329 -330. 7866/135 08/23/2021 Page 31 of 39 Appendix A Zubrod Performance Scale Performance status will be assessed according to the current ECOG performance scale* Grade Description 0 Fully active, able to carry on all pre -disease performance without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2 Ambulatory and capable of all self -care but unable to carry out any work activities. Up and about more than 50% of waking hours 3 Capable of only limited self -care, confined to bed or chair more than 50% of waking hours 4 Completely disabled. Cannot carry on any self -care. Totally confined to bed or chai r 5 Dead Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649- 655, 1982. *The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 7866/135 08/23/2021 Page 32 of 39 Appendix B Schedule of Events Visit Time Point Procedures Vaccine #1: Day 1 (First Visit) • Consent • Medical history, physical examination, symptom assessment and medication/supplement changes • Clinical Labs: CBC and CMP • Vital signs and weight • Urine pregnancy test if applicable • Research Labs: 200 mls for immunologic monitoring • Tetanus -diphtheria (Td) immunization • HER2 Vaccination • Administration of total daily dose of PSK or placebo then 10 ml blood draw 30 minutes and 4 hours post -administration for cytokine kinetics Vaccine #1: Day 2 • Research Labs: 10 mls for cytokine kinetics at CRC then take Day 2 dose of PSK or placebo as instructed • Take home 30 day supply plus 7 additional days of PSK or placebo Vaccine #1: Day 2 until Vaccine #2 visit • PSK or placebo daily as instructed and complete daily tea diary Vaccine #2: Day 1 • Interim medical history, physical examination, vital signs and weight • Symptom/toxicity assessment and medication/supplement changes • Review tea diary • Clinical Labs: CBC and CMP • Research Labs: 40 mls for immunologic monitoring • Urine pregnancy test if applicable • HER2 Vaccination • Take home 30 day supply plus 7 additional days of PSK or placebo Vaccine #2: Day 1 until Vaccine #3 visit • PSK or placebo daily as instructed and complete daily tea diary Vaccine #3: Day 1 • Interim medical history, physical examination, vital signs and weight • Symptom/toxicity assessment and medication/supplement changes • Review tea diary • Clinical Labs: CBC and CMP • Research Labs: 4 0 mls for immunologic monitoring • Urine pregnancy test if applicable • HER2 Vaccination • Take home of 30 day supply plus 7 additional days of PSK or placebo Vaccine #3: Day 1 until Month 4 visit • PSK or placebo daily as instructed and complete daily tea diary Month 4 (1 month after the last vaccine) • Interim medical history, physical examination, vital signs and weight • Symptom/toxicity assessment and medication/supplement changes • Review tea diary • Clinical Labs: CBC and CMP • Research blood: 200 mls • Take home of 30 day supply of PSK or placebo Month 4 : Day 1 until Month 5 visit • PSK or placebo daily as instructed and complete daily tea diary Month 5 (2 months after the last vaccine) • Research Labs: 40 mls for immunologic monitoring • Send tea diary to study nurse Month 6 (3 months after the last vaccine) • Collection of recent oncologist notes and lab results • Collection of recent imaging reports if available Month 12 (9 months after last vaccine) • Research blood: 200 mls • Collection of physician notes including most recent lab results and imaging reports May be done up to 2 weeks prior to initial vaccine visit Clinical Labs: Complete blood count (CBC) includes differential/platelets; and Comprehensive Metabolic Panel (CMP) includes serum electrolytes, creatinine, BUN, AST, ALT, alkaline phosphatase, total bilirubin 7866/135 08/23/2021 Page 33 of 39 Appendix C Data Safety Monitoring Plan A. Purpose To ensure that the Tumor Vaccine Group (TVG) follows NIH/NCI/CTEP/FDA guidelines with respect to: (1) accurate assessment and timely reporting of adverse drug reactions associated with investigational drugs, (2) adherence to protocol, and (3) accurate reporting of data. The DSMP will be approved by Fred Hutchinson Cancer Research Center – Cancer Consortium IRB (FHCRC – CC IRB) in Seattle, Washington. The Principal Invest igator (P.I.) , for this project, is responsible for every aspect of the design, delegating responsibility/authority, study conduct and final analysis of the protocol. Regulations defining the responsibilities for assessment and reporting of adverse events (AE), serious AE (SAE), and unexpected AEs are defined by the Code of Federal Regulations: 21 CFR 312.32 and Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 published by the Cancer Therapy Evaluation Program (CTEP), a division of the N CI/NIH. A matrix of reporting requirements and schedules is at the CTEP web- site at http://ctep.infi.nih/gov . This clinical study will rely upon the monitoring of the trial by the P.I. in conjunction with a Research Nurse, a Statistician, an Independent Medical Monitor, and an Independent Study Monitor assigned by the Clinical Trials Support Office (CTSO) of the University of Washington (UW)/Fred Hutchinson Cancer Research Center (FHCRC) Cancer Consortium. The Medical Monitor , Robert Montgomery, M.D. will meet openly with the P.I. and/or their designee, Statistician, Research Nurse, Research MD and/or Research Coordinator(s) prior to patients being recruited in order to orient committee participants to the study . The Medical Monitor will then discuss the study every 6 months throughout the study treatment period with the P.I., Research MD(s), Research Nurse(s), Research Coordinator(s), and/or other related clinical research staff. The Medical Monitor will review patient recruitment and retention, adherence to protocol, follow -up, data quality, and participant risk versus benefit. B. Objectives 1. To ensure that the Principal Investigator and clinical research staff follow federal and institutional regulatory guideli nes with respect to timely reporting of adverse reactions associated with investigational drugs. 2. To define classification of adverse drug reactions as expected or unexpected. 3. To define classification of adverse drug reactions as serious or non- serious. 4. To ensure compliance and accuracy of documentation of adverse drug reactions reportable to: (1) FHCRC – CC IRB , (2) FDA , (3) UW Clinical Research Center, (4) Independent Medical Monitor and (5) NIH - NCCAM . C. Adverse event reporting policy and procedures 1. Evaluation of adverse events: AEs are graded on a scale of 1- 5 and attribution is assigned, using the CTCAE v4 common terminology. Patients are monitored at: (1) eligibility, (2) at each vaccination visit, and (3) at Month 4, for the development of end organ damage by assessing AEs with serum chemistries, liver function studies, complete blood counts and physical exams. Information pertaining to toxicity is recorded into a database AE Log. 2. Definitions of adverse events: Adverse Event - any unfavorable and unintended sign (including abnormal laboratory finding* ), symptom or disease temporally associated with the use of a medical treatment or procedure regardless of whether it is considered related to the medical trea tment or procedure. 7866/135 08/23/2021 Page 34 of 39 a. An adverse event may include: • an exacerbation of a pre -existing illness • an increase in frequency or intensity of a pre- existing episodic event or condition • a condition detected or diagnosed after study drug administration • continuously persistent disease or symptoms that were present at baseline and worsen following the start of the study • *An abnormal laboratory value will be considered an AE if the laboratory abnormality is characterized by any of the following: o Results in discontinuation from the study; o Is associated with clinical signs or symptoms; o Requires treatment or any other therapeutic intervention; o Is associated with death or another serious adverse event, including hospitalization; or o Is judged by the Investigator to be of significant clinical impact. If any abnormal laboratory result is considered clinically significant, the investigator will provide details about the action taken with respect to the test drug and about the patient’s outcome. b. An adverse event does not include: • medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, or transfusion); however, the condition that leads to the procedure may be an adverse event • pre-existing diseases, conditions, or laboratory abnormalities present or detected at the start of the study that do not worsen • hospitalizations or procedures that are done for elective purposes not related to an untoward medical occurrence (e.g., hospitalizations for cosmetic or elective surgery or social/convenience admis sions) • the disease being studied or signs/symptoms associated with the disease unless more severe than expected for the patient's condition • overdose of study drug without any clinical signs or symptoms c. Expected Adverse Event - an event that may be reasonably anticipated to occur as a result of the study procedure and is described in the Investigators Brochure and/or consent form. d. Unexpected Adverse Event - an AE that is not described in the investigator brochure and/or consent form and is unanticipated. An event that might have been anticipated but is more serious than expected or occurs more frequently than expected, would be considered an unexpected AE. e. Life-threatening Adverse Event - the patient was at substantial risk of dying at the time of the AE or it is suspected that the use or continued use of the product would have resulted in the patient’s death. f. Serious Adverse Event - grade 4 or 5 toxicity or any AE occurring at any dose that results in any of the following outcomes: death, a life threatening AE, inpatient hospitalization or prolongation of existing hospitalization due to the AE, a persistent or significant disability/incapacity or a congenital anomaly/birth defect that is unexpected and unrelated. g. Hospitalizations that do not meet these criteria are: • reasons described in the protocol, e.g., drug administration, protocol -required testing • social reason in the absence of an AE • surgery or procedure planned prior to entry into the trial Note: Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations; for example, important medical events may not be immediately life - 7866/135 08/23/2021 Page 35 of 39 threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the outcomes listed in the definition above. Any AE is considered a serious AE if it is associated with clinical signs or symptoms judged by the investigator to have a significant clinical impact. 3. Adverse event score a. Grade 1 = mild adverse event b. Grade 2 = moderate adverse event c. Grade 3 = severe adverse event d. Grade 4 = life -threatening or disabling adverse event e. Grade 5 = death related to adverse event. 4. Attribution of adverse event a. 5 (definite): the adverse event is clearly related to the investigational agent b. 4 (probable): the adverse event is likely related to the investigational agent c. 3 (possible): the adverse event may be related to the investigational agent d. 2 (unlikely): the adverse event is doubtfully related to the investigational agent e. 1 (unrelated): the adverse event is clearly NOT related to the investigational agent 5. Adverse event reporting This procedure is outlined below by regulatory agency (Table 1). Fred Hutchinson Cancer Research Center: Cancer Consortium IRB - We will follow the current AE reporting policy of the FHCRC – CC IRB. FDA (for trials using an Investigational New Drug (IND) – Adverse events will be reported per 21 CFR 312.32 by telephone or facsimile transmission (using MedWatch Form 3500A) as soon as possible but no later than 7 calendar days after initial receipt of the information concerning the event. All unexpected, serious adverse events are reported in w riting (using MedWatch Form 3500A) to the FDA (Center for Biologics) within 15 calendar days after initial receipt of the information concerning the event. Yearly written progress reports to the FDA will summarize expected or non -serious unexpected AEs. NCCAM – Serious adverse events will be reported to NCCAM Program Officer within 24 hours of FDA notification. A copy of the documents submitted to the FDA will also be submitted to NCCAM within 7- 15 calendar days. Submit written summaries of all reviews conducted by the monitoring group to the responsible NCCAM Program Officer within 30 days of reviews or meetings. If reviews are frequent, quarterly reports are sufficient. University of Washington Clinical Research Center (UW CRC) – The CRC will receive c opies of the documents submitted to the FHCRC – CC IRB within 7 -10 calendar days. Independent Medical Monitor - At a minimum, the medical monitor should comment on the outcomes of serious adverse event(s) and relationship of the AE to the vaccine or prepar e an unbiased written report of the event. They should also indicate whether they agree with the details of the report provided by the study investigator.