Sponsor: Io Therapeutics, Inc. J15219 (IRB00083855) TITLE: Phase I/II study of IRX5183 in relapsed and refractory acute myeloid leukemia and high risk myelodysplastic syndrome Protocol designation: P_195183-201-2015 Principal Investigator: B Douglas Smith, M.D. 1650 Orleans Street, Room 246, CRB1 Baltimore, Maryland 21231 Telephone 410-614-5068; Fax 410-614-7437 [email protected] Co-Investigators: Kelly Norsworthy, M.D. 1650 Orleans Street, Room 2M48, CRB1 Baltimore, Maryland 21231 Telephone 443-694-0509; Fax 410-614-1005 [email protected] Gabriel Ghiaur, M.D./Ph.D. 1650 Orleans Street, Room 243, CRB1 Baltimore, Maryland 21231 Telephone 410-502-3183; Fax 410-614-7279 [email protected] Rick Jones, M.D. 1650 Orleans Street, Room 244, CRB1 Baltimore, Maryland 21231 Telephone 443-287-7104; Fax 410-614-7279 [email protected] Statistician: Ravi Varadhan, Ph.D., Ph.D. Study Sponsors: Io Therapeutics, Inc. 1805 East Garry Avenue, Suite 110 Santa Ana, CA 92705 Responsible Research Nurse: Seana Coffin Telephone 410-614-2023 [email protected] Responsible Data Manager: Colin Huck Telephone 410-614-3725 [email protected] Regulatory: Suzanne Bell Telephone 919-946-9901 [email protected] Version date: September 8, 2017 Io Page 1 of 66 Sponsor: Io Therapeutics, Inc. J15219 (IRB00083855) TABLE OF CONTENTS STUDY SCHEMA and SYNOPSIS......................................................................................................................................................... 4 1. OBJECTIVES ....................................................................................................................................................................................... 7 1.1. PRIMARY OBJECTIVES: .......................................................................................................................................................... 7 1.2. SECONDARY OBJECTIVES: .................................................................................................................................................... 7 2. BACKGROUND ................................................................................................................................................................................... 7 2.1. Acute myeloid leukemia: .............................................................................................................................................................. 7 2.2. Myelodysplastic syndrome: .......................................................................................................................................................... 9 2.3. Previous Cell Differentiation Therapies in Myeloid Malignancies: ........................................................................................ 11 2.4. Impact of bone marrow microenvironment on sensitivity to retinoids: ................................................................................. 12 2.5. IRX5183: ...................................................................................................................................................................................... 13 2.6. Rationale: ..................................................................................................................................................................................... 15 3. PATIENT SELECTION ................................................................................................................................................................... 16 3.1. Eligibility criteria: ....................................................................................................................................................................... 16 3.2. Exclusion criteria: ....................................................................................................................................................................... 17 3.3. Pregnancy: ................................................................................................................................................................................... 17 3.4. Inclusion of women and minorities:........................................................................................................................................... 18 3.5. Off-Study Criteria:...................................................................................................................................................................... 18 3.6. Informed Consent: ...................................................................................................................................................................... 18 4. PRETREATMENT PLAN ................................................................................................................................................................ 19 5. TREATMENT PLAN ........................................................................................................................................................................ 19 5.1. IRX5183 Administration: ........................................................................................................................................................... 19 5.2. Definition of dose-limiting toxicity: ........................................................................................................................................... 23 5.3. General concomitant medication and supportive care guidelines: ......................................................................................... 24 5.3.1. Differentiation syndrome....................................................................................................................................................... 24 5.3.2. Leukocytosis .......................................................................................................................................................................... 24 5.3.3. Hypertriglyceridemia……………………………………………………………………………………………………...…24 5.4. Duration of therapy: ................................................................................................................................................................... 25 5.5. Duration of follow-up: ................................................................................................................................................................ 26 5.6. Criteria for removal from study: ............................................................................................................................................... 26 6. DOSING DELAYS/DOSE MODIFICATIONS: ............................................................................................................................ 26 6.1. Dose Modifications for IRX5183: .............................................................................................................................................. 27 6.2. Discontinuation of IRX5183 for related adverse events: ......................................................................................................... 29 6.3. Exceptions to permanent discontinuation: ................................................................................................................................ 29 7. TREATMENT EVALUATION AND TOXICITY MONITORING ............................................................................................ 30 7.1. Clinical Responses:...................................................................................................................................................................... 30 7.2. Assessment of Response: ............................................................................................................................................................. 30 7.3. Measurement of Response / Response Criteria: ....................................................................................................................... 31 7.4. Adverse Events: ........................................................................................................................................................................... 31 7.5. Serious Adverse Event (SAE): ................................................................................................................................................... 32 7.6. Toxicity Reporting: ..................................................................................................................................................................... 32 7.7. Toxicity Monitoring: ................................................................................................................................................................... 32 7.8. Pharmacokinetics: ....................................................................................................................................................................... 33 8. CORRELATIVE STUDIES ............................................................................................................................................................. 34 8.1. Biologic activity: .......................................................................................................................................................................... 34 8.2. Cellular Collection and Processing: ........................................................................................................................................... 35 9. PHARMACEUTICAL INFORMATION ......................................................................................................................................