Individual Subject Criteria. If any of the criteria below are met by an individual subject, then no further dosing will occur at any of the study sites until a review of all available safety information is performed by the DSMB, Medical Monitor, and Sponsor. Appropriate Regulatory Agencies and Ethics Committees will be informed as applicable. If it is later determined that further dosing can be performed safely then an application for a substantial protocol amendment will be submitted to the appropriate Regulatory Agencies and Ethics Committees, if applicable. Stopping criteria for an individual subject includes: • Grade 3 or higher CTCAE AEs possibly or probably related to study drug as determined by the investigator and sponsor; • Grade 4 CTCAE AEs regardless of relation to study drug as determined by the investigator and sponsor; • Any SAEs thought to be related to the study drug as determined by the investigator and sponsor. For subjects experiencing any hepatic AEs or SAEs judged by the investigator or sponsor to be related to study drug, the investigator, DSMB, Medical Monitor and Sponsor will review all available safety data and make a determination to proceed with one of the following options: • If the event was a drug-induced liver injury (DILI), considered as increases in aminotransferases (AT) >3 x ULN or >3 x baseline where baseline is defined as the average values of Screening and Day -1, no additional subjects will be dosed until it is determined that it is safe to proceed and in addition the frequency of blood chemistries will increase to daily, if appropriate. − Repeat testing of ALT, AST, ALP, TBL will be performed within 48-72 hours to confirm the abnormality. − If there are persistent elevations of AT > 3 x ULN or a 2-fold increase above baseline values (for those subjects with elevated values prior to drug exposure) upon repeat testing then close observation visits should be implemented and/or discontinuation of drug should be considered. Close Observations are described in Section 7.8. • If the event was not a DILI, as defined above, one of the following actions will be taken: − Dose an entire additional cohort at the same or lower dose than the dose taken by the subject that experienced the event in question; − Continue to pause the study, until it is determined, that it is safe to proceed. A decision to discontinue or temporarily interrupt the study drug for a subject will be considered based on following criteria: • If ALT/AST baseline measurements (BLM) are <2...
