*** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression. Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as “symptomatic deterioration .” Every effort should be made to document the objective progression even after discontinuation of treatment. For Patients with Non-Measurable Disease (i.e., Non-Target Disease) Non-Target Lesions New Lesions Overall Response CR No CR Non-CR/Non-PD No Non-CR/Non-PD* Not all evaluated No Not evaluated Unequivocal PD Yes or No PD Any Yes PD * ‘Non-CR/non-PD’ is preferred over ‘stable di sease’ for non-target disease since SD is increasingly used as an endpoint for assessment of efficacy in some trials; so, to assign this category when no lesions can be measured is not advised. 6.3.4 Duration of Response Duration of overall response: Th e duration of overall respons e is measured from the time measurement criteria are met for CR or PR (whichev er is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented. Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements. Abbreviated Title: mRNA-Based, Cancer Vaccine Version Date: January 23, 2019 43 TOXICITY CRITERIA The following adverse event management guidelines are intended to ensure the safety of each patient while on the study. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP website (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 7 SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN DEFINITIONS 7.1.1 Adverse Event Any untoward medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in re search, whether or not considered related to the subject’s participation in the research. 7.1.2 Suspected Adverse Reaction Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug. 7.1.3 Unexpected Adverse Reaction An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the Investigator’s Brochure or is not listed at th e specificity or severity that has been observed; or, if an Investigator’s Brochure is not required or available, is not consistent with the risk information described in the gene ral investigational plan or else where in the current application. "Unexpected” also refers to adverse events or suspected adverse reactions that are mentioned in the Investigator’s Brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are no t specifically mentioned as occurring with the particular drug und er investigation. 7.1.4 Serious An unanticipated problem or prot ocol deviation is serious if it meets the definition of a serious adverse event or if it compromises the safety, welfare, or rights of subjects or others. 7.1.5 Serious Adverse Event An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the Sponsor, it results in any of the following: x Death x A life-threatening adverse drug experience x Inpatient hospitalization or prolongation of existing hospitalization Abbreviated Title: mRNA-Based, Cancer Vaccine Version Date: January 23, 2019 44x Persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions x A congenital anomaly/birth defect x Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 7.1.6 Disability A substantial disruption of a person’s ability to conduct normal life functions. 7.1.7 Life-Threatening Adverse Drug Experience Any adverse event or suspected adverse reaction that places the patient or subject, in the view of the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that had it occurred in a more severe form, might have caused death. 7.1.8 Protocol Deviation (NIH Definition) Any change, divergence, or departure from the NIH Intramural IRB-approved research protocol. 7.1.9 Non-Compliance (NIH Definition) The failure to comply with applicable NIH Human Research Protections Program (HRPP) policies, NIH Intramural IRB requirements, or regulatory requirements for the protection of human research subjects. 7.1.10 Unanticipated Problem Any incident, experience, or outcome that: 1. Is unexpected in terms of nature, severity, or frequency in relation to: a. the research risks that are described in the NIH Intramural IRB-approved research protocol and informed consent document; Investigator’s Brochure or other study documents, and b. the characteristics of the s ubject population being studied; AND 2. Is related or possibly related to participation in the research; AND 3.