single-arm open label interventional phase
untitled h2

| IND Sponsor:            | John E. Wagner, MD                    |
|-------------------------|---------------------------------------|
| Principal Investigator: | Margaret L. MacMillan, MD             |
| Lead Co-Investigator:   | Claudio Brunstein, MD, PhD            |
| Co-Investigators:       | Shernan Holtan, MD Christen Ebens, MD |
| RadiationTherapy:       | Kathryn Dusenbery, MD                 |
| MCT cGMP Facility:      | David H. McKenna, Jr., MD             |
| Biostatistician:        | Todd E. DeFor, MS                     |
| Development Phase:      | 2                                     |
| Version Date:           | April 23, 2021                        |  
This document contains confidential information that is the property of the University of Minnesota Blood and Marrow Transplant Program Do not copy, disclose or circulate this protocol without written authorization from the Principal Investigator or Medical Directors of the University of Minnesota Medical Center-Fairview Blood and Marrow Transplant Service Line
single-arm open label interventional phase
revision history

| Revision                                                                                                                                                                                                                                                                                                                                                                                                                                                | Version  Date                                                                | Summary of Changes                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Consent   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------|
| #                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Revision                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |           |
| 04/01/2018                                                                                                                                                                                                                                                                                                                                                                                                                                              | Original to CPRC Updated background section 2.2 with pediatric data; changed |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |           |
| 1A                                                                                                                                                                                                                                                                                                                                                                                                                                                      | 05/02/2018                                                                   | abbreviations MAC and NMAC to MA and NMA; section 6.4 fixed typos per CPRC stipulations Section 4.2 & eligibility checklist - edits and corrections to  bring study to current standard of care; schedules standard  and research assessments edited for current standard testing  and added research labs; minor administrative edits and  corrections.                                                                                                                                                                              |           |
| 1B                                                                                                                                                                                                                                                                                                                                                                                                                                                      | 06/12/2018                                                                   | Title page - added IND number; Section 4.2 & Eligibility  checklist– added minimum weight requirement (>11kg);  removed Lymphoplasmacytic lymphoma and clarified  myelodysplastic syndrome refractory anemia; in Section 4.4 &  eligibility checklist - clarified ineligibility after prior autologous  or allogeneic transplant and added additional ineligibility  criteria added, eg patients with a HLA matched sibling and,  patients with a HLA matched unrelated donor who is available  at the time the transplant is needed. |           |
| 1C                                                                                                                                                                                                                                                                                                                                                                                                                                                      | 08/13/2018                                                                   | No                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |           |
| Sections 2.2 and Section 2.5 - updated background section of  the consent based on IRB stipulations and fixed typographical  error in the inclusion criteria and eligibility checklist; changed  references of study product from HSC835v1 to MGTA--456                                                                                                                                                                                                 |                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |           |
| 1D                                                                                                                                                                                                                                                                                                                                                                                                                                                      | 08/23/2018                                                                   | Yes                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |           |
| Updates made by pharmacy to conform to local standard  clinical care: -Updated treatment plan and section 6 to reflect Cy to be  given on days -7 & -6 -Removed wording that fludarabine had to be given at 10am in  section 6.1.1.1 and section 6.1.2.2 -Updated Cytoxan adjusted body weight dosing calculation to  local standard in section 6.1.1.2 -Section 6.2.2 clarified peds MMF dosing - Appendix III - added Bartelink dosing nomogram table |                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |           |
| 2                                                                                                                                                                                                                                                                                                                                                                                                                                                       | 09/28/2018                                                                   | Section 4.1 Updated to note that cord blood selection will be  per Magenta's algorithm Section 8 - removed 1 and 2 year chest x-ray; updated  research labs Appendix III - Inpatient Pharmacy updated busulfan dosing  and monitoring guidelines Consents - updated information on sponsor data use                                                                                                                                                                                                                                   |           |
| 3                                                                                                                                                                                                                                                                                                                                                                                                                                                       | 12/20/2018                                                                   | Yes                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |           |
| Section 4.1 minor edits for clarity Appendix III - Inpatient Pharmacy updated busulfan dosing  and monitoring guidelines Parent consent age 0-3, error correction on study calendar                                                                                                                                                                                                                                                                     |                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |           |
| 3A                                                                                                                                                                                                                                                                                                                                                                                                                                                      | 01/07/2019                                                                   | Yes                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |           |  
| Section 1.6 (Exploratory Endpoints), Section 2.6, Section 6.5,  Section 7.3, Section 8, Section 12.2, References: Added  Immune reconstitution sub-study in order to investigate long  term functional immune response Synopsis, Section 4.1, and section 6.3: Clarified selection  criteria and parameters of required cell dose Section 8, noted that chimerism will not be drawn if WBC <  500                                                                     |            |                                                                                      |     |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------|--------------------------------------------------------------------------------------|-----|
| 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | 04/24/2019 | Yes                                                                                  |     |
| Section 6.5, Section 8, - clarified that vaccinations may not be  given if active acute or chronic GVHD or other evidence of  poor immunologic recovery. Section 6.3, Section 8 - clarified cell dosing; added that there  is no lower limit for TNC. Section 8 - Standard of care calendar, added Tcell subsets Removed Appendix I eligibility checklist, per new SOP, this  document is kept in Oncore. Throughout document minor edits for consistency and clarity |            |                                                                                      |     |
| 5                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | 11/25/2019 | No                                                                                   |     |
| 6                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | 04/23/2021 | Dr.MacMillan takes over as principal investigator; Dr.  Stefanski removed from study | Yes |
single-arm open label interventional phase
table of contents

| REVISION HISTORY .                                                                                                                                             |                                                                                                                                                    |                                                                                                          |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------|
| LIST OF ABBREVIATIONS                                                                                                                                          |                                                                                                                                                    |                                                                                                          |
| Protocol Synopsis                                                                                                                                              |                                                                                                                                                    |                                                                                                          |
| T Treatment Plan .                                                                                                                                             |                                                                                                                                                    |                                                                                                          |
| 1                                                                                                                                                              | Hypothesis and Objectives .............................................................................................................15          |                                                                                                          |
| 1.1                                                                                                                                                            | Hypothesis .                                                                                                                                       |                                                                                                          |
| 1.2                                                                                                                                                            | Primary Objective.                                                                                                                                 |                                                                                                          |
| 1.3                                                                                                                                                            | Primary Endpoint .                                                                                                                                 |                                                                                                          |
| 1.4                                                                                                                                                            | Secondary Endpoints                                                                                                                                |                                                                                                          |
| 1.5                                                                                                                                                            | Transplant Related Secondary Endpoints ..................................................................................... 15                    |                                                                                                          |
| Exploratory Endpoints.                                                                                                                                         |                                                                                                                                                    |                                                                                                          |
| 1.6                                                                                                                                                            |                                                                                                                                                    |                                                                                                          |
| 2                                                                                                                                                              | Background......................................................................................................................................16 |                                                                                                          |
| 2.1                                                                                                                                                            | Overview of UCB Transplantation .............................................................................................................. 16  |                                                                                                          |
| 2.1.1                                                                                                                                                          | Single Unit UCBT .                                                                                                                                 |                                                                                                          |
| 2.1.2                                                                                                                                                          | D Double Unit UCBT .                                                                                                                               |                                                                                                          |
| 2.1.3                                                                                                                                                          | Comparisons with Other HSC Sources [12]                                                                                                            |                                                                                                          |
| National BMT-CTN 0501 Study - Single versus Double UCBT [22]. ........................ 20                                                                      |                                                                                                                                                    |                                                                                                          |
| 2.1.4                                                                                                                                                          |                                                                                                                                                    |                                                                                                          |
| 2.1.5                                                                                                                                                          | Impact of Conditioning on Engraftment and Survival after UCBT [23]..................... 21                                                         |                                                                                                          |
| 2.2                                                                                                                                                            | MGTA-456 - Aryl Hydrocarbon Receptor (AHR)-Antagonist Mediated HSPC Expansion                                                                      |                                                                                                          |
| 2                                                                                                                                                              |                                                                                                                                                    |                                                                                                          |
| 2.3                                                                                                                                                            | Human Pharmacokinetic Data .                                                                                                                       |                                                                                                          |
| 2.4                                                                                                                                                            | Cryopreserved MGTA-456 .                                                                                                                           |                                                                                                          |
| Summary and Rationale for the Proposed Study .                                                                                                                 |                                                                                                                                                    |                                                                                                          |
| 2.5                                                                                                                                                            |                                                                                                                                                    |                                                                                                          |
| 2.6                                                                                                                                                            | Immune Reconstitution Sub-study                                                                                                                    |                                                                                                          |
| 3                                                                                                                                                              | Study Design                                                                                                                                       |                                                                                                          |
| Patient Selection                                                                                                                                              |                                                                                                                                                    |                                                                                                          |
| 4                                                                                                                                                              | Age, Weight, Unit Cell Dose and HLA Match Criteria ................................................................... 27                          |                                                                                                          |
| 4.1                                                                                                                                                            | Eligible Diseases                                                                                                                                  |                                                                                                          |
| 4.2                                                                                                                                                            |                                                                                                                                                    |                                                                                                          |
| 4.3                                                                                                                                                            | Organ Specific Inclusion Criteria                                                                                                                  |                                                                                                          |
| 4.4                                                                                                                                                            | Exclusion Criteria .                                                                                                                               |                                                                                                          |
| Patient Registration .......................................................................................................................................29 |                                                                                                                                                    |                                                                                                          |
| 5                                                                                                                                                              | 5.1                                                                                                                                                | Registration with the Masonic Cancer Center Clinical Trials Office .................................. 29 |
| 5.2                                                                                                                                                            | .Study Enrollment with the Masonic Cancer Center Clinical Trials Office ...................... 30                                                  |                                                                                                          |  
__  
| 5.3                                                                                                                                                                                                                                                                                                               | Patients Who Are Enrolled But Do Not Receive Study Treatment 30                  |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------|
| 6                                                                                                                                                                                                                                                                                                                 | Treatment Plan 30                                                                |
| 6.1                                                                                                                                                                                                                                                                                                               | Conditioning Regimen (day - 8 through day -1) 32                                 |
| 6.1.1                                                                                                                                                                                                                                                                                                             | TBI-Containing Regimen 32                                                        |
| 6.1.2                                                                                                                                                                                                                                                                                                             | Non-TBI-Containing Regimen 32                                                    |
| 6.2                                                                                                                                                                                                                                                                                                               | Immunoprophylaxis 33                                                             |
| 6.2.1                                                                                                                                                                                                                                                                                                             | Tacrolimus 33                                                                    |
| 6.2.2                                                                                                                                                                                                                                                                                                             | Mycophenolate Mofetil 33                                                         |
| 6.3                                                                                                                                                                                                                                                                                                               | MGTA-456 Infusion 34                                                             |
| 6.4                                                                                                                                                                                                                                                                                                               | Hematopoietic Growth Factor and Other Supportive Care 34                         |
| 6.5                                                                                                                                                                                                                                                                                                               | Immunizations (Immune Reconstitution Sub-study) 35                               |
| 6.6                                                                                                                                                                                                                                                                                                               | Duration of Study Participation 35                                               |
| 7                                                                                                                                                                                                                                                                                                                 | Expected Treatment Related Toxicities 35                                         |
| 7.1                                                                                                                                                                                                                                                                                                               | Potential Toxicities of the Conditioning Regimen 35                              |
| 7.2                                                                                                                                                                                                                                                                                                               | Potential Toxicities of GVHD Immunoprophylaxis and G-CSF 38                      |
| 7.3                                                                                                                                                                                                                                                                                                               | Potential Side effects of Immunizations 38                                       |
| 7.4                                                                                                                                                                                                                                                                                                               | Potential Adverse Events (AE) associated with the Infusion of Cryopreserved HSPC |
| Products (including MGTA-456) 39 7.5 Recommended Treatment of Adverse Events 39 7.5.1 Slow Engraftment/Graft Failure 39 7.5.2 Anemia 40 7.5.3 Thrombocytopenia 40 7.5.4 Nutrition 40 7.5.5 Acute GVHD 40 7.5.6 Infusional Reaction 40 7.5.7 Engraftment Syndrome/Transfusion Related Acute Lung Injury (TRALI) 41 |                                                                                  |
| 8                                                                                                                                                                                                                                                                                                                 | Schedule of Patient Activities 41                                                |
| 9                                                                                                                                                                                                                                                                                                                 | Adverse Event Monitoring, Recording and Reporting 47                             |
| 9.1                                                                                                                                                                                                                                                                                                               | Definitions 47                                                                   |
| 9.2                                                                                                                                                                                                                                                                                                               | Adverse Event Monitoring, Recording and Reporting 48                             |
| 9.2.1                                                                                                                                                                                                                                                                                                             | Event Monitoring 48                                                              |
| 9.2.2                                                                                                                                                                                                                                                                                                             | Event Recording/Documentation 48                                                 |
| 9.2.3                                                                                                                                                                                                                                                                                                             | Event Reporting to the IRB, FDA and Cancer Center 48                             |
| 9.3                                                                                                                                                                                                                                                                                                               | Monitoring for Stopping Rule Events 49                                           |  
MT2018-06  
| 10                                                                                                                                      | Study Data Collection and Monitoring ....................................................................................49                                  |
|-----------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------|
| DATA Management                                                                                                                         |                                                                                                                                                              |
| 10.1                                                                                                                                    |                                                                                                                                                              |
| 10.2                                                                                                                                    | Case Report Forms.                                                                                                                                           |
| 10.3                                                                                                                                    | Data and Safety Monitoring Plan.                                                                                                                             |
| IND Annual Reports .                                                                                                                    |                                                                                                                                                              |
| 10.4                                                                                                                                    | D DATA SHARING WITH MAGENTA                                                                                                                                  |
| 10.5                                                                                                                                    |                                                                                                                                                              |
| 10.6                                                                                                                                    | Monitoring .                                                                                                                                                 |
| 10.7                                                                                                                                    | Study Record Retention .                                                                                                                                     |
| 11                                                                                                                                      | Definition of Study Endpoints                                                                                                                                |
| 11.1                                                                                                                                    | Neutrophil Recovery                                                                                                                                          |
| 11.2                                                                                                                                    | Platelet Recovery                                                                                                                                            |
| 1.3                                                                                                                                     | Engraftment                                                                                                                                                  |
| Graft Failure                                                                                                                           |                                                                                                                                                              |
| 1.4                                                                                                                                     |                                                                                                                                                              |
| 1.5                                                                                                                                     | Graft-versus-Host Disease                                                                                                                                    |
| 1.6                                                                                                                                     | Transplant-Related Mortality .                                                                                                                               |
| 1.7                                                                                                                                     | Relapse                                                                                                                                                      |
| Non-Catheter Associated Bacterial Infection                                                                                             |                                                                                                                                                              |
| 1.8                                                                                                                                     |                                                                                                                                                              |
| 1.9                                                                                                                                     | Event Free Survival (EFS)                                                                                                                                    |
| 12                                                                                                                                      | Statistical Considerations                                                                                                                                   |
| 12.1                                                                                                                                    | Study Design, Objectives and Endpoints .                                                                                                                     |
| Primary Endpoint .                                                                                                                      |                                                                                                                                                              |
| 12.1.1                                                                                                                                  |                                                                                                                                                              |
| 12.1.2                                                                                                                                  | Secondary and Transplant Related Secondary Endpoints ............................................. 54                                                        |
| 12.1.3                                                                                                                                  | Exploratory Endpoints                                                                                                                                        |
| Statistical Analysis .                                                                                                                  |                                                                                                                                                              |
| 12.2                                                                                                                                    |                                                                                                                                                              |
| 12.3                                                                                                                                    | Rationale for Sample Size.                                                                                                                                   |
| 12.4                                                                                                                                    | Monitoring Guidelines                                                                                                                                        |
| 12.5                                                                                                                                    | Gender and Ethnicities Statement                                                                                                                             |
| 13                                                                                                                                      | Conduct of the Study .....................................................................................................................................56 |
| 13.1                                                                                                                                    | Good Clinical Practice                                                                                                                                       |
| 13.2                                                                                                                                    | Ethical Considerations .                                                                                                                                     |
| 13.3                                                                                                                                    | Informed Consent .                                                                                                                                           |
| References                                                                                                                              |                                                                                                                                                              |
| 14                                                                                                                                      |                                                                                                                                                              |
| Appendix I - Karnofsky and Lansky Scales ............................................................................................61 |                                                                                                                                                              |
| Appendix II - Recommended TBI Guidelines ....................................................................................62         |                                                                                                                                                              |
|                                                                                                                                         | __                                                                                                                                                           |  
| Modification Using Once Daily IV Dosing 63 Appendix IV - GVHD Scoring 67 Appendix V - Targeted Toxicities 68   |
|----------------------------------------------------------------------------------------------------------------|  
| John E. Wagner, MD Director and Professor Division of Blood and Marrow Transplantation Department of Pediatrics 660 Cancer Research Building 425 East River Road Minneapolis, MN 55455 612 626-2961 (phone) 612 626-4074 (fax) wagne002@umn.edu (email) Principal Investigator/Contact Information: Margaret L. MacMillan, MD, MSc, FRCPC Professor of Pediatrics Blood and Marrow Transplantation & Cellular  Therapy Program  University of Minnesota  MMC 484  420 Delaware Street SE Minneapolis, MN 55455 612 626-2961 (phone) 612-626-2815 (fax) macmi002@umn.edu (email)   | Lead Co- Investigator/Contact Information: Claudio Brunstein, MD, PhD Associate Professor Division of Hematology, Oncology and  Transplantation Department of Medicine Mayo Mail Code 480 420 Delaware Street SE Minneapolis, MN 55455 612 625-3918 (phone) 612 899-6170 (pager) bruns072@umn.edu   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| LIST OF ABBREVIATIONS ABBREVIATION DEFINITION AE ADVERSE EVENT aGVHD ACUTE GRAFT VERSUS HOST DISEASE AHR ARYL HYDROCARBON RECEPTOR ALL ACUTE LYMPHOCYTIC LEUKEMIA ALT ALANINE AMINOTRANSFERASE AML ACUTE MYELOCYTIC LEUKEMIA ANC ABSOLUTE NEUTROPHIL COUNT AST ASPARTATE AMINOTRANSFERASE ATG ANTITHYMOCYTE GLOBULIN AUCcum CUMULATIVE AREA UNDER THE PLASMA CONCENTRATION-TIME CURVE AUC AREA UNDER THE PLASMA CONCENTRATION-TIME CURVE AUC∞ AREA UNDER THE PLASMA CONCENTRATION-TIME CURVE FROM TIME ZERO TO INFINITY AUClast AREA UNDER THE PLASMA CONCENTRATION-TIME CURVE FROM TIME ZERO TO TIME OF LAST  MEASURABLE CONCENTRATION BMT BONE MARROW TRANSPLANT BU BUSULFAN CBU CORD BLOOD UNIT CFR CODE OF FEDERAL REGULATIONS cGVHD CHRONIC GRAFT VERSUS HOST DISEASE CLIA CLINICAL LABORATORY IMPROVEMENT AMENDMENT Cmax MAXIMUM OBSERVED CONCENTRATION CML CHRONIC MYELOGENOUS LEUKEMIA CMV CYTOMEGALOVIRUS COBLT CORD BLOOD TRANSPLANT CONSORTIUM CRF CASE REPORT FORM CsA CYCLOSPORINE A CTCAE COMMON TOXICITY CRITERIA ADVERSE EVENT CTO CLINICAL TRIALS OFFICE CY CYCLOPHOSPHAMIDE DNA DEOXYRIBONUCLEIC ACID DMC DATA MONITORING COMMITTEE DUCBT DOUBLE UMBILICAL CORD BLOOD TRANSPLANTATION ECG ELECTROCARDIOGRAM EBV EPSTEIN-BARR VIRUS EFS EVENT FREE SURVIVAL FLU FLUDARABINE FDA FOOD AND DRUG ADMINISTRATION GCP GOOD CLINICAL PRACTICE   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| ABBREVIATION   | DEFINITION                                   |
|----------------|----------------------------------------------|
| G-CSF          | GRANULOCYTE-COLONY STIMULATING FACTOR        |
| GVHD           | GRAFT VERSUS HOST DISEASE                    |
| HBcAb          | HEPATITIS B CORE ANTIBODY                    |
| HBsAg          | HEPATITIS B SURFACE ANTIGEN                  |
| hCG            | HUMAN CHORIONIC GONADOTROPIN                 |
| HCV            | HEPATITIS C VIRUS                            |
| HIV            | HUMAN IMMUNODEFICIENCY VIRUS                 |
| HLA            | HUMAN LEUKOCYTE ANTIGEN                      |
| HSC            | HEMATOPOIETIC STEM CELLS                     |
| HSCT           | HEMATOPOIETIC STEM CELL TRANSPLANTATION      |
| HSV            | HERPES SIMPLEX VIRUS                         |
| HTLV1/2        | HUMAN T CELL LYMPHOTROPIC VIRUS 1/2          |
| IB             | INVESTIGATOR'S BROCHURE                      |
| ICF            | INFORMED CONSENT FORM                        |
| ICH            | INTERNATIONAL COUNCIL ON HARMONIZATION       |
| IEC            | INDEPENDENT ETHICS COMMITTEE                 |
| IRB            | INSTITUTIONAL REVIEW BOARD                   |
| IUD            | INTRAUTERINE DEVICE                          |
| IUS            | INTRAUTERINE SYSTEM                          |
| IV             | INTRAVENOUS                                  |
| LDH            | LACTATE DEHYDROGENASE                        |
| LFT            | LIVER FUNCTION TEST                          |
| LLOQ           | LOWER LIMIT OF QUANTIFICATION                |
| LMW            | LOW MOLECULAR WEIGHT                         |
| LVEF           | LEFT VENTRICULAR EJECTION FRACTION           |
| MA             | MYELOABLATIVE CONDITIONING                   |
| Magenta        | MAGENTA THERAPEUTICS, INC.                   |
| MDS            | MYELODYSPLASTIC SYNDROME                     |
| MFI            | MEAN FLUORESCENCE INTENSITY                  |
| MedDRA         | MEDICAL DICTIONARY FOR REGULATORY ACTIVITIES |
| MMF            | MYCOPHENOLATE MOFETIL                        |
| MSD            | MATCHED SIBLING DONOR                        |
| NC             | NUCLEATED CELLS                              |
| NMA            | NON-MYELOABLATIVE CONDITIONING               |
| NOAEL          | NO OBSERVED ADVERSE EFFECT LEVEL             |
| PES            | PRE-ENGRAFTMENT SYNDROME                     |  
| ABBREVIATION   | DEFINITION                                                         |
|----------------|--------------------------------------------------------------------|
| PFT            | PULMONARY FUNCTION TEST                                            |
| PK             | PHARMACOKINETIC                                                    |
| PBMC           | PERIPHERAL BLOOD MONONUCLEAR CELLS                                 |
| SAB            | SINGLE ANTIGEN BEAD                                                |
| SAE            | SERIOUS ADVERSE EVENT                                              |
| SOP            | STANDARD OPERATING PROCEDURE                                       |
| SR-1           | STEMREGENIN-1                                                      |
| SUCBT          | SINGLE UMBILICAL CORD BLOOD TRANSPLANTATION                        |
| TBI            | TOTAL BODY IRRADIATION                                             |
| TCF            | TOTAL BODY IRRADIATION, CYCLOPHOSPHAMIDE, FLUDARABINE CONDITIONING |
| TEAE           | TREATMENT-EMERGENT ADVERSE EVENTS                                  |
| TKI            | TYROSINE KINASE INHIBITOR                                          |
| TRALI          | TRANSFUSION-RELATED ACUTE LUNG INJURY                              |
| TNC            | TOTAL NUCLEATED CELL                                               |
| TREC           | T CELL RECEPTOR EXCISION CIRCLES                                   |
| TRM            | TRANSPLANT-RELATED MORTALITY                                       |
| UCB            | UMBILICAL CORD BLOOD                                               |
| UCBT           | UMBILICAL CORD BLOOD TRANSPLANT                                    |
| ULN            | UPPER LIMIT OF NORMAL                                              |
| US             | UNITED STATES                                                      |
| WHO            | WORLD HEALTH ORGANIZATION                                          |
single-arm open label interventional phase
protocol synopsis single-arm open label

| MGTA-456 IN PATIENTS WITH HIGH-RISK MALIGNANCY   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                     |
|--------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------|
| Study Design:                                    | This is an single arm, open label, interventional phase II trial evaluating the efficacy of umbilical cord blood (UCB) hematopoietic stem and progenitor cells  (HSPC) expanded in culture with stimulatory cytokines (SCF, Flt-3L, IL-6 and  thromopoietin) in the presence of an aryl hydrocarbon receptor antagonist,  LHD221, on lympho-hematopoietic recovery. Patients will receive a uniform  myeloablative conditioning and post-transplant immunoprophylaxis. |                                                                                     |
| Investigational                                  | MGTA-456 is the cellular product composed of the UCB hematopoietic stem and                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                     |
| Agent:                                           | progenitor cells after expansion culture in the presence of the low molecular  compound LHD221 and its companion CD34 depleted fraction.                                                                                                                                                                                                                                                                                                                               |                                                                                     |
| Primary                                          | Determine if transplantation of MGTA-456 significantly reduces the expected                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                     |
| Objective:                                       | duration of neutropenia and number of hospital days to day 100 relative to that  observed in recipients of an unmanipulated single UCB unit                                                                                                                                                                                                                                                                                                                            |                                                                                     |
| Primary                                          | Incidence of neutrophil recovery by day 14                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                     |
| Endpoint: Secondary                              | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Number of days alive without hospitalization between days 0 and 100 after           |
| Endpoints:                                       | transplantation                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                     |
| -                                                | Incidence of secondary graft failure                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                     |
| -                                                | Incidence of platelet recovery at day 42                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                     |
| -                                                | Incidence of transplant-related mortality (TRM) at 6 months                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                     |
| Transplant  Related  Secondary  Endpoints:       | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Incidence of grades II-IV and III-IV acute graft vs host disease (GVHD) at day  100 |
| -                                                | Incidence of chronic GVHD at 1 year                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                     |
| -                                                | Incidence of relapse at 2 years                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                     |
| -                                                | Incidence of non-catheter associated bacterial infections by day 100                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                     |
| -                                                | Probability of overall survival and event-free survival (EFS) at 2 years                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                     |
| Exploratory                                      | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Description of immunological recovery                                               |
| Endpoints:                                       | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Incidence of absolute CD4 T cell ≥0.2 x 109 /L by day 100                           |
| -                                                | Incidence of opportunistic infection (viral/fungal) by day 100                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                     |
| -                                                | Description of hospital costs by day 100                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                     |
| -                                                | Description of number of red cell and platelet transfusions by day 100                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                     |
| -                                                | Assess B and T cell immune reconstitution as well as functional responses at  day 100 and day 180                                                                                                                                                                                                                                                                                                                                                                      |                                                                                     |
| Eligible                                         | Acute myeloid leukemia (AML) Acute lymphocytic leukemia (ALL)                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                     |
| Diseases:                                        | Biphenotypic/undifferentiated leukemia                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                     |
| April 23, 2021                                   | Page 11 of 68                                                                                                                                                                                                                                                                                                                                                                                                                                                          | CPRC #2018LS051                                                                     |  
Chronic myelogenous leukemia excluding refractory blast crisis Myelodysplasia (MDS) IPSS Int-2 or High risk (i.e. RAEB, RAEBt) or other high risk features  
| Unit Selection for Expansion  Culture:   | Cell dose ≥1 x 107 nucleated cells per kilogram (kg) recipient body weight and  HLA match at a minimum of 5 of 8 HLA alleles at high resolution A, B, C, DRB1  typing- based on the current Magenta cord blood algorithm.   |
|------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Transplant                               | Cryopreserved MGTA-456 with a cell dose of a minimum of 1 x 106 CD34/kg but                                                                                                                                                 |
| HSC Product:                             | ideally will be 10 x 106 per kg recipient body weight and the cryopreserved CD34- fraction.                                                                                                                                 |
| Key Inclusion                            | Aged ≤ 55 years                                                                                                                                                                                                             |
| Criteria:                                | Weight >11kg Karnofsky performance status >70 (≥16 years) or Lansky Play Score >50  Adequate organ function (per section 4.3)                                                                                               |
| Key Exclusion                            | Available HLA matched related or unrelated donor                                                                                                                                                                            |
| Criteria:                                | Pregnancy or breastfeeding History of HIV infection or known HIV positive serology Active serious infection Prior autologous or allogeneic hematopoietic stem cell transplant                                               |
| Accrual                                  | 40 patients enrolled over 3 years                                                                                                                                                                                           |
| Objective:                               |                                                                                                                                                                                                                             |
single-arm open label interventional phase
treatment plan

All patients will receive MGTA-456 on the day of transplantation after myeloablative conditioning. All patients aged 3-55 years will be conditioned with cyclophosphamide (CY) 120 mg/kg total dose, fludarabine (FLU) 75 m/m2 total dose and total body irradiation (TBI) 1320 cGy total dose as well as tacrolimus (Tac) and mycophenolate mofetil (MMF) immunoprophylaxis and granulocyte-colony stimulating factor (G-CSF) as detailed below:  
| Day                         | Conditioning Regimen                                                                        | Immunoprophylaxis                                                                                                   |
|-----------------------------|---------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------|
| Hematopoietic Growth Factor |                                                                                             |                                                                                                                     |
| -8                          | FLU 25 mg/m2 IV over 1 hour (<10 kg: 0.83 mg/kg IV over 1 hour) FLU 25 mg/m2 IV over 1 hour |                                                                                                                     |
| -7                          | (<10 kg: 0.83 mg/kg IV over 1 hour) CY 60 mg/kg IV over 2 hours FLU 25 mg/m2 IV over 1 hour |                                                                                                                     |
| -6                          | (<10 kg: 0.83 mg/kg IV over 1 hour) CY 60 mg/kg IV over 2 hours                             |                                                                                                                     |
| -5                          | Rest                                                                                        |                                                                                                                     |
| -4                          | TBI 165 cGy twice daily                                                                     |                                                                                                                     |
| -3                          | TBI 165 cGy twice daily                                                                     | Begin Tac / MMF (section 6.2)                                                                                       |
| -2                          | TBI 165 cGy twice daily                                                                     |                                                                                                                     |
| -1                          | TBI 165 cGy twice daily                                                                     |                                                                                                                     |
| 0                           | MGTA-456 infusion                                                                           | Begin G-CSF 5 ug/kg/d until the  absolute neutrophil count (ANC) is  >2500/uL for 2 consecutive days  (section 6.4) |
| +1                          |                                                                                             |                                                                                                                     |  
All young children <3 years of age at the time of diagnosis will receive MGTA-456 on the day of transplantation after a non-TBI containing myeloablative conditioning as TBI may have a damaging effect on brain development in the very young child. All patients aged 0-3 years will be conditioned with busulfan (BU), FLU and melphalan (MEL) as well as Tac/MMF
immunoprophylaxis and G-CSF, as detailed below:  
| Day                                 | Conditioning Regimen                                                                              | Immunoprophylaxis   |
|-------------------------------------|---------------------------------------------------------------------------------------------------|---------------------|
| Hematopoietic Growth Factor         |                                                                                                   |                     |
| BU IV once daily with dose based on |                                                                                                   |                     |
| -8                                  | Pharmacokinetics (PK) calculator over 3  hours                                                    |                     |
| -7                                  | Bu IV once daily adjusted based on PK  results over 3 hours Bu IV once daily adjusted based on PK |                     |
| -6                                  | results                                                                                           |                     |  
| Day                                                                                                                                                                                          | Conditioning Regimen                                                                                                                            | Immunoprophylaxis             |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------|
| Hematopoietic Growth Factor                                                                                                                                                                  |                                                                                                                                                 |                               |
| Bu IV once daily adjusted based on PK                                                                                                                                                        |                                                                                                                                                 |                               |
| -5                                                                                                                                                                                           | results over 3 hours FLU 25 mg/m2/day (0.83 mg/kg/day if < 10  kg*) IV over 60 min MEL 50 mg/m2/day (1.7 mg/kg/day if < 10  kg*) IV over 30 min |                               |
| -4                                                                                                                                                                                           | FLU 25 mg/m2/day (0.83 mg/kg/day if < 10  kg*) IV over 60 min MEL 50 mg/m2/day (1.7 mg/kg/day if < 10  kg*) IV over 30 min                      | Begin Tac / MMF (section 6.2) |
| -3                                                                                                                                                                                           | FLU 25 mg/m2/day (0.83 mg/kg/day if < 10  kg*) IV over 60 min MEL 50 mg/m2/day (1.7 mg/kg/day if < 10  kg*) IV over 30 min                      |                               |
| -1                                                                                                                                                                                           | Rest                                                                                                                                            |                               |
| 0                                                                                                                                                                                            | MGTA-456 Infusion                                                                                                                               |                               |
| -2                                                                                                                                                                                           | Begin G-CSF 5 ug/kg/d until the  absolute neutrophil count (ANC) is  >2500/uL for 2 consecutive days  (section 6.4)                             |                               |
| *Patients <11kg are currently ineligible because of the expected volume of DMSO in thawed  products. Once a wash step after thawing has been validated and approved by the FDA, patients  +1 |                                                                                                                                                 |                               |
single-arm open label interventional phase
1 hypothesis and objectives 1.1hypothesis

In vitro expansion of the hematopoietic stem and progenitor cells (HSPC) obtained from a single umbilical cord blood (UCB) unit prior to transplantation will significantly reduce the number of days of neutropenia relative to that observed after the transplantation of an unmanipulated single UCB unit (standard of care).
single-arm open label interventional phase
1.2primary objective

Determine if transplantation of MGTA-456 significantly reduces the expected duration of neutropenia and number of hospital days to day 100 relative to that observed in recipients of an unmanipulated single UCB unit.
single-arm open label interventional phase
1.3primary endpoint

Determine the incidence of neutrophil recovery by day 14 after transplantation in recipients of MGTA-456.
single-arm open label interventional phase
1.4secondary endpoints

- Number of days alive without hospitalization between days 0 and 100 after transplantation
- Incidence of secondary graft failure
- Incidence of platelet recovery at day 42
- Incidence of TRM at 6 months
single-arm open label interventional phase
1.5transplant related secondary endpoints

- Incidence of grades II-IV and III-IV acute GVHD at day 100
- Incidence of chronic GVHD at 1 year
- Incidence of relapse at 2 years
- Incidence of non-catheter associated bacterial infections by day 100
- Probability of overall survival (OS) and event-free survival (EFS) at 2 years
single-arm open label interventional phase
1.6exploratory endpoints

Additional analyses will be performed that may be important for the design of future trials. These include:
- Description of immunological recovery
- Incidence of absolute CD4 T cell >0.2 x 109/L by day 100
- Incidence of opportunistic infection (viral / fungal) by day 100 - Description of hospital costs by day 100
- Description of number of red cell and platelet transfusions by day 100
- Assess B and T cell immune reconstitution as well as functional responses at day 100 and day 180.
single-arm open label interventional phase
2 background

Hematopoietic stem cell transplantation (HSCT) is a standard treatment option for an increasing number of malignant and non-malignant disorders [1]. To reconstitute hematopoiesis after an intensive myeloablative therapy, the transplantation of hematopoietic stem cells (HSCs) is required. Such HSCs are typically recovered from the bone marrow or apheresed peripheral blood of the patients themselves, or suitably HLA matched related and unrelated volunteer donors [1,2]. Unfortunately, suitable donors are frequently not available either because the patient's own marrow is contaminated with tumor cells or potential allogeneic marrow donors are HLA mismatched or not healthy enough due to preexisting co-morbidities [3]. UCB is an established alternative source of HSCs that is capable of reconstituting hematopoiesis after intensive myeloablative therapy. It is immediately available at the time it is needed (in contrast to unrelated volunteer donors which takes a median of 3-4 months) and poses no risk to the donor [4,5].
single-arm open label interventional phase
2.1overview of ucb transplantation

As a result of the early successes with UCBT from sibling donors [6,7], pilot programs for the banking of unrelated donor UCB were initiated in many countries worldwide [8,9,10]. In addition to rapid availability, absence of donor risk, absence of donor attrition, and very low risk of transmissible infectious diseases, such as CMV and EBV, UCB is associated with a lower risk of acute GVHD despite HLA mismatch. UCB is especially beneficial for patients of ethnic and racial minority descent for whom suitably matched adult marrow and blood donors often cannot be identified [11]. UCBT is also associated with a potent anti-leukemia effect [12, 13, 14], lost in recipients of T cell depleted HSCs. While there is growing interest in the use of HLA mismatched haploidentical related donors with promising early data using post-transplant cyclophosphamide (CY) [15, 16], risks of relapse and clonal hematopoiesis has been observed
[17]. Therefore, UCB remains an important alternative particularly for children and young adults. The University of Minnesota has the largest single center experience worldwide with UCBT, having performed more than 1400 primary transplants with UCB between January 1, 1992 and the present.
single-arm open label interventional phase
2.1.1 single unit ucbt

2.1.1.1 **University of Minnesota Single Center Experience [18]**
Between 1994 and 2001, 102 consecutive patients (median age 7.4 years) received a single, unrelated UCB unit after a myeloablative conditioning for malignant (n = 65; 68% high-risk) and non-malignant diseases (n = 37). The median infused cell dose of UCB was 3.1 x 107 nucleated (NC)/kg (range 0.7-57.9), and 2.8 x 105 CD34+ cells/kg (range 0.4-39.1). Fourteen percent had an HLA
matched unit with the remaining 86% having a mismatch at 1 to 3 HLA-antigens.  
Neutrophil recovery (defined as an absolute neutrophil count [ANC] ≥ 500/uL) occurred at a median of 23 days (range 9-54) with the cumulative incidence of engraftment of 88% (95% CI: 81-95) by day 42. Speed of neutrophil recovery and engraftment were strongly associated with cell dose, with markedly inferior engraftment (72% at a median of 34 days) in patients receiving a CD34+ cell dose
<1.7 x 105 cells/kg.  
The incidences of grade II-IV and III-IV acute GVHD were 39% (95% CI: 29-49) and 11% (95% CI: 5-17), respectively, at day 100, with 10% (95% CI: 4-14) of patients having chronic GVHD at 1 year. One year TRM was 30% (95% CI: 21-39)
which was strongly associated with CD34+ cell dose. The probabilities of 1 and 2year survival were 58% (95% CI: 49-70) and 47% (95% CI: 36-57), respectively.  
Importantly, with a graft cell dose >1.7 x 105 CD34+ cells/kg, survival was 70%
(95% CI: 49-90) at 1 year. The principal conclusions of this study were: 1) a CD34 dose threshold is >1.7 x 105/kg and nucleated cell dose threshold is >2.5 x 107/kg; 2) neutrophil recovery is slow at a median of 23 days with more rapid recovery in recipients of higher cell doses, 3) risks of acute and chronic GVHD are low despite HLA mismatch; 4) cell dose significantly limits the applicability of UCB, particularly in adult size recipients.  
2.1.1.2 **National COrd BLood Transplant (COBLT) Study [19]**
On the basis of promising single center results and registry reports, the National Heart, Lung and Blood Institute (NHLBI) proposed COBLT study, a phase 2 trial to determine if unrelated UCB could serve as an adequate HSC source. The primary endpoint of the study was survival at 180 days after transplantation. The secondary endpoints included engraftment (neutrophil and platelet), acute and chronic GVHD,
disease-free survival, long-term survival, relapse, and regimen-related toxicities. For children with malignancy over the age of 2 years, the conditioning regimen and GVHD prophylaxis consisted of TBI 1350 cGy, CY 120 mg/kg and anti-thymocyte globulin (ATG, equine) 90 mgkg and CsA and methylprednisolone (MP) for GVHD
prophylaxis.  
One hundred and ninety-three children with hematologic malignancy were enrolled. The median age was 7.7 years (range, 0.9-17.9 years) and median weight was 25.9 kg
(range, 7.5-118.4 kg) with 40% being nonwhite, 61% being male, and 51% being seropositive for cytomegalovirus (CMV). The majority of patients had either ALL (n = 109
[57% of total patients] with 17 in first complete remission [CR]; 65 in second CR;
20 in third CR; 6 in relapse; and, 1 with primary induction failure) or AML (n = 51
[27%] with 13 in first CR; 21 in second CR; 6 with primary induction failure; and 11 in relapse). The UCB grafts were 6/6 HLA matched (8.9%), 5/6 matched (30.4%) or 4/5 matched (58.1%). The median TNC, CD34+,
and CD3 doses of the UCB grafts were 5.1 × 107 cells/kg (range, 1.5-23.7), 1.9 ×
105/kg (range, 0.0-25.3), and 7.9 × 106/kg (range, 0.1-35.6), respectively.  
The incidence of neutrophil recovery by day 42 was 79.9% (95% confidence interval [CI] 75.1%-85.2%) with 14 patients recovering neutrophils between days 43 and 90. At 6 months, 86.9% of patients had sustained neutrophil engraftment.  
The median time to neutrophil recovery was 27 days (range, 11-90 days). Primary and secondary graft failure occurred in 21 and 2 patients, respectively. The incidence of platelet engraftment (defined as platelet count ≥ 50000/uL without transfusion for 1 week) was 50.0% (95% CI, 42.1%-56.5%) at day 180. Notably, the probability of EFS was 49.5% at 2 years with no impact of HLA match based on HLA A and B at antigen level and DRB1 at allele level (Figure 1) and the incidences of grade II-IV acute GVHD at day 100, chronic GVHD at 2 years, and relapse at 2 years were 19.5%, 21% and 20%, respectively. In univariate analysis, lower recipient weight (p=.02), better allele level HLA match
(p=.03), higher TNC (p=.03), and higher CD34+ dose (p=.01) positively impacted neutrophil recovery. In a multivariate Cox model, only better allele level HLA match (p=.04) and higher TNC dose were independently significant (p=.04). The principal conclusions of this study were: 1) slow neutrophil recovery and poor engraftment are significant limitations of UCBT, 2) risks of GVHD are low relative to other HSC sources, and 3) HLA mismatch is tolerable with improved survival in recipients of better HLA matched grafts with higher TNC.
single-arm open label interventional phase
2.1.2 double unit ucbt 2.1.2.1

Since cell dose was identified as a major limitation of UCBT, often preventing the consideration of UCB for adult recipients, we explored the possibility of infusing two partially HLA matched units to augment cell dose. After 2000, two UCB units were increasingly utilized, particularly in adults and adolescents for whom an adequately dosed single UCB unit could not be identified. The underlying hypothesis was that the addition of the second unit would enhance the engraftment and the speed of hematopoietic recovery.  
In the first pilot study [20] of double UCBT (DUCBT), 31 adult and adolescent patients [median age 24 years (range: 13-53); median weight 73 kg (range: 48120)] with high-risk hematologic malignancy were transplanted with two partially HLA-matched UCB units after a myeloablative conditioning. The median total infused dose 3.7 x 107 nucleated cells (NC) per kilogram (range 1.1-6.3) and 4.9 x 105 CD34 per kilogram (range, 0.9-14.5).  
Of 29 patients surviving 21 days after transplant, 100% engrafted at a median of 23 days (range 14-41), comparing favorably with 65% engraftment in the prior 23 adults treated with a single UCBT. The incidence of platelet recovery (>50,000/uL) was 73% (95% CI, 51-95) at day 180. Incidence of grades II-IV and III-IV acute GVHD was 65% (95% CI, 42-88) and 17% (95% CI, 2-32) at day 100. EFS was 72% at 1 year for patients transplanted in CR.  
The principal conclusions of this study were: 1) DUCBT is safe with engraftment observed in all patients, 2) one unit predominates within the first 100 days, 3)
>90% of adults will be able to identify two units that are partially HLA matched with the patient and each other, 4) incidence grade III-IV acute GVHD is similar to that observed after single UCBT; and 5) survival exceeds that of historical data in adult recipients of a single UCB unit.
single-arm open label interventional phase
2.1.3 comparisons with other hsc

In order to determine the relative effectiveness of DUCBT compared to other HSC sources
(marrow or peripheral blood from matched and mismatched sibling and unrelated donors),
consecutive patients aged ≥ 10 years and undergoing first allogeneic HSCT for hematologic malignancy were evaluated. All 536 patients received myeloablative conditioning with CY 120 mg/kg and TBI 1200 to 1320 cGy with the addition of FLU 75 mg/m2 in recipients of DUCBT; GVHD immunoprophylaxis included a calcineurin inhibitor.  
Allografts were from a matched unrelated donor (MRD, n=204), matched unrelated donor
(MUD, n=152), mismatched unrelated donor (MMUD, n=52), or DUCB (n=128). Differences between donor groups included, higher median age in MRD recipients, more frequent diagnosis of CML in recipients of MUD or MMUD grafts, lower incidence of CMV seropositivity in recipients of MUD grafts, and greater HLA mismatch and shorter follow-up in recipients of DUCB. The primary endpoint of this analysis was leukemia free survival (LFS). LFS at 5 years  
 was similar for all 4 groups. After adjusting for disease risk and time from diagnosis to transplantation, multivariable analysis did not reveal any difference in the relative risk of EFS by donor type.  
The incidence of relapse at 5 years was comparable in recipients of MRD, MUD, and MMUD grafts but lower in recipients of DUCBT (Figure 2) with similar outcomes in the subset of patients ≤ 45 years. After adjusting for disease risk, interval from diagnosis to transplantation, age at transplantation and diagnosis, multivariable analysis showed lower relative risk of relapse was associated with DUCBT. Similarly, the relative risk of relapse remained lower among DUCBT recipients regardless of risk group and additional analyses revealed similar outcomes when restricted to patients aged ≥18 years. Leukemia relapse was the most frequent cause of mortality in recipients of MRD, MUD, and MMUD grafts.  
The incidence of TRM at 2 years, however, was higher in recipients of UCB even after adjusting for age at transplantation and diagnosis. Analysis of risk factors for TRM among DUCB recipients demonstrated a higher risk in patients with delayed neutrophil recovery
(41% [95% CI, 26%-56%] if neutrophil recovery took ≥26 days (which was the median time to neutrophil recovery) compared 16% [95% CI, 7%-25%] if recovery was <26 days). If restricted to DUCB recipients with earlier (<median 26 days) neutrophil recovery after UCBT, the incidence of TRM was similar in all groups, emphasizing that delayed engraftment is the single greatest barrier to successful UCBT and the most important contributor to early TRM. Infection was the most common cause of death among recipients of UCB.  
The principal conclusions of this study were: 1) Higher TRM after DUCBT is still driven by prolonged neutropenia, and 2) relapse is low after DUCBT relative to other HSC sources.
single-arm open label interventional phase
2.1.4 national bmt-ctn 0501 study

As a result of these promising single institutional data, a national trial was developed to compare single versus DUCBT to determine if two UCB units would confer a survival advantage. Between December 1, 2006, and February 24, 2012, a total of 224 patients 1 to 21 years of age with hematologic cancer were randomly assigned to undergo DUCBT
(111 patients) or single UCBT (113 patients) after a uniform myeloablative conditioning regimen regimen of FLU 75 mg/m2, TBI 1320 cGy and CY 120 mg/kg. The primary end point was 1-year overall survival. Treatment groups were balanced with respect to all baseline covariates, including sex, age, results of serologic testing for cytomegalovirus, disease type and status at transplantation, performance score, degree of donor–recipient HLA matching and ABO matching, and self-reported Hispanic or Latino background and race or ethnic group. The median age at transplantation was 9.9 years (range, 1.1 to 21.2) for DUCBT recipients and 10.4 years (range, 1.4 to 21.4) for single UCBT recipients, and the median body weight was 37.0 kg (range, 9.7 to 81.7) and 35.7 kg (range, 10.0 to 93.0),
respectively. All received a graft containing >2.5 x 107 NC/kg. The median number of infused NC/kg was 7.2 x 107 for recipients of DUCBT and 3.9 x 107 for recipients of single UCBT grafts, and the number of infused CD34+ cells/kg was 3.7 x 105 and 1.9 x 105, respectively.  
The overall survival rate was 65% (95% CI, 56 to 74) among DUCBT recipients and 73%
(95% CI, 63 to 80) among single UCBT recipients (p=0.17). In a multivariate analysis, the risk of death did not differ significantly between recipients of DUCBT and recipients of single UCBT (hazard ratio, 1.34; 95% CI, 0.86 to 2.09; p=0.20, with the single-unit group used as the referent), even after adjustment for disease type (AML vs. other), which was the only factor associated with an increased risk of death.  
The 1-year EFS rate was 64% (95% CI, 54 to 72) among DUCBT recipients and 70%
(95% CI, 60 to 77) among single UCBT recipients (p=0.11). In a multivariate analysis, the risk of relapse or death (i.e., the risk of treatment failure, the inverse of the EFS rate) did not differ significantly between groups, even after adjustment for leukemia type, selfreported race (white vs. nonwhite), and HLA match score (better HLA match had worse outcome), which were the factors associated with EFS.  
Notably, the incidence of neutrophil recovery was 88% (95% CI, 82 to 94) among DUCBT
recipients and 89% (95% CI, 83 to 95) among single UCBT recipients (p=0.29), at a median of 23 days (range, 11 to 133) and 21 days (range, 11 to 62) after transplantation, respectively. No patients in either group had secondary graft failure. The incidence of platelet recovery, however, was significantly higher and recovery occurred more quickly among recipients of a single UCBT than among recipients of a DUCBT (incidence, 76% [95% CI, 68 to 85] vs. 65% [95% CI, 56 to 74]; P=0.04). The median time to platelet recovery was 58 days (range, 28 to 295) in the single unit group and 84 days (range, 22 to 716) in the double-unit group.  
For the other endpoints, the incidence of grade II–IV acute GVHD was similar in the two treatment groups (p=0.78); however, recipients of DUCBT had a higher incidence of grade III and IV acute GVHD (23% [95% CI, 15 to 31] vs. 13% [95% CI, 7 to 20], p=0.02). The incidence of any chronic GVHD at 1 year was 32% (95% CI, 23 to 40) and 30% (95% CI, 22 to 39), respectively (p=0.51), with a higher incidence of extensive disease (15% [95% CI, 8 to 22] vs. 9% [95% CI, 4 to 14], respectively p=0.05). Among the 220 patients (91%)
with at least one infection after transplant, 120 (55%) had a severe infection, and 32 (15%)
had a life-threatening or fatal infection. No significant differences were observed between the treatment groups. The incidences of relapse and TRM were also similar in the two treatment groups. Notably, the incidence of relapse at 1 year was low in both groups: 14% (95% CI, 7 to 21) in recipients of a DUCBT and 12% (95% CI, 6 to 18) in recipients of a single UCBT (p=0.12). The incidence of TRM at 1 year was 22% (95% CI, 14 to 30)
among DUCBT recipients and 19% (95% CI, 11 to 26) among single UCBT recipients (p=0.43). The principal conclusions of this study were: 1) rates of engraftment, relapse and survival were similar between recipients of DUCBT and an adequately dosed single UCBT, and 2)
patients in both treatment groups had better engraftment and survival outcomes than those previously reported, supporting the use of FLU rather than ATG in the conditioning, and MMF rather than methylprednisolone in the post-transplant immunoprophylaxis in future trials.
single-arm open label interventional phase
2.1.5 impact of conditioning on

The BMT CTN 0501 trial not only demonstrated similar survival rates in recipients of double vs single UCBT in children with hematologic malignancies but suggested that the treatment package, ie conditioning and post-transplant immunoprophylaxis, might be superior to other regimens. This prompted a comparison of survival of 0501 trial versus nontrial patients to determine the generalizability of trial results and whether survival was better because of the trial treatment regimen. During the trial period, 396 recipients of a single UCB unit met trial eligibility but were not enrolled. Trial patients (n = 100) received TBI 1320 cGy, CY120 mg/kg, and FLU 75 mg/m2 (TCF). Non-trial patients either received the same TCF regimen (n = 62; nontrial TCF) or alternative regimens
(n = 334; nontrial regimens). Five-year survival between trial and nontrial patients conditioned with TCF was similar (70% versus 62%) (Figure 3). However, 5-year survival was significantly lower with nontrial TBI-containing (47%; hazard ratio [HR], 1.97; P =
.001) and chemotherapy-only regimens (49%; HR, 1.87; P = .007). The survival difference between the trial-specified regimen and other regimens indicate the importance of the treatment package for UCBT.  
The principal conclusions of this study were: 1) engraftment was better in recipients of  
  
employed in BMT CTN 0501 developed at the University of Minnesota and used in all UCBT after 2000.
single-arm open label interventional phase
2.2mgta-456 - aryl hydrocarbon receptor

StemRegenin-1 (SR-1) was first identified in an unbiased screen for compounds that promoted expansion of CD34+ hematopoietic progenitors [25]. SR-1 is an AHR antagonist which impedes HSC differentiation during cytokine-driven expansion culture. Thus far, 36 patients with hematological malignancy have been treated with UCB CD34+ cells after a 15day expansion culture using this strategy (cross-reference IND\# 14822 Novartis Sponsor). The cellular product that results from this expansion culture as well as its companion CD34 depleted fraction (cryopreserved on the day the CD34+ cells are placed in expansion culture), was previously referred to as HSC835 and is now referred to as 'MGTA-456'. MGTA-456 has been tested in 2 human studies in patients with hematologic malignancies Study CHSC835X2201 and Study CHSC835X2202.  
Study CHSC835X2201 was a first-in-human, single-arm, single-center, open-label, proof-ofconcept study to evaluate the safety, tolerability, and preliminary efficacy of infusing MGTA456 (expanded UCB HSC) in patients with hematological malignancies who have undergone myeloablative conditioning. The conditioning regimen comprised fludarabine administered at 25 mg/m2/day i.v. for three days (Day -8 to -6), cyclophosphamide administered at 60 mg/kg/day for two days (Day -7 to -6) and total body irradiation (TBI) at 165 cGy given twice daily for four days (Day -4 to -1). The study initially enrolled adult patients who were administered a DUCBT - one unit consisting of unmanipulated cells and the other of the expanded MGTA-456 product. After the first planned interim analysis at which five evaluable patients demonstrated that administration of MGTA-456 showed no unexpected infusional toxicity and resulted in hematopoietic reconstitution within the expected time frame, the protocol was amended to include pediatric patients (≥ 10 years) into the study. A subsequent interim review of the data for the first nine adult patients showed that the safety findings were consistent with the published findings for DUCBT [12]. The expanded cord blood product led to sustained, long-term hematopoietic engraftment in an accelerated fashion that correlated with the CD34+ cell dose. Furthermore, patients in whom MGTA-456 predominated recovered their neutrophils faster than patients in whom the unmanipulated CBU predominated.  
Following this, the protocol was amended such that adult patients were transplanted with a SUCBT with MGTA-456. Once safety data of SUCBT in adults and of DUCBT in the pediatric population were available, the protocol was amended such that pediatric patients were transplanted with SUCBT. A total of 31 patients were enrolled in this study; 27 of whom were transplanted during the study and 16 of whom completed the study.  
In the initial analysis of the trial identified by CHSC835X2201, 18 patients were treated with MGTA-456 along with a second unmanipulated UCB unit, in case the MGTA-456 did not engraft. All 18 patients engrafted at a median of 14.5 days (range, 7-23 days), substantially better than identically treated historical controls (n=151) in whom the incidence of engraftment was 89% (95% CI 83-93) at a median of 23 days (range, 19-31 days) (p<0.01). In two Phase 2 clinical trials using MGTA-456 as a stand-alone graft, 18 patients with high-risk hematologic malignancy and a partially HLA matched UCB unit were treated. Patients received the CD34-positive fraction along with the CD34-negative fraction of the expanded UCB unit which was separated prior to initiating the expansion culture. It is known that CD34negative cells contain CD3+ T lymphocytes and have been shown to be important in unit predominance long term and therefore may have a protective effect. Nine were treated with myeloablative (MA) conditioning consisting of CY 120 mg/kg, FLU 75 mg/m2 and TBI 1320 cGy, which was an extension of CHSC835X2201 and 9 were treated with non-myeloablative (NMA) conditioning consisting of CY 50 mg/kg, FLU 200 mg/m2 and TBI 200 cGy, identified by CHSC835X2202 with all receiving CsA and MMF immunoprophylaxis.  
The AHR antagonist expansion culture yielded a median of 1,227 x 106 CD34+ cells (range, 201-8969) as compared to the input number of 4.2 x 106 (range, 1.4-16.3) after CD34 selection - a 324-fold (range, 42-1643) expansion of CD34+ cells. As transplant results vary by intensity of the conditioning regimen, patient outcomes were compared to similarly treated historical cohorts (n=151 MA conditioning; 32 NMA conditioning). For both groups, demographics were similar except for more recent year of transplant for recipients receiving MGTA-456. For recipients of MA, MGTA-456 engrafted in 100% of patients at a median of 14 days (range, 7-32 days) as compared to 89% engraftment at a median of 23 days in historical cohort (range, 19-31 days) (p<0.01). Similar to the historical cohort, complete chimerism was rapid for both myeloid and T cells with no late graft failures in recipients of MGTA-456. For recipients of NMA conditioning, MGTA-456 also engrafted in 100% of patients but at a median of 7 days (range, 6-14 days) as compared to 95% of patients at a median of 15 days (range, 7-22 days) in the historical cohort. In contrast to MA conditioning, chimerism was often mixed for the first month in both myeloid and T cells after NMA conditioning. Compared to the historical cohort, recipients of MGTA-456 had more rapid chimerism after NMA conditioning.  
CD34 cell dose correlated with speed of recovery but only in recipients with MA conditioning; in recipients of non-MA conditioning, recovery was uniformly rapid regardless of CD34 cell dose. With regard to other transplant outcomes, results are encouraging. For recipients of MGTA-456 compared to the historical cohort after MA conditioning, incidence of AGVHD 3-4 was 22% vs 24%; CGVHD, 11% vs 21%; TRM, 11% vs 34%; and OS, 67% vs 55%). After NMA conditioning, results are similar between cohorts, specifically, incidences of acute GVHD
3-4 were 56% vs 15%; CGVHD, 0% vs 19%; TRM, 22% vs 20%; and OS, 44% vs 49%).
single-arm open label interventional phase
2.3human pharmacokinetic data

Patients enrolled onto Novartis study CHSC835X2201 were evaluated for the presence of the AHR antagonists, LFU835 or LHD221, infused with the washed cells of MGTA-456.  
Pharmacokinetic (PK) data from patients receiving MGTA-456 expanded with LFU835, showed an exposure to LFU835 slightly lower than predicted from animal data. Safety margins were very large (based on one-fifth of NOAEL in female monkeys) and maximum observed concentration (Cmax) and area under the plasma concentration-time curve (AUC)
ranged from 9.9 to >10,000 ng/mL and from 68 to 2734 h × ng/mL in individual patients who received total cell doses between 4 and 114 million cells/kg body weight. For LHD221, which will be used in the present study, Table 1 shows the available results. The amount of co-infused LHD221 remaining on the washed cells ranged from 55 to 693 μg
(predicted based on in vitro measurements of 0.044 pg/cell). The highest measured concentration in a plasma sample was 1.36 ng/mL and in many samples no LHD221 could be detected (lower limit of quantification [LLOQ]: 0.1 ng/mL). No pharmacokinetic parameters (AUC, Cmax) were derived, but compared to the exposure in female monkeys at the no observed adverse effect level (NOAEL) (0.5 mg/kg of LHD221; AUC=637 h × ng/mL,
Cmax=1112 ng/mL) it can be assumed that the safety margins are very large.  
| Scheduled Time (hours)   |             |                       |      |      |      |
|--------------------------|-------------|-----------------------|------|------|------|
| Calculated               |             |                       |      |      |      |
| LHD221 Dose  (μg)        | 1.0         | 5.0                   | 12.0 |      |      |
| Study ID                 | Patient No. | Concentration (ng/mL) |      |      |      |
| CHSC835X2201             | 0001-05123  | 226                   | NA   | 0.00 | NA   |
| 0001-05124               | 125         | 1.09                  | 0.17 | 0.00 |      |
| 0001-05126               | 55          | 0.00                  | 0.00 | 0.00 |      |
| 0001-05127               | 203         | 0.34                  | 0.00 | 0.00 |      |
| CHSC835X2202             | 1001-25101  | 76                    | 0.00 | 0.00 | 0.00 |  
| Scheduled Time (hours)                                                                     |             |                       |      |      |
|--------------------------------------------------------------------------------------------|-------------|-----------------------|------|------|
| Calculated                                                                                 |             |                       |      |      |
| LHD221 Dose  (μg)                                                                          | 1.0         | 5.0                   | 12.0 |      |
| Study ID                                                                                   | Patient No. | Concentration (ng/mL) |      |      |
| 1001-25102                                                                                 | 693         | 0.14                  | 0.00 | 0.00 |
| 1001-25103                                                                                 | 169         | 1.36                  | 0.34 | 0.00 |
| 1001-25104                                                                                 | 95          | 0.00                  | 0.00 | 0.00 |
| 1001-25105                                                                                 | 592         | 0.28                  | 0.00 | 0.00 |
| For LFU835 the calculated safety margins are very large. As the LHD221 concentrations were |             |                       |      |      |  
For LFU835 the calculated safety margins are very large. As the LHD221 concentrations were very low and no PK parameters could be derived, it can be assumed that the safety margins are also very large for LHD221 as well. For additional information, please refer to the IND
Master File.
single-arm open label interventional phase
2.4cryopreserved mgta-456

A manufacturing process was developed to allow the formulation of the expanded CD34+ fraction as a cryopreserved product. The cryopreserved product improves on the quality of key manufacturing reagents and results in a final product with a pre-defined volume and DMSO content. DMSO content in the cryopreserved product is lower in concentration than the amount present in the FDA-approved, cryopreserved unmanipulated UCB units. The total amount of administered DMSO is expected to be generally well tolerated with some risk of infusional toxicities. Such infusional toxicities may include but are not limited to fever, nausea, vomiting, excessive sweating (diaphoresis), labored breathing (dyspnea), chest discomfort, desaturation (reduced oxygen saturation), hypotension, hypertension, headache, and bradycardia (slow heart rate). If thawed product units are washed prior to infusion, the amount of DMSO will be significantly reduced and expected to be very well tolerated.
single-arm open label interventional phase
2.5summary and rationale for the

MGTA-456 is an allogeneic UCB cell therapy product that consists of 2 cell fractions derived from the same UCB unit. The manufacturing process consists of expanding the CD34-positive (CD34+) cells derived from the UCB in vitro in the presence of cytokines and a low molecular weight (LMW) compound (AHR antagonist) and the resulting product is provided to the patient directly after the manufacturing process. The other cell fraction consists of CD34-depleted cells from the same UCB unit. Results with MGTA-456 in 38 patients with hematological malignancies support additional evaluation.  
Therefore, we propose a phase II trial evaluating the effectiveness of MGTA-456 in children and adults with selected hematological malignancies eligible to receive MA conditioning.  
Eligible patients will undergo single UCBT consisting of the investigational therapy of MGTA456. In addition to the conventional endpoints of neutrophil and platelet engraftment, acute and chronic GVHD, TRM, relapse and survival, other functional endpoints, such as noncatheter associated bacterial infections by day 100, risk of opportunistic infections, number of red cell and platelet transfusions will be evaluated. Surrogate endpoints, such as number of hospital days and treatment costs over the first 100 days will also be evaluated. With regard to the primary endpoint, this trial is powered to verify the effectiveness of MGTA-456 as measured by the proportion of patients engrafting by day 14 after transplantation.  
This trial is supported by an NCI Program Project Grant and other local support. Magenta Therapeutics will provide LHD221 (StemRegenin-1) for the proposed trial and permit use of the manufacturing SOPs previously developed at the University of Minnesota under Novartis/Magenta sponsorship as well as provide support for the manufacture of MGTA-456.
single-arm open label interventional phase
2.6 immune reconstitution sub-study

Immunity is impaired after hematopoietic stem cell transplant (HSCT), and the recovery of cell counts can take years. The innate immune system is comprised of neutrophils, monocytes, macrophages, dendritic cells, and natural killer (NK) cells. These cells are able to recognize and eradicate pathogens without the need for antigen presentation. In contrast, the adaptive immune system is comprised of T and B cells. These cells require priming by the antigen, leading to long-term specific responses using unique receptor sequences. The desired outcome of HSCT is the reestablishment of an effective immune system that accurately delineates self from non-self. If adequate antigen-specific immune function is present, functional immune reconstitution has the potential to decrease leukemic relapse and TRM. Clear understanding of the functional immune recovery is needed for successful HSCT. Also, understanding the different time courses of functional recovery of each immune cell subset can help to predict the course of disease in individual patients after HSCT. Recent work has been done to understand immune reconstitution. In a recent study by Park et al (2015) 95 patients with hematologic malignancies who underwent allogeneic HSCT were evaluated [45]. Patients received different conditioning regimens depending on donor type which included sibling matched, unrelated matched or haploidentical HSCT. Lymphocyte subsets showed different sequential patterns according to HSCT type but no differences were seen according to primary diagnosis or conditioning regimen. Specifically they found that the number of white blood cells (WBCs) recovered within 1 month of HSCT and T and B lymphocyte numbers recovered at 2 months after HSCT. Interestingly, the CD4/CD8 ratio was reversed during all periods after HSCT. Among T cell subpopulations, NK-T cells, and effector memory T cells recovered within 1–2 months after HSCT, but central memory T cells were not detected in peripheral blood throughout the study period. There were low levels of naïve thymic T cells after HSCT, while the number of naive central T cells peaked immediately after HSCT. The percentage of Tregs started to increase at 3 months after HSCT, but maintained at a relatively low level during the entire study period.  
B cell reconstitution is less studied and understood after HSCT. Recent work form AbdelAzim et al (2017) evaluated 71 pediatric patients undergoing HSCT from 2004-2011 [46].  
They found that tetanus toxoid antibody levels were normal at 1 year after HSCT whereas antipolysaccharide carbohydrate antibodies remained persistently low for up to 5 years. While naive B cell counts normalized by 6 months, IgM memory B cell deficiency persisted for up to 2 years. Moreover, switched memory B cell deficiency normalized by 1 year after HSCT.  
CD4+ T cell play a large part in humoral immunity; data showed the CD4 cell immune reconstitution correlated with that of switched memory B cells as early as 6 months after HSCT but did not correlate with IgM memory B cells at any time point after HSCT. Taken together, this data suggests that antibody immune reconstitution is impaired mainly due to IgM
memory B cell maturation block. They also found that the use of naïve UCB was associated with better naive and IgM [47] memory B cell immune reconstitution at 6 months after HSCT, compared with the use of bone marrow and peripheral blood stem cells. Moreover, the use of UCB was also associated with better switched memory B cell immune reconstitution at 6 months after HSCT, compared with the use of PBSC. As there is currently an unmet need in regards to understanding both B and T cell immune reconstitution as well as functional responses post expanded UCB HSCT this sub-study aims to prospectively assess both subsets of immune cells and determine functional immune responses at certain time points.
single-arm open label interventional phase
3 study design

This is a prospective single-arm, open label, interventional phase II clinical trial evaluating MGTA456 in children and adults with selected hematopoietic malignancies to elucidate its effect on reducing the duration of neutropenia and thrombocytopenia, and consequently reducing risks of bacterial infections and numbers of platelet transfusions, and risks of infections. Success will be measured by 33% of patients achieving neutrophil recovery by day 14.
single-arm open label interventional phase
4 patient selection

Study entry is open to persons aged <55 years regardless of gender or ethnic background. While there will be every effort to seek out and include females and minority patients, the patient population is expected to reflect those with high risk leukemia and MDS referred to the institution.
single-arm open label interventional phase
4.1age weight unit cell dose

- Subjects must weigh >11 kg
- Subjects must have a partially HLA matched UCB unit with a pre-cryopreserved TNC
dose >1.0 x 107 per kilogram recipient weight. HLA matching is initially based on a minimum of 5 of 8 HLA alleles at high resolution A, B, C, DRB1 typing; searches will be performed according to the current Magenta Cord Blood Search Algorithm.
single-arm open label interventional phase
4.2eligible diseases

- Acute myelogenous leukemia (AML) in morphological complete remission with:  
o Minimal residual disease (MRD) by flow cytometry, or o Intermediate to high risk leukemia in first (CR1) based on institutional criteria, eg. not favorable risk AML which is defined as having one of the following:
- t(8,21) without *cKIT* mutation
- inv(16) or t(16;16) without *cKIT* mutation - Normal karyotype with mutated *NPM1* but *FLT3-ITD* wild type
- Normal karyotype with double mutated CEBPA
- Acute promyelocytic leukemia (APL) in first molecular remission at the end of consolidation
o Any second or subsequent CR, or o Secondary AML with prior malignancy that has been in remission for at least 12 months.  
- Acute lymphocytic leukemia (ALL) at the following stages:
o High risk first morphological, cytogenetic and molecular CR with:
- MRD by flow cytometry, or
- Diagnosis of Philadelphia chromosome (Ph)+ ALL, or - MLL rearrangement at diagnosis with slow early response at Day 14, or - Hypodiploidy (< 44 chromosomes or DNA index < 0.81) at diagnosis, or
- End of induction M3 bone marrow, or
- End of induction M2 with M2-3 at Day 42.  
o High risk second CR based on institutional criteria (eg, for children, bone marrow relapse <36 months from induction or T-lineage bone marrow relapse or very early isolated central nervous system (CNS) relapse <6 months from diagnosis, or slow re-induction (stage M2-3 at day 28 after induction) regardless of length remission.  
All patients with MRD by flow cytometry.  
o Any third or subsequent CR.
single-arm open label interventional phase
- secondary all

- Biphenotypic/undifferentiated leukemia in morphological, cytogenetic and molecular CR .  
- Chronic Myelogenous Leukemia (CML) in high risk first chronic phase (failure of two tyrosine kinase inhibitors (TKI) or TKI intolerance), accelerated phase or second chronic phase.  
- Myelodysplasia (MDS) IPSS Int-2 or High risk (i.e. RAEB, RAEBt <5% blasts) or other high risk features, including multiple cytopenias, high risk cytogenetics or lack of response to standard therapy.  
- Relapsed large-cell lymphoma, mantle-cell lymphoma and Hodgkin lymphoma that is chemotherapy sensitive and ineligible for an autologous transplant.  
- Burkitt's lymphoma in CR2 or subsequent CR.  
- Relapsed T-cell lymphoma that is chemotherapy sensitive in CR/PR that is ineligible for an autologous transplant.
single-arm open label interventional phase
4.3organ specific inclusion criteria

- Karnofsky score ≥70 (16 years and older), Lansky play score >50 (children 2-16 years, or 'adequate' score for children <2 years, as detailed in Appendix I.  
- Adequate organ function defined as:
o Renal: Serum creatinine within normal range for age, or if serum creatinine outside normal range for age, then creatinine clearance >40 ml/min or GFR normal for age o Hepatic: Bilirubin <3x upper limit of normal (ULN) and AST, ALT and alkaline phosphatase <5x ULN.  
o Pulmonary function: DLCO, FEV1, FEC (diffusion capacity) >50% of predicted
(corrected for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation >95% on room air.  
o Cardiac: No uncontrolled arrhythmia and left ventricular ejection fraction at rest must be >45%.  
- Available 'back-up' HSPC graft (e.g, second UCB unit, haploidentical related donor).  
- Females of child bearing potential and sexually active males must agree to use adequate birth control during study treatment.  
- Voluntary written consent signed (adult or parental) before performance of any studyrelated procedure not part of normal medical care.
single-arm open label interventional phase
4.4exclusion criteria

- Patients with a HLA matched sibling donor or a HLA matched unrelated donor who is available for marrow or peripheral blood stem cell collection at the desired time of transplant.  
- Pregnant or breast feeding. The agents used in this study may be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. Females of childbearing potential must have a blood test or urine study within 14 days prior to study enrollment to rule out pregnancy.  
- Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology.  
- Active bacterial, viral or fungal infection (currently taking medication and persistence of clinical signs and symptoms) with a minimum of 4 weeks of anti-fungal treatment
- Prior autologous or allogeneic transplant. - Other active malignancy. - Subjects >3 years of age unable to receive TBI 1320 cGy due to extensive prior therapy including >12 months alkylator therapy or >6 months alkylator therapy with extensive radiation, or prior Y-90 ibritumomab (Zevalin) or I-131 tostumomab (Bexxar), as part of their salvage therapy.
single-arm open label interventional phase
5 patient registration

Registration will occur after the patient or patient's guardian has signed the subject consent but before any treatment has been administered. To be eligible for registration to this study, the patient must meet each criterion listed on the eligibility checklist based on the eligibility assessment documented in the patient's medical record. A copy of the eligibility checklist is under attachments within the study in OnCore.
single-arm open label interventional phase
5.1registration with the masonic cancer

Any patient who has been consented is to be registered in OnCore by the Primary Clinical Research Coordinator (PCRC) or designee. If a patient is consented, but not enrolled, the patient's record is updated in OnCore as a screen failure and reason for exclusion recorded
single-arm open label interventional phase
5.2.study enrollment with the masonic

To be eligible for study enrollment, the patient must sign the treatment consent and meet each of the inclusion criteria and none of the exclusion on the eligibility checklist based on the eligibility assessment documented in the patient's medical record.  
The Primary Clinical Research Coordinator (PCRC) or designee will assign the study treatment arm and add the on-treatment date to complete enrollment.
single-arm open label interventional phase
5.3patients who are enrolled but

If a patient is enrolled onto the study and is later found not able to begin the planned study treatment for whatever reason, the patient will be removed from study and treated at the physician's discretion. The study coordinator or designee will update OnCore of the patient's non-treatment status and notify the Principal Investigator. The reason for removal from study prior to starting study treatment will be clearly indicated in OnCore. The patient may be replaced.
single-arm open label interventional phase
6 treatment plan

In order to provide optimal patient care and to account for individual medical conditions, investigator discretion may be used in the prescribing of all supportive care drug therapy (i.e. acetaminophen, diphenhydramine, antimicrobials, etc.). All patients aged 3-55 years inclusive will receive the same conditioning and immunoprophylaxis for the prevention of acute and chronic GVHD, previously demonstrated to offer the best outcomes in recipients of partially HLA matched UCB. Patients 0-3 years will receive a non-TBI containing conditioning regimen which is standard of care.
single-arm open label interventional phase
tbi-containing regimen

All patients aged 3-55 years will receive CY 120 mg/kg total dose, FLU 75 m/m2 total dose and TBI 1320 cGy total dose. Standard supportive care, including the use of G-CSF and prophylactic anti-bacterial, protozoal, viral and fungal agents, will also be prescribed. Supportive care will be modified throughout the transplant course at the treating physician's judgement.  
| Day                         | Conditioning Regimen                                                                        | Immunoprophylaxis   |
|-----------------------------|---------------------------------------------------------------------------------------------|---------------------|
| Hematopoietic Growth Factor |                                                                                             |                     |
| -8                          | FLU 25 mg/m2 IV over 1 hour (<10 kg: 0.83 mg/kg IV over 1 hour) FLU 25 mg/m2 IV over 1 hour |                     |
| -7                          | (<10 kg: 0.83 mg/kg IV over 1 hour) CY 60 mg/kg IV over 2 hours FLU 25 mg/m2 IV over 1 hour |                     |
| -6                          | (<10 kg: 0.83 mg/kg IV over 1 hour) CY 60 mg/kg IV over 2 hours                             |                     |
| -5                          | Rest                                                                                        |                     |  
| Day                         | Conditioning Regimen                                                     | Immunoprophylaxis                        |
|-----------------------------|--------------------------------------------------------------------------|------------------------------------------|
| Hematopoietic Growth Factor |                                                                          |                                          |
| -4                          | TBI 165 cGy twice daily                                                  |                                          |
| -3                          | TBI 165 cGy twice daily                                                  | Begin Tac / MMF (section 6.2)            |
| -2                          | TBI 165 cGy twice daily                                                  |                                          |
| -1                          | TBI 165 cGy twice daily                                                  |                                          |
| 0                           | MGTA-456 infusion                                                        | Begin G-CSF 5 ug/kg/d until the absolute |
| +1                          | neutrophil count (ANC) is >2500/uL for 2  consecutive days (section 6.4) |                                          |  
Non-TBI-Containing Regimen For children <3 years of age will be conditioned with BU, FLU and MEL, as detailed below:  
| Day                         | Conditioning Regimen                                                                                                                            | Immunoprophylaxis             |
|-----------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------|
| Hematopoietic Growth Factor |                                                                                                                                                 |                               |
| -8                          | BU IV once daily with dose based on PK  calculator over 3 hours                                                                                 |                               |
| -7                          | Bu IV once daily adjusted based on PK  results over 3 hours Bu IV once daily adjusted based on PK                                               |                               |
| -6                          | results over 3 hours Bu IV once daily adjusted based on PK                                                                                      |                               |
| -5                          | results over 3 hours FLU 25 mg/m2/day (0.83 mg/kg/day if < 10  kg*) IV over 60 min MEL 50 mg/m2/day (1.7 mg/kg/day if < 10  kg*) IV over 30 min |                               |
| -4                          | FLU 25 mg/m2/day (0.83 mg/kg/day if < 10  kg*) IV over 60 min MEL 50 mg/m2/day (1.7 mg/kg/day if < 10  kg*) IV over 30 min                      | Begin Tac / MMF (section 6.2) |
| -3                          | FLU 25 mg/m2/day (0.83 mg/kg/day if < 10  kg*) IV over 60 min MEL 50 mg/m2/day (1.7 mg/kg/day if < 10  kg*) IV over 30 min                      |                               |
| -1                          | Rest                                                                                                                                            |                               |
| 0                           | MGTA-456 Infusion                                                                                                                               |                               |
| -2                          | Begin G-CSF 5 ug/kg/d until the  absolute neutrophil count (ANC) is  >2500/uL for 2 consecutive days  (section 6.4)                             |                               |
| +1                          |                                                                                                                                                 |                               |  
*Patients <11kg are currently ineligible because of the expected volume of DMSO in thawed products. Once the washed product has been validated and approved by the FDA, patients <11 kg may be eligible.
single-arm open label interventional phase
6.1conditioning regimen (day - 8

Conditioning will be administered according to institutional guidelines. Potential toxicities for each agent are detailed in section 7.1.
single-arm open label interventional phase
6.1.1 tbi-containing regimen 6.1.1.1 fludarabine

FLU will be administered at dose of 25 mg/m2 once a day as a 1 hour IV infusion on days -8, -7 and -6; total dose: 75 mg/m2. The dose is calculated based on actual body weight (ABW); however, if < 10 kg dosing will be 0.83 mg/kg/dose once a day as a 1 hour IV infusion). The dose will be adjusted if the GFR is ≤ 70. There are no special precautions.
single-arm open label interventional phase
6.1.1.2 cyclophosphamide

CY will be administered at a dose of 60mg/kg once a day as a 2 hour IV infusion on days -7 and -6; total dose: 120 mg/kg. The dose will be administered after a high volume fluid flush and mesna administration per institutional guidelines. Cyclophosphamide dosing is calculated based on actual weight (ABW) unless ABW >150% above Ideal Body Weight (IBW). Then the dose should be computed using adjusted body weight. The adjusted body weight = IBW + 0.5(ABW - IBW). For patients 1-18 years of age, the ideal body weight is calculated using the Traub and Johnson formulas: i.e, <60 inches = ((height in cm)2 x 1.65)/1000; >/= 60 inches = 39 +[2.27 x (height in inches - 60)] for males and 42.2 + [2.27 x (height in inches - 60)] for females. For patients >18 years of age, the ideal body weight is calculated using Devine's formula: i.e., 50 kg + (2.3 kg x (height in inches - 60)) for men; 45.5 kg + (2.3 kg x (height in inches - 60)) for women.
single-arm open label interventional phase
6.1.1.3 total body irradiation

TBI at a dose of 165 cGy will be administered twice a day on days -4, -3, -2 and -1; total dose 1320 cGy. TBI administration procedure is described in Appendix II.
single-arm open label interventional phase
6.1.2 non-tbi-containing regimen 6.1.2.1 busulfan

BU compounding, administration and monitoring should be performed per institutional guidelines and infused over 3 hours. The initial BU dose will be determined based on the weight of the patient upon admission and per our institutional BU standard of practice dose calculator. The first BU dose will be determined by a weight-based dosing nomogram. Refer to institutional guidelines for dosing of BU (Appendix III). Seizure and VOD prophylaxis are prescribed according to institutional guidelines. Concomitant administration of azole anti-fungal agents (except fluconazole) and acetaminophen should be avoided within 72 hours before and after BU
administration.
single-arm open label interventional phase
6.1.2.2 fludarabine

FLU will be administered at dose of 25 mg/m2 once a day (<10 kg, dosing will be weight based: 0.83 mg/kg/day IV) as a 1 hour IV infusion on days -4, -3 and -2; total dose: 75 mg/m2. The dose is calculated based on ABW. The dose will be adjusted if the GFR is ≤ 70. There are no special precautions.
single-arm open label interventional phase
6.1.2.3 melphalan

MEL 50 mg/m2 IV will be administered over 30 minutes, 12 hours after FLU on days -4 to -2 (total of 150 mg/m2). For children <10 kg dosing will be weight based, with MEL 1.7 mg/kg (total of 5.1 mg/kg). Maintenance hydration of >1500 ml/m2/day will be administered with MEL and for 24 hours following infusion.
single-arm open label interventional phase
6.2immunoprophylaxis

GVHD immunoprophylaxis will consist of Tacrolimus and MMF and will be administered according to institutional guidelines. Potential toxicities for each agent are detailed in section 7.2.
single-arm open label interventional phase
6.2.1 tacrolimus

Tacrolimus will start day -3 and will be administered as a continuous IV infusion at a starting dose of 0.03 mg/kg/day. Goal trough levels will be 10-15 ng/mL for the first 14 days post-transplant and then decreased to a goal of 5-10 ng/ml thereafter. Tacrolimus dosing will be monitored and altered as clinically appropriate per institutional pharmacy guidelines. Dose adjustments will be made on the basis of toxicity and/or tacrolimus levels outside of goal range. Conversion from IV to oral tacrolimus will be done per institutional pharmacy guidelines as the patient tolerates and prior to discharge. Potential toxicities are detailed in section 7.2.  
Patients will receive tacrolimus until day +100. If no GVHD, the dose will be tapered 10%
per week beginning on day 101, to discontinue at approximately day +180.  
In the presence of severe tacrolimus toxicities, other alternative agents may be used after review and approval by the co-PIs.
single-arm open label interventional phase
6.2.2 mycophenolate mofetil

MMF 3 gram/day IV/PO for adult patients divided in 2 or 3 doses. Pediatric patients will receive MMF at the dose of 15 mg/kg/dose (max 1 gram per dose) every 8 hours beginning day -3. MMF dosing will be monitored and altered as clinically appropriate based on institutional guidelines. Patients will be eligible for MMF dosing and pharmacokinetics studies.  
Stop MMF at day +30 or 7 days after the ANC is >0.5 x 109 /L, whichever day is later.  
However, if there is acute GVHD, MMF should be continued for an additional 7 days after initiation of systemic therapy for acute GVHD. Afterward, use of MMF is at the discretion of the attending physician.
single-arm open label interventional phase
6.3 mgta-456 infusion

All cell products will be handled by the Cell Therapy Laboratory in the Molecular and Cellular Therapeutics (MCT) facility using validated standard operating procedures
(SOPs). The cell product will be released for human use to the inpatient unit after assessing the identity, sterility, purity and viability of the product.  
The target cell dose is >10 x 106 CD34/kg. However, if the cell dose is < the target of 10 x 106 CD34/kg, it may be infused as long as it exceeds 1 x 106 CD34/kg. With regard to TNC, the maximum cell dose is 2.7 x 108/kg for children (<18 years) and 8.1 × 108 cells/kg for adults [expanded product only] based on the highest cell dose windows evaluated in prior studies. There is no lower limit for TNC dose, only a lower limit for CD34 dose.  
The infusion will be performed according to FACT accredited institutional policies. The pre-medication and hydration regimen will be given following institutional guidelines (refer to section 6.4). No steroids will be given prior to infusion.  
Under no circumstances will MGTA-456 (both the expanded product and its CD34 negative fraction) be irradiated. There must be no in-line leukocyte filter used with product infusion nor any medications or fluids infused in the same line with MGTA-456. Vital signs will be checked before and every 15 minutes during the infusion, at the completion of the infusion, and one hour post infusion per institutional guidelines. More frequent vital signs may be required depending on reactions to the product infusion.  
Potential toxicities are detailed in section 7.3. The infusion will be around 30 minutes for all patients at a rate per institutional guidelines.  
Emergency drugs for hypersensitivity reactions should be available and administered according to institutional guidelines. Oxygen with nasal prongs for standby use should be present in the room.  
Recipients of MGTA-456 will receive the associated CD34 negative fraction 1 hour after the infusion of the expanded product. However, if the expanded product results in a reaction that necessitates intervention, the CD34 negative fraction infusion may be delayed but should be given within 24 hours after the infusion of the expanded product.
single-arm open label interventional phase
6.4hematopoietic growth factor and other

All patients will receive G-CSF 5 mcg/kg/day IV (maximum dose 480 mcg) based on the actual body weight IV beginning on day +1 after MGTA-456 infusion. G-CSF will be administered daily until the ANC is >2.5 x 109/L for two consecutive days and then discontinued. If the ANC decreases to <1.0 x 109/L, G-CSF should be reinstituted as needed to maintain an ANC >1.0 x 109/L. Potential toxicities are detailed in section 7.2.  
Patients will receive transfusions, infection prophylaxis and nutritional support according to institutional guidelines. Infection prophylaxis should include, but is not limited to, agents or strategies (e.g., PCR screening and preemptive therapy) to prevent herpes simplex, cytomegalovirus (CMV), Pneumocystis carinii, and fungal infections. Transfusion thresholds for blood product are based on standard institutional guidelines. All blood products other than MGTA-456 will be irradiated.  
IVIG infusions (500 mg/kg/dose) is recommended for immunoprophylaxis for total serum IgG levels <400. IgG levels will be monitored monthly for first 3 months and then as directed by the care team.
single-arm open label interventional phase
6.5immunizations (immune reconstitution sub-study)

To evaluate the pace of 'functional' immune recovery, Pediarix and Pneumovax will be administered at day 60, day 120, day 180 unless there is active acute or chronic GVHD. We will test for serologies for Hepatitis B, polio, pertussis, diphtheria, tetanus and pneumococcus pre-transplant, day 60, day 100, day 180 and one year post transplant.  
Other standard immunizations will be given at 12 months and two years unless there is active acute or chronic GVHD or other evidence of poor immunologic recovery.
single-arm open label interventional phase
6.6duration of study participation

Patients will be followed for 2 years after transplant. Follow-up after 2 years will be institutional standard of care follow up for all patients treated by HSCT at the institution.
single-arm open label interventional phase
7 expected treatment related toxicities

7.1Potential Toxicities of the Conditioning Regimen  
| Cyclophosphamide Common                                                                                                                                                                                                                                                                                                                                  | Less Common                                                                                                                                                                                      | Rare   |                                                                                         |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------|-----------------------------------------------------------------------------------------|
| - low white blood cell count  with increased risk of  infection  - hair loss or thinning,  including face and body  hair (usually grows back  after treatment)  - nausea  - vomiting  - loss of appetite  - sores in mouth or on lips  - bleeding from bladder,  with blood in urine - diarrhea - long-term or short-term  infertility in women and  men | - low platelet count  (mild) with  increased risk of  bleeding  - darkening of nail  beds  - acne  - tiredness  - infection - fetal changes if  pregnancy occurs  while taking  cyclophosphamide | -      | heart problems with high doses, with  chest pain, shortness of breath, or  swollen feet |
| -                                                                                                                                                                                                                                                                                                                                                        | severe allergic reactions                                                                                                                                                                        |        |                                                                                         |
| -                                                                                                                                                                                                                                                                                                                                                        | skin rash                                                                                                                                                                                        |        |                                                                                         |
| -                                                                                                                                                                                                                                                                                                                                                        | scarring of bladder                                                                                                                                                                              |        |                                                                                         |
| -                                                                                                                                                                                                                                                                                                                                                        | kidney damage (renal tubular  necrosis) which can lead to kidney  failure                                                                                                                        |        |                                                                                         |
| -                                                                                                                                                                                                                                                                                                                                                        | heart damage, with trouble getting  your breath, swelling of feet, rapid  weight gain                                                                                                            |        |                                                                                         |
| -                                                                                                                                                                                                                                                                                                                                                        | scarring of lung tissue, with cough  and shortness of breath                                                                                                                                     |        |                                                                                         |
| -                                                                                                                                                                                                                                                                                                                                                        | second cancer, which can happen  years after taking this drug                                                                                                                                    |        |                                                                                         |
| -                                                                                                                                                                                                                                                                                                                                                        | death from infection, bleeding, heart  failure, allergic reaction, or other  causes                                                                                                              |        |                                                                                         |  
| Busulfan Common                                                                                                                                | Less Common                                                                                       | Rare   |
|------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------|--------|
| - Nausea/vomiting - Mucositis - Rash - Severe suppression of  blood counts - Diarrhea - Fluid weight gain/edema - Alopecia - Hyperpigmentation | - Veno-occlusive  disease - Alveolar  hemorrhage - Pulmonary fibrosis - Interstitial  pneumonitis | - Seizures (low frequency with antiseizure prophylaxis) - Hepatic fibrosis/liver failure        |  
| Fludarabine Common                                                                                                                                                                                                                                                    | Less Common                                                   | Rare                                                                                                                                                                                                                                                                                                                                      |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| - low white blood cell count  with increased risk of  infection  - low platelet count with  increased risk of bleeding  - low red blood cell count  (anemia) with tiredness  and weakness - tiredness (fatigue)  - nausea  - vomiting  - fever and chills - infection | - pneumonia  - diarrhea  - loss of appetite - weakness - pain | - numbness and tingling in hands  and/or feet related to irritation of  nerves  - changes in vision  - agitation  - confusion - clumsiness - seizures - coma  - cough  - trouble breathing  - intestinal bleeding - weakness  - death due to effects on the brain,  infection, bleeding, severe anemia,  skin blistering, or other causes |
| Melphalan Common                                                                                                                                                                                                                                                      | Less Common                                                   | Rare                                                                                                                                                                                                                                                                                                                                      |
| - Hypotension - Nausea and vomiting - Diarrhea - Hives/allergic reaction                                                                                                                                                                                              | - Veno-occlusive                                              | - Dyspnea                                                                                                                                                                                                                                                                                                                                 |
| disease                                                                                                                                                                                                                                                               | - Lung scarring                                               |                                                                                                                                                                                                                                                                                                                                           |
| Total Body Irradiation (TBI) Common                                                                                                                                                                                                                                   | Less Common                                                   | Rare                                                                                                                                                                                                                                                                                                                                      |
| - nausea and vomiting - diarrhea - cataracts - sterility - endocrinopathies - growth failure - intestinal cramps - mucositis                                                                                                                                          | -                                                             | parotitis                                                                                                                                                                                                                                                                                                                                 |
| -                                                                                                                                                                                                                                                                     | interstitial  pneumonitis                                     |                                                                                                                                                                                                                                                                                                                                           |
| -                                                                                                                                                                                                                                                                     | generalized mild  erythema                                    |                                                                                                                                                                                                                                                                                                                                           |
| -                                                                                                                                                                                                                                                                     | veno-occlusive  disease                                       | - dysphagia - vertebral deformities - nephropathy - risk of 2nd malignancy years later  (when given along with  chemotherapy)                                                                                                                                                                                                             |
single-arm open label interventional phase
7.2potential toxicities of gvhd immunoprophylaxis

| GVHD Immunoprophylaxis  Tacrolimus (Tac)   | Mycophenolate mofetil (MMF)                            |            |                     |      |
|--------------------------------------------|--------------------------------------------------------|------------|---------------------|------|
| -                                          | high blood pressure                                    |            |                     |      |
| -                                          | abnormalities in blood chemicals                       |            |                     |      |
| -                                          | seizures                                               |            |                     |      |
| -                                          | headaches                                              |            |                     |      |
| -                                          | renal dysfunction to renal failure requiring  dialysis | -          | nausea and vomiting |      |
| -                                          | diarrhea                                               |            |                     |      |
| -                                          | constipation                                           |            |                     |      |
| -                                          | lowering of blood counts                               |            |                     |      |
| -                                          | leg cramps                                             |            |                     |      |
| -                                          | skin rash                                              |            |                     |      |
| -                                          | difficulty sleeping                                    |            |                     |      |
| -                                          | chemical                                               | imbalances | including           | high |
| blood sugar                                |                                                        |            |                     |      |
| -                                          | headaches                                              |            |                     |      |
| -                                          | dizziness                                              |            |                     |      |
| -                                          | high blood pressure                                    |            |                     |      |
single-arm open label interventional phase
pediarix

- injection site reactions
- fever
- joint pain
- body aches,
- loss of appetite
- nausea
- vomiting
- diarrhea
single-arm open label interventional phase
pneumovax

- injection site reactions
- muscle or joint aches or pain
- fever - chills
- headache - nausea
- vomiting
- stiffness of the arm or the leg where the vaccine was injected
- weakness
- fatigue
- skin rash
single-arm open label interventional phase
7.4potential adverse events (ae) associated

- nausea and vomiting
- possible allergic reaction (including itching, hives, flushing [red face], shortness of breath, wheezing, chest tightness, skin rash, fever, chills, stiff muscles, or trouble breathing)
- acute hemolytic reactions in setting of ABO incompatibility - febrile nonhemolytic reactions
- anaphylactoid or anaphylactic reactions
- transfusion-related acute lung injury (TRALI) - DMSO toxicities (eg headache, hypertension, cardiac toxicity, nausea and vomiting) - transmission of occult bacterial, viral or protozoal infections - transfusion-associated circulatory overload (TACO) - hypothermia - non-immunologic hemolysis  
Later AEs **after the Initial 48 Hours**
- Failure to engraft
- GVHD - acute and chronic
- Slow immune recovery and high risks of opportunistic infection
- Diminished graft-versus-leukemia effect and greater risk of relapse
single-arm open label interventional phase
7.5recommended treatment of adverse events

The clinical management of the complications discussed below will be per institutional guidelines. The following text is considered general guidance only.
single-arm open label interventional phase
7.5.1 slow engraftment/graft failure

The clinical management of slow engraftment/graft failure will be per institutional guidelines. Management of slow engraftment is triggered by the assessment of peripheral blood and bone marrow on Day 21. If at Day 21, the ANC is ≤0.5 × 109/L and bone marrow cellularity is ≤5%, G-CSF dose may be doubled or granulocyte macrophagecolony stimulating factor (GM-CSF) may be added at 250 mcg/m2/d, the availability of the back-up UCB unit(s) that was put on hold at the time of patient enrolment is confirmed and a Day 28 bone marrow biopsy is scheduled.  
If on Day 28 ANC remains ≤0.5 × 109/L and bone marrow cellularity is ≤5%, consideration will be given to performing a second HSC infusion using the previously identified back up source after some form of preconditioning per institutional standard of care.
single-arm open label interventional phase
7.5.2 anemia

Transfusions of packed red blood cells are indicated for symptomatic management of anemia. An attempt should be made to maintain the hematocrit >24% and hemoglobin >8 g/dL. Irradiated (1500 to 3000 cGy) blood products will be used in accordance with the institutional standard of care.
single-arm open label interventional phase
7.5.3 thrombocytopenia

Prophylactic platelet transfusions should be given to maintain the platelet count >10 ×
109/L or above the level at which signs of bleeding are known to occur, whichever is greater. All aspirin containing drugs are to be avoided. The patients should receive no intramuscular injections while thrombocytopenic. Irradiated (1500 to 3000 cGy) blood products will be used in accordance with the institutional standard of care.
single-arm open label interventional phase
7.5.4 nutrition

All patients will be candidates for total parenteral nutrition; length of use is per institutional guidelines.
single-arm open label interventional phase
7.5.5 acute gvhd

Patients will be considered evaluable for acute GVHD unless they are known to have autologous recovery or die before Day 21 without GVHD. Organ involvement will be staged using the criteria outlined in the Appendix IV. Biopsy of each organ site at diagnosis or major change in disease activity will be performed unless clinical circumstances make it impossible.
single-arm open label interventional phase
7.5.6 infusional reaction

MGTA-456 expanded cell product, like other blood products, may cause infusional reactions, including hemodynamic effects or acute hypersensitivity. Furthermore, the coinfusion of residual components of the expansion culture carries theoretical attendant risks. These time-limited events are expected to occur within the first 24 hours [38, 39],
and may range from mild to moderate in severity and may include gastrointestinal (nausea, vomiting, diarrhea and abdominal cramps), respiratory (cough, dyspnea),
cardiovascular (hypotension, hypertension, bradycardia), neurological, or dermatological (skin flushing, rash) events, infection, and anaphylaxis [40]. Emergency drugs should be available and administered per institutional guidelines.  
Oxygen with nasal prongs for standby use should be present in the room.
single-arm open label interventional phase
7.5.7 engraftment syndrome/transfusion related acute

Engraftment syndrome is a syndrome characterized by fever, fluid retention, rash and pulmonary infiltrates proximal to the time of neutrophil recovery after high dose conditioning and HSCT, likely mediated by activated leukocytes and proinflammatory cytokines. Treatment is supportive, including antipyretics, oxygen and diuretics, and systemic corticosteroids or therapies directed to specific proinflammatory cytokines (eg, IL6).  
TRALI is a rare but serious syndrome characterized by sudden acute respiratory distress following transfusion. It is defined as new, acute lung injury during or within six hours after blood product administration in the absence of other risk factors for acute lung injury. TRALI is thought to be caused by activation of recipient neutrophils by donor-derived antibodies targeting HLA or human neutrophil antigen, in most cases. Non-antibodymediated cases occur and may be mediated by biologic response modifiers present in the transfused blood product, along with recipient factors. Treatment is supportive and consists of oxygen, ventilator support and management of fluid balance.