Imaging studies and other relevant test for determining disease status will be obtained, if necessary. 5.0 STUDY MATERIALS AND PROCEDURES 5.1 Products 5.1.1 TAPA- Pulsed Dendritic Cells (DCs) The procedure for generating TAPA -pulsed DCs suitable for clinical use will be carried out at Kiromic’s Cell Processing laboratory specifically designed for the generation of GMP clinical grade cellular materials. DCs will be derived from monocyte precursors present in peripheral blood mononuclear cells (PBMC) cultures following phlebotomy and/or leukapheresis. PBMC will be separated by Ficoll gradients and/or CliniMACs separation system and cultured in CellGro medium (CellGenix, USA), IL -4 and GM -CSF (CellGenix, USA) for up to seven (7) days. DCs will be grown in culture flasks and/or G- Rex growth system and vaccine will be prepared by exposing DCs to a maturation cytokine cocktail (IL -1β and TNFα (CellGenix, USA), poly ( I: C) (InvivoGen, USA) and INFα for 16-72 hrs. DCs will then be “pulsed” with relevant, recombinant TAPAs for 2- 4 hours. Successful generation of mature DCs will be confirmed in each case by immunophenotyping for classical DC markers, including CD1a, CD58 , CD80, CD83, CD86 and HLA -DR. Recombinant, clinical grade TAPAs will be obtained from CS Bio Company, Inc. a company specialized in manufacturing cGMP peptides located at 20 KELLY CT. Menlo Park, CA 94025. Following the maturation period DCs will be aliquoted into six or more equal volumes for cryopreservation until further use. Alternatively, one DC vaccine dose will be manufactured, with additional doses prepared subsequently from cryopreserved PBMNCs. DCs may also be generated following the same but inverted procedure (TAPA pulsing prior to exposure to maturation cytokine cocktail, See SOP). All reagents and plastics to be used for this purpose will be stored at Kiromic’s GMP laboratory and used solely for the DC generation and maturation process. A ll procedures will be carried out in sterile conditions and the final products will be evaluated by an independent CLIA -certified laboratory for sterility, including presence of endotoxin, mycoplasma contamination, fungal, aerobic and anaerobic bacterial cultures and Gram staining, prior to human administration. Results of these tests will be obtained prior to release of the final product for human administration. Mature DCs (or PBMCs for later generation of fresh mature DCs) will be cryopreserved and stored in a dedicated liquid KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 31 of 47 nitrogen container at Kiromic , until being used. 5.2 Storage and Drug Accountability 5.2.1 TAPA- Pulsed Dendritic Cells (DCs) 1. A minimum of three (3) and a maximum of six (6) vials of TAPA -pulsed DCs (containing up to 1 X 107 DCs each) will be cryopreserved as a master vaccine bank for each patient. TAPA-pulsed DC vaccine will be frozen in 90% heat- inactivated normal human AB serum and 10% dimethyl sulfoxide. Alternatively, an aliquot of the original pool of PBMCs will be cr yopreserved , as described above, for subsequent thawing and generation of fresh DCs prior to each vaccination schedule (see SOP). This process may improve the viability of DCs. A dedicated liquid nitrogen storage container will be used exclusively for patient PBMCs and DC vaccine preparations for this study. 2. All specimens and vaccines will be transported to/from the participating institution in compliance with standard biohazard protocol. 6.0 TREATMENT 6.1 Selection of TAPA -Pulsed DC Dose Level 6.1.1 Rationale A phase I dose escalation clinical trial of DC vaccination in patients with cervical cancer indicated optimal stimulation of tumor antigen -specific cytotoxic T cell responses with a dose of up to 1.0 x 107 DCs and delivered SC and ID at 21 day intervals (10). Thus, in this study we will explore one (1) dose of TAPA -pulsed DC vaccination (up to 1 X 107 DCs) and determine the toxicity, immune efficacy (IE) and clinical response in patients with progressive and /or refractory SM without available, potentially curative therapeutic options. Preliminary studies indicate that leukapheresis (10 -liter volume) followed by CliniMACS isolation of CD14+ cells and high-density DC culture in G -Rex flasks provides an optimal yield of 2.5 x10 8 mature DCs from 109 CD14+ cells. This would be sufficient for cryopreservation of 12 vials at 1 x107 DC/vial. Phlebotomy of 250 mL of whole blood yields approximately 1.2 X 108 monocytes and 3 X 107 mature DCs (see Section 7.2). The CliniMACS separation system and the G -Rex DC growth system may be used as an alternative to Ficoll-gradient monocyte separation and standard DC growth protocol using flasks. 6.1.2 TAPA-Pulsed DC Vaccination This is a phase I/II safety and efficacy study. Only one dose level of TAPA -pulsed DC will be used. KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 32 of 47 Dose Level Minimal Number of Patients DCs per Vaccination 1 6 1 x 107 The first six (6) patients will receive up to 1 x 107 DCs divided into 4 intradermal (ID) injections, every seven (7) days, for up to a maximum of six three (3) treatments. The (ID) DC vaccinations will be administered in an approximate volume of 0.25 ml per injection site (total vaccination dose -volume 1.0 ml). Thirty minutes prior to receiving the DC vaccination, all patients will receive premedication with diphenhydramine (12.5- 50 mg) and acetaminophen (325 -1000 mg) orally. Topical lidocaine based anesthetic applications may also be administered prior to the vaccination at the discretion of the study coordinator. During the Phase I stage of this study up to six (6) consecutive subjects will be enrolled. If one (1) or less than six (6) patients develops DLT, the Phase II/immune efficacy stage will proceed. If two or more (≥ 2) of the first six (6) patients develop DLTs, the study will be terminated. A minimum of six (6) patients will be treated for evaluation of safety/toxicity (Phase I level). If toxicity criteria f or continuation is fulfilled during the phase I stage, patient enrollment in the Phase II/immune efficacy stage may proceed. Up to seventeen (17) patients will be treated in the study for evaluation of immune efficacy and possible clinical response (Phase II stage ), with IE determined following completion of three (3) DC vaccine doses (day 22 and day 45). 6.1.3. Imiquimod Treatment Following each DC vaccination, the patient will receive a single dose of Imiquimod cream. 6.2 Study Drug Administration 6.2.1 Cyclophosphamide (CYP) The patient will receive a 5-day course of CYP ( 1.6 mg/kg/day with maximum dose of 100 mg/day ), which may be taken at home, beginning 5-7 days prior to each DC vaccination. 6.2.2 TAPA- Pulsed Dendritic Cells (DC) TAPA-pulsed DC will be administered at a vaccine dose of up to 1 x 107 DC, in injection -grade saline solution to bring total volume to 1 mL, if necessary. The vaccine volume will be up to 1.0 mL and will be administered in 4 separate intradermal (ID) injections at the 12 o’clock, 3 o’clock, 6 o’clock and 9 o’clock positions in the upper outer arm or the upper anterior thigh region) in order to increase proximity to local lymph node draining basins and optimize propagation of TAPA -pulsed DCs to secondary lymphoid organs. Thus approximately 0.25 mL will be injected at each injection site (total volume 1.0 mL). Axillary lymph node region area is the preferred vaccination site for this study. DC vaccination will be alternated between the upper outer arm, and upper anterior thigh of both limbs. T hree (3) DC vaccines will be administered at 7-day intervals . Patients may be observed for up to one (1) to three (3) hours following each vaccine dose administration . KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 33 of 47 6.3 Study Drug Quality and Safety Measures 6.3.1 TAPA- Pulsed Dendritic Cells (DCs) 1. TAPA- pulsed DCs will be administered ID at 7-day intervals . plus or minus 2 days. 2. Safety tests before release of TAPA -pulsed DCs: a. Bacterial and fungal sterility test. b. Mycoplasma test. c. Endotoxin test: Endotoxin must be less than 1 IU/ml by the LAL method. 3. Plan of action in the event of DC vaccine test failures: a. If a sterility and/or endotoxin test is positive, the vaccine dose will be discarded. A second dose of DC vaccine will be thawed and tested. If test results on the second dose are negative, the patient will receive treatment. If test results on the second dose are positive, the entire batch of DC vaccine will be discarded, and the patient will be withdrawn from study. b. In the unlikely event that a dose gives a positive result by bacterial growth test (agar sterility test) after administration to the patient, the patient’s physician will be notified immediately, with the recommendation that the patient be treated with antibio tics, even if the patient shows no clinical signs of infection. A second DC vaccine dose will be thawed and subjected to the bacterial growth test. If the second dose tests positive, the DC vaccine batch will be discarded, and treatment discontinued. If the second dose tests negative, patient treatment will proceed. c. If an entire DC vaccine batch is discarded, treatment may proceed if it is possible to prepare a new vaccine batch (usually contingent on a second leukapheresis/phlebotomy procedure). 4. All clinical laboratory tests will be performed in a CLIA certified facility. 6.4 Specific Restrictions and Requirements 6.4.1 Concomitant Therapy 1. Immunosuppressive or anti -inflammatory drugs (including hydrocortisone) that inhibit cellular immune responses should not be taken, unless otherwise indicated for the management of study -related toxicities, adverse events, symptomatic KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 34 of 47 disease progression, or pre -existing conditions (i.e., chronic adrenal cortical insufficiency). All medications (prescription and over the counter), vitamin and mineral supplements, and/or herbs taken by the study subjects will be documented. Topical steroids are permissible . 6.4.2 Compliance with Therapy 1. All treatments and study procedures will be administered in the clinic except for the cyclophosphamide that can be taken at home as per the protocol schedule. 7.0 SAMPLE SIZE AND ST ATISTICAL METHODS 7.1 Determination of Sample Size 7.1.1 Sample Size for Safety Evaluation An initial cohort of up to six (6) subjects will receive low -dose CYP, TAPA -pulsed DC vaccination and topical Imiquimod for determination of safety/toxicity (phase I stage). 7.1.2 Sample Size for Evaluation of Immune Efficacy Up to seventeen (17) patients may be enrolled for evaluation of immune efficacy (Phase II stage). Enrollment will begin if toxicity criteria are fulfilled and interim evaluation of IE is completed during the phase I stage (first 6 patients). Stopping criteria for the study, based on IE, will follow the Immune Efficacy Rules described in 3.7.1. 7.2 Statistical Methods 7.2.1 Safety and Toxicity A single dose of CYP, TAPA -pulsed DC vaccine and topical Imiquimod will be evaluated in this study. Six (6) consecutive patients will be treated as proposed for toxicity evaluation (Phase I stage). If no limiting toxicity is encountered, additional patients will be enrolled to determine immune efficacy (Phase II stage) . 7.2.2 Immune Efficacy (IE) For the IE part of the study, a Simon 2- stage design with a null hypothesis of 5% IE (p 0 = 0.05) and alternative hypothesis of 35% IE (p 1 = 0.35), with desired significance level (α) and desired power (1-β) of 0.05 and 0.9, respectively, will be utilized. An interim analysis of immune response will be conducted after accrual and treatment of the first six (6) patients, following completion of the planned s ix three (3) DC vaccine doses , with immune response evaluat ion on day 22 and day 45. Patients who are unable to complete the planned six three (3) DC vaccine doses will be withdrawn from the study. If no immune responses are observed at interim analysis, termination of the study will be considered based on lack of efficacy of the intervention. The probability of early termination, if no immune responses are observed in the first six (6) patients and the alternative hypothesis is true, is 7.5%. If 3 or more responses out of a total of 17 patients KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 35 of 47 are observed, the null hypothesis can be rejected and DC vaccination may move to a formal Phase II/III developmental stage. 8.0 ETHICAL CONSIDER ATIONS 8.1 Protection of Patients from Unnecessary Harm Safety of subjects involved in human experimentation is protected by both the participating clinical investigators and independently by the Institutional Protocol Review Committee (IPRC) and/or the Institutiona l Review Board (IRB). The IRB reviews all proposed studies involving human experimentation and ensures that the subject’s rights and welfare are protected and that the potential benefits and/or the importance of the knowledge to be gained outweigh the risks to the individual. The IRB also reviews the informed consent document associated with each study in order to ensure that the consent document accurately and clearly communicates the nature of the research to be done and its associated risks and benefits. 8.2 Privacy and Confidentiality Patients will be informed of the extent to which their confidential health information generated from this study may be used for research purposes. Following this discussion, they will be asked to sign the HIPAA form an d informed consent documents. The original signed document will become part of the patient’s medical records, and each patient will receive a copy of the signed document. The use and disclosure of protected health information will be limited to the individ uals described in the informed consent document. In order to protect patient’s privacy, all study data will be identified only by initials and a specifically assigned study number. However, in compliance with Good Clinical Practices, the PI will allow the independent study monitor(s) to review that portion of the patient’s medical record that is directly related to the study. This shall include all relevant study documentation, including patient medical histories to verify eligibility, laboratory test results, x -ray reports, and admission/discharge summaries while the patient is on -study, and autopsy reports for deaths occurring during the study (if available). 8.3 Informed Consent In obtaining and documenting informed consent, the investigators will compl y with the IRB guidelines and the ethical principles originating in the Declaration of Helsinki. 8.4 IRB Approval This protocol and the associated informed consent documents must be submitted to the IRB for review and approval. KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 36 of 47 9.0 SAFETY CONSIDERA TIONS 9.1 TAPA -Pulsed DC Vaccination DC-based treatments have been applied and studied clinically in many different diseases. Both monocyte -derived DCs (as being proposed for this study) and CD34+ -derived DCs have been used in the presence of serum -free or autologous serum -containing mediums. Because these cells have been generated from autologous cells, their administration intravenously (IV), subcutaneously (SC) or intradermally (ID) has not been associated with any significant adverse reactions, with the exception of low grade fever and local reactions, such as erythema, at the sites of injection (See discussion above). 9.2 Adverse Immune Responses Against TAPA -Pulsed DC Vaccinations The specific panel of TAPAs used in this study is novel and has not been explored extensively as a target for immunotherapy in humans. Therefore, there is no significant clinical data to support its safety in patients. Nevertheless, the available data showing these TAPAs are selectively expressed in tumor cells and normal testi s (but not in normal tissues), it is expected the immune responses generated by TAPA -pulsed DC therapy will only affect tumor cells (and possibly normal testis). Further evidence supporting the safety of TAPA immunotargeting is the lack of toxicity associa ted with spontaneous development of anti-TAPA antibodies following vasectomy ( 25). 9.3 Regulatory A spects This study will be conducted as part of an Investigational New Drug (IND) Application approved by the FDA (IND #12612). The study will not commence until full approval is obtained from either the central and/or local IRB. 10.0 FINANCIAL CONSIDERATIONS The expenses and costs incurred by this study for the generation and processing of TAPA - pulsed DC vaccines, oral CYP dose, topical Imiqumod , and leukapheresis/phlebotomy, will be provided by financial support entirely or partially from Kiromic, and/or external funding sources. It is expected that standard of care treatments and studies during and after the course of the study plus the follow -up monitoring (as part of the standard of care for patients with SM) will be paid either by the patie nt or their insurance companies. This arrangement will be clarified in the Patient Consent Form. 11.0 POTENTIAL CONFL ICT OF INTEREST It is possible that in the future Kiromic , may apply for a patent covering the potential use of some TAPAs in cancer therap eutics and diagnostics. The investigators will declare this potential conflict of interest in the Patient Consent Form so that all patients recruited to this study will be aware that some or all data obtained may be used to support future application that may result in commercial value of the DC vaccination strategy. A panel of independent KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 37 of 47 physicians/investigators will serve as an external Independent Clinical and Scientific Review Board monitor team (ICSRB) that will review the clinical and immunologic da ta generated in the study in order to guarantee the un -biased evaluation of study results. 12.0 QUALITY CONTROL AND QUALITY ASSURAN CE The quality of the vaccine product will be determined and guaranteed by strict adherence to the Standard Operating Procedure (SOP) for DC Vaccine Production following Good Manufacturing (GMP) and Good Laboratory Processing (GLP). 13.0 PUBLICATION POL ICY Results of this clinical study may be presented and/or published in National Meetings and/or peer -reviewed medical or scientific journals, partially or completely. Patient’s personal data will remain anonymous during such presentations/publications and integrity of data preserved and guaranteed during the dissemination process. 14.0 DIRECT ACCESS T O SOURCE DATA AND DO CUMENTS, DAT A HANDLING, AND RECORD KEEPING AND RETENTI ON OF STUDY DOCUMENTS Only the Study Chair, PI and Kiromic’s Clinical Research personne l may have access to the study source data and documents. Data will be handled exclusively by the Study Chair, PI, designated Clinical Research personnel and/or an officially designated person or persons such as one of the study sub-investigators and membe rs of the ICSRB. Data will be handled under strict confidentiality and kept in a secure place at Kiromic. Only the Study Chair, PI, designated Clinical Research personnel and members of the ICSRB may have access to the study data, including patient information and study outcomes. Study documents will be retained at Kiromic for at least 5 years following completion and closure of the study. KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 38 of 47 APPENDIX 1: STUDY CALENDAR Study calendar is designed to track the administration and application of the study protocol parameters and may adjusted as logistically needed as allowed protocol variances. PROCEDURE -28 -14 -7 1 3 8 10 15 17 22 45 Informed consent X Documentation of confirmed refractory disease X Confirm completion of salvage therapy > 3wks prior to vaccination X Pregnancy Evaluation X Birth Control agreement X Evaluation of disease status X TAPA expression X Infectious Disease history evaluation (HIV, Hepatitis A, B,or C) X Medical History X History & Physical X X X X X X Karnofsky Performance Status X X X X X X Concomitant Medications X CBC with diff X X X X X X CMP X X X X X X Phlebotomy/Leukapheresis X Immune Assays X X X DTH skin test X X X Oral Cyclophosphamide Max 100mg/day x 5 days X X X Topical Imiquimod X X X TAPA -pulsed DC Vaccine X X X Dose limiting toxicity assessment X X X X X X X KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 39 of 47 APPENDIX 2: KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) CRITERIA Able to carry on normal activity and to work; No special care needed. 100 Normal no complaints; no evidence of disease Unable to work; able to live at normal home and care for most personal needs; varying amount of assistance needed. 90 Able to carry on normal activity; Minor signs or symptoms of disease. 80 Normal activity with efforts; some sign s or symptoms of disease Unable to work; able to live at normal home and care for most personal needs; varying amount of assistance needed. 70 Cares for self; unable to carry on activity or to do active work. 60 Requires occasional assistance, but is able to care for most of his personal needs. 50 Requires considerable assistance and frequent medical care. Unable to care for self; Requires equivalent of institutional or hospital care; diseases may be progressing rapidly. 40 Disabled; requires special care and assistance 30 Severely disabled; hospital admission is indicated although death not imminent. 20 Very sick; hospital admission necessary; Active supportive treatment necessary. 10 Moribund; fatal processes progressing rapidly. 0 Dead KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 40 of 47 APPENDIX 3: RESPONSE CRITERIA Immune-R elated Response Criteria (irRC) (73) Baseline tumor assessment is determined by the sum of the products of the two largest perpendicular diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral lesions and five cutaneous index lesions) is calculated. At each subsequent tumor assessment, the SPD of the index lesions and of new, measurable lesions (≥ 5 × 5 mm; up to 5 new lesions per organ) are added together to provide the total tumor burden: Tumor Burden = SPD (index) lesions + SPD (new) lesions Time -point response assessment using irRC. Percen tage changes in tumor burden per assessment time point describe the size and growth kinetics of both conventional and new, measurable lesions as they appear. At each tumor assessment, the response in index and new, measurable lesions is defined based on the change in tumor burden (after ruling out irPD). Decreases in tumor burden must be assessed relative to baseline measurements (i.e., the SPD of all index lesions at screening). Overall response using the irRC The overall response according to the irRCis derived from time -point response assessments (based on tumor burden) as follows: • irCR : complete disappearance of all lesions (whether measurable or not, and no new lesions) confirmation by a repeat, consecutive assessment no less than 4 wk from the date first documented • irPR: decrease in tumor burden ≥50%relative to baseline confirmed by a consecutive assessment at least 4 wk after first documentation • irSD: not meeting criteria for irCR or irPR, in absence of irPD • irPD : increase in tumor burden ≥ 25% relative to nadir (minimum recorded tumor burden) confirmation by a repeat, consecutive assessment no less than 4 wk from the date first documented KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 41 of 47 Derivation of irRC overall responses MEASURABLE RESPONSE NONMEASURABLE RESPONSE OVERALL RESPONSE Index and new, measurable lesions (tumor burden), *% Non -Index lesions New, nonmeasurable lesions Using irRC ↓100 Absent Absent irCR† ↓100 Stable Any irPR† ↓100 Unequivocal progression Any irPR† ↓≥50 Absent/Stable Any irPR† ↓≥50 Unequivocal progression Any irPR† ↓<50 to <25↑ Absent/Stable Any irSD ↓<50 to <25↑ Unequivocal progression Any irSD ≥25? Any Any irPD† *Decreases assessed relative to baseline, including measurable lesions only (>5 × 5 mm). †Assuming response (irCR) and progression (irPD) are confirmed by a second, consecutive assessment at least 4 weeks apart. Patients are considered to have irPR or irSD even if new lesions were present, as long as they met the respective thresholds of response as described above. Patients are not considered to have irPD if new lesions were present and the tumor burden of all lesions did not increase by ≥25%. In contrast to irCR, irPR, and irPD, a response of irSD does not require confirmation. It is important to note that irCR, irPR, and irSD include all patients with CR, PR, or SD by WHO criteria as well as those patients that shift to these irRC categories from WHO PD. Patients with irSD, particularly those with slow -declining tumor burden ≥25% from baseline at the last tumor assessment, are considered clinically meaningful because they show an objectively measurable reduction in tumor burden without reaching the 50% threshold that defines irPR. If a patient is classified as having irPD at a post -baseline tumor assessment, then confirmation of irPD by a second scan in the absence of rapid clinical deterioration is required. The definition of confirmation of progression represents an increase in tumor burden ≥25% compared with the nadir at two consecutive time points at least 4 wk apart. It is recommended that this be done at the discretion of the investigator because follow -up with observation alone may not be appropriate for patients with a rapid decline in performance status. Confirmation of irPD allows for the capture of all observed responses using the irRC, as most of these late responding patients have a trend toward response within 4 wk after initial irPD. Whereas WHO criteria consider any new measurable lesion to indicate PD, determination of immune -related best overall response (irBOR) is based on changes in total tumor burden from the baseline (nadir, for irPD) tumor assessment, regardless of any initial increase in baseline lesions or the appearance of new lesions. Wolchok,J, Hoos A, O'Day S, et al. Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune -Related Response Criteria. Clin Cancer Res 15(23):7412– 20, 2009 KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 42 of 47 APPENDIX 4: NCI CTCAE V4.0 http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.04_20100-06-14_QuickReference_8.5x11.pdf KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 43 of 47 APPENDIX 5: ADVERSE EVENT LOG STUDY TITLE SITE Principal Investigator (PI) Patient Number Patient Initials Has the participant had any A E during this study? Yes No If Yes, how many? _________ Dates: ______________________________ ______________________ _____________ _____________________ ____________ Clinician Name Clinician Initials Clinician Signature Date ______________________ _____________ _____________________ ____________ PI Name PI Initials PI Signature Date ADVERSE EVENT START DATE/TIME STOP DATE/TIME Brief Summary : Severity Relation to Study Drug Action taken with Investigational drug Corrective Action Outcome Expected Serious 1= Mild 2= Moderate 3= Severe 4= Life Threatening 1= Definitely 2= Possibly 3= Not related 4= Unknown 1= None 2= Discontinued permanently 3= Discontinued temporarily 4= Reduced Dose 5= Increased Dose 6= Delayed Dose 1=Remedial Therapy (Pharmacologic) 2= Remedial Therapy (Non pharmacologic) 3=Hospitalization 4=Medication 1= Resolved 2= Resolved with sequel 3= Not resolved 4= Residual effects present 5= Death 1=Yes 2=No 1=Yes 2=No KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 44 of 47 15.0 REFERENCES 1. R.