  
50. Hobeika, A.C., et al., Enumerating antigen-specific T-cell responses in peripheral blood:
a comparison of peptide MHC Tetramer, ELISpot, and intracellular cytokine analysis. J
Immunother, 2005. 28(1): p. 63-72.  
51. Andersen, R.S., et al., Parallel detection of antigen-specific T cell responses by combinatorial encoding of MHC multimers. Nat Protoc, 2012. 7(5): p. 891-902.  
52. Cheung, R.K. and P.J. Utz, *Screening: CyTOF-the next generation of cell detection.* Nat Rev Rheumatol, 2011. 7(9): p. 502-3.  
53. Westfall, P.H. and S.S. Young, *Resampling-Based Multiple Testing: Examples and* Methods for p-Value Adjustment. 1993, New York: John Wiley & Sons, Inc.
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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                                              |
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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                                                   |
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national cancer institute common terminology

This study will collect adverse events using the NCI Common Terminology Criteria for Adverse Events v5.0 (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.
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definitions for adverse event reporting

As defined in 21 CFR 312.32:
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
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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.
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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.
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d. serious adverse event (sae)

As defined in 21 CFR 312.32:  
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
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e. protocol exceptions

Definition: A planned change in the conduct of the research for one participant.
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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. **(A2)**
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reporting timelines

| Reporting Timelines                                                                                                     | Expedited Reporting Timelines                                                                                                                                                                                                                                                                                    |                                            |     |
|-------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------|-----|
| Event                                                                                                                   | HRPO                                                                                                                                                                                                                                                                                                             | QASMC                                      | FDA |
| Serious AND unexpected                                                                                                  | Report no later than 15 calendar days after it                                                                                                                                                                                                                                                                   |                                            |     |
| suspected adverse reaction                                                                                              | is determined that the information qualifies for  reporting                                                                                                                                                                                                                                                      |                                            |     |
| Unexpected fatal or life-threatening                                                                                    | Report no later than 7 calendar days after                                                                                                                                                                                                                                                                       |                                            |     |
| suspected adverse reaction                                                                                              | initial receipt of the information                                                                                                                                                                                                                                                                               |                                            |     |
| Unanticipated problem involving                                                                                         | Report within 10 working days. If the event                                                                                                                                                                                                                                                                      |                                            |     |
| risk to participants or others                                                                                          | 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 deviations that  are being reported as a continuing  noncompliance                                    | Report within 10 working days.                                                                                                                                                                                                                                                                                   |                                            |     |
| 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 confidentiality                                                                                               | Within 10 working days.                                                                                                                                                                                                                                                                                          |                                            |     |
| 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                                                                                                                                     |                                            |     |  
**(A2)**
be withdrawn, report at continuing review.  
| Routine Reporting Timelines                                      |                                                                                                                                                                                                                                                                                                                 |                                                                                                                   |                                                                                                            |
|------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------|
| Event                                                            | HRPO                                                                                                                                                                                                                                                                                                            | QASMC                                                                                                             | FDA                                                                                                        |
| Adverse event or SAE  that does not require  expedited reporting | 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. | 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 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                                                                          |
| Serious AND unexpected                              | Report no later than 11 calendar days after it is                               | Report all applicable events                                |                                                                              |
| suspected adverse reaction                          | determined that the information qualifies for reporting.                        | to local IRB according to  local institutional  guidelines. | The research team at Washington  University is responsible for reporting all |
| Unexpected fatal or lifethreatening suspected adverse                                                     | applicable events to the FDA as  needed.                                        |                                                             |                                                                              |
| reaction                                            | Report no later than 4 calendar days after initial receipt  of the information. |                                                             |                                                                              |
| Unanticipated problem involving                     | Report no later than 4 calendar days after initial receipt                      |                                                             |                                                                              |
| risk to participants or others                      | of the information.                                                             |                                                             |                                                                              |
| Adverse event or SAE that does                      | As per routine data entry expectations                                          |                                                             |                                                                              |
| not require expedited reporting Protocol exception  | Approval must be obtained prior to implementing the  change.                    |                                                             |                                                                              |
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washington university unanticipated problem reporting

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