Propylene Glycol-Free Melphalan HCl (EVOMELA®) in Combination With Fludarabine and Total Body Irradiation Based Reduced Intensity Conditioning for Haploidentical Transplantation
Phase: PHASE2
Conditions: Hematological Malignancy, Multiple Myeloma
Sponsor: Medical College of Wisconsin

Protocol 
Official Title of Record:  Propylene Glycol-Free Melphalan HCl (EVOMELA®) in 
Combination with Fludarabine and Total Body Irradiation Based Reduced 
Intensity Conditioning for Haploidentical Transplantation 
NCT03159702 
October 14, 2022 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
1 
Version No.: 3  
Version Date: 10-14-2022  
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
 
A Phase II, Open-Label Study of Propylene Glycol-Free Melphalan for Injection 
(EVOMELA®) in Combination with Fludarabine and Total-Body, Irradiation-Based, 
Reduced-Intensity Conditioning for Haploidentical Transplantation 
 
 
Mehdi Hamadani, MD 
Version 2, Sept 4, 2018 
Version 3, Oct. 14, 2022 
 
 
 
Proprietary and Confidential 
The information in this document is considered privileged and confidential, and may not 
be disclosed to others except to the extent necessary to obtain Institutional Review 
Board approval and informed consent, or as required by federal and state laws. Persons 
to whom this information is disclosed should be informed that this information is 
privileged and confidential and should not further disclosed. 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
2 
Version No.: 3  
Version Date: 10-14-2022  
 
Title: A Phase II, Open-Label Study of Propylene Glycol-Free Melphalan for 
Injection (EVOMELA®) in Combination with Fludarabine and Total-Body, 
Irradiation- Based, Reduced- Intensity Conditioning for Haploidentical 
Transplantation 
 
MCW Protocol No: 29507 
Sponsor-Investigator 
Mehdi Hamadani, MD 
Associate Professor 
Division of Hematology and Oncology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, Wis. 53226 
Phone: 414-805-4600 
Fax: 414-805-0596 
Email: mhamadani@mcw.edu 
 
Pharmacy 
Froedtert & the Medical College of Wisconsin 
Clinical Cancer Center at Froedtert Hospital 
campus 
IDS Pharmacy  
9200 W. Wisconsin Ave. 
Milwaukee, Wis. 53226 
Phone: 414-805-3145 
 Fax: 414-805-1010 
Email: IDS.Pharmacy@froedtert.com 
Biostatistician 
Mei-Jie Zhang, MS, PhD 
Professor 
Division of Biostatistics 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, Wis. 53226 
Phone: 414-805-8375 
Email: meijie@mcw.edu 
 
OnCore® Contact 
Rachel Thuemling, CCRP 
Cancer Center Clinical Trials Office 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, Wis. 53226 
Phone: 414-805-4376 
Fax: 414-805-8840 
Email: rthuemli@mcw.edu 
 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
3 
Version No.: 3  
Version Date: 10-14-2022  
 
PROTOCOL SUMMARY 
 
Study Title: A Phase II, Open-Label Study of Propylene Glycol-Free Melphalan for 
Injection (EVOMELA®) in Combination with Fludarabine and Total-Body, Irradiation- 
Based, Reduced- Intensity Conditioning for Haploidentical Transplantation 
 
Investigators/Study Sites: This is a single-center study that will be conducted through the 
Froedtert & the Medical College of Wisconsin Clinical Cancer Center. 
Study Duration: We plan to accrue a total of 43 haploidentical transplant patients in 2.5 
years with two years additional follow-up. The study will be closed to accrual when the 
last patient is enrolled. 
Phase:  Phase II 
Study Objectives 
Primary Objectives: 
1. To assess one-year, progression-free survival (PFS) of patients with hematological 
malignancies undergoing treatment with propylene glycol-free melphalan for injection 
(EVOMELA®), fludarabine (Flu) and total-body, irradiation (TBI)-based, reduced-intensity 
conditioning (RIC) for haploidentical hematopoietic cell transplantation (haplo-HCT). 
2. To determine the safety of PG-Mel/Flu/TBI-based RIC haplo-HCT. 
Secondary Objectives: 
1. To assess OS, following RIC haplo HCT at one year. 
2. To assess non-relapse mortality (NRM), following RIC haplo-HCT at day +100 and 
one year. 
3. To assess relapse rate, following RIC haplo-HCT at day +100 and one year. 
4. To assess time from RIC haplo-HCT to neutrophil and platelet recovery. 
5. To assess rates of acute graft-versus-host disease (GVHD) at days +100 and +180. 
6. To assess rates of chronic GVHD at one-year post-transplantation. 
7. To assess lineage-specific chimerism kinetics of donor cells (or FISH XX/XY per 
physician discretion) following PG-Mel/Flu/TBI-based RIC haplo-HCT at 
baseline (approximately day +30) and day +100. 
8. To determine kinetics of immune reconstitution, following RIC haplo-HCT at baseline 
(approximately day +30), day +100, day +180, day +365. 
9. To assess rates of primary-graft failure. 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
4 
Version No.: 3 
Version Date: 10-14-2022
 
10. To assess rates of primary- and secondary-graft rejection. 
Number of Patients:  Total estimated accrual is 43 patients. 
Study Design: This is an open-label, single-arm, phase II study. The primary end point of 
the study is one-year PFS and safety of EVOMELA®/Flu/TBI-based RIC haplo-HCT. 
Study Population 
Inclusion criteria: 
1. Patients with a diagnosis of hematological malignancy, undergoing a related-donor 
haploidentical HCT. 
2. Patients aged ≥18 are eligible. 
3. Bilirubin ≤ 2 x the ULN. For patients with Gilbert’s syndrome or suspected mild veno- 
occlusive disease, bilirubin ≤ 3 x ULN is permitted. 
4. Adequate renal function, as defined by a serum creatinine clearance of > 30 mL/min, 
calculated by Cockcroft-Gault equation. 
5. Left ventricular ejection fraction ≥40%. No uncontrolled arrhythmias or New York Heart 
Association class III-IV heart failure. 
6. FEV1 or DLCO (diffusion capacity; corrected for hemoglobin) ≥ 50% of predicted. 
7. Karnofsky Performance Status Scale score > 60. 
8. Graft source of peripheral blood (the infused CD34+ cell dose will be capped at 5 x 106 
CD 34+ cells/kg recipients actual body weight) or bone marrow (the ideal infused total 
nucleated cell dose (TNC) will be targeted at 4 x 108/kg recipient actual body weight). 
9. A negative pregnancy test will be required for all women of childbearing potential. 
Females of childbearing potential should agree to practice two effective methods of 
contraception, at the same time, from the time of signing the informed consent form 
through 90 days after the last dose of study drug. They must also adhere to the 
guidelines of any treatment-specific pregnancy prevention program, if applicable, or 
agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable methods of contraception.). 
Breast-feeding is not permitted. 
10. Male patients, even if surgically sterilized (i.e., status postvasectomy), must agree to one 
of the following: practice an effective barrier contraception during the entire study 
treatment period and through 90 days after the last dose of study drug, or must also 
adhere to the guidelines of any treatment-specific pregnancy prevention program, if 
applicable, or agree to practice true abstinence, when this is in line with the preferred 
and usual lifestyle of the subject. (Periodic abstinence (e.g., calendar, ovulation, 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
5 
Version No.: 3 
Version Date: 10-14-2022
 
symptothermal, postovulation methods] and withdrawal are not acceptable methods of 
contraception.) 
11. No evidence of uncontrolled bacterial, viral or fungal infections at the time of enrollment. 
12. Transplant recipient able to give informed consent. 
Exclusion Criteria: 
1. Patient must not have a healthy, eligible and readily available HLA-identical sibling 
donor or a volunteer adult unrelated donor (matched at allele-level at HLA-A, -B, -C and 
–DRB1). 
2. No serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 
3. AML/MDS/myeloproliferative neoplasia patients with >5% blasts in bone marrow and/or 
circulating leukemic blasts in peripheral blood; patients with known active central 
nervous disease involvement with leukemia/lymphoma or lymphoma patients with 
progressive disease on clinical and/or radiographic assessment are not eligible for this 
study. 
Study Treatments (prior to haplo-HCT): 
For patients who are < 60 years of age: 
• 
Melphalan: 140 mg/m2/day IV on Day -6. 
• 
Fludarabine: 40 mg/m2/day IV Days -5 -4, -3, -2 (Adults: creatinine clearance may be 
estimated by the Cockcroft Formula: CrCl = [(140-age) x weight (kg) x 0.85 (for 
women only)]/ [72 x creat (mg/dl)].) 
• 
TBI: 200 cGy Day -1. 
For patients who are ≥ 60 years and/or HCT-CI score of >3 (at the discretion of 
treating physician will have an option to receive): 
• 
Melphalan: 70 mg/m2/day IV on Day -6. 
• 
Fludarabine: 40 mg/m2/day IV Days -5, -4, -3, -2. 
• 
TBI: 200 cGy; Days -1 
Propylene glycol-free melphalan for injection (EVOMELA®) will be diluted with 0.9% normal 
saline to a final concentration equal to 2 mg/mL and infused over 30±5 minutes via a central 
venous catheter. 
EVOMELA® will be dosed according to the adjusted body weight (AjBW), if the patient’s 
actual body weight (ABV) is greater than the ideal body weight (IBW) (using the formula: 
 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
6 
Version No.: 3 
Version Date: 10-14-2022
 
AjBW=IBW + [(0.40) x (-IBW)]). If the IBW > actual body weight, then, actual body 
weight will be used. 
For the calculation of BSA, actual body weight should be used for patients who weigh less 
than their IBW. For patients who weigh more than their IBW, BSA should be calculated, 
based on adjusted body weight. 
The dose of fludarabine is based on actual body weight. 
Statistical Procedures: 
Sample size estimates: 
The primary endpoint of the study is one-year PFS. The historical one-year PFS since 
transplant, under standard treatment, is 45%; the assumption is that the one-year PFS for 
haploidentical transplant is 59%. We plan to accrue haploidentical transplant patients in 2.5 
years with two years additional follow up. The study will be closed to accrual after the last 
patient has enrolled. Based on exponential distribution and on a one-sided test with 
significance level of 5%, we will have 80% power to detect at least a 14% increase in one-
year PFS for 41 patients. Allowing 5% subjects to be replaced, we plan to accrue 43 
patients in the final study. NRM rate at day +100 and one year will be the key end points to 
monitor the safety in using this approach. 
Independent stopping enrollment for monitoring adverse events 
Stopping rule for excess non-relapse mortality: 
Based on historical control data, a NRM rate at Day 100 of ≥15% in the current study will be 
considered unacceptable. We will evaluate and monitor transplant-related mortality (TRM) 
after the first 15 and 25 patients enrolled in the study. The assumption is that 15% of TRM 
occurring will stop the enrollment for protocol review. A Pocock-type boundary with the 
lower limit of 95% confidence interval will be used for monitoring TRM. At planned interim 
monitoring points, if no more than six or seven TRMs occur, the study will continue to its full 
enrollment of 43. 
Stopping rule for excess primary graft rejection: 
Primary graft rejection rate of ≥20% by day +45 would be considered unacceptable. 

Version No.: 3 
Version Date: 10-14-2022
 
MCW Protocol No: Hamadani-Flu-MEL-TBI 
 
7 
 
 
STUDY CALENDAR 
 
Study Assessment 
Baseline1 PG-free Mel/Flu/TBI 
Days Post-Transplant (~ ±14 days up to day 365 and then 
±28 days)13 
- 
6 
- 
5 
- 
4 
- 
3 
- 
2 
- 
1 
0 
30 
 
60 
100 
180 
1 year 
2 years 
Informed consent 
X 
H & PE2 
X 
X X X X X X X X 
X 
X 
X 
X 
X 
Vital signs3 
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
Karnofsky performance status 
X 
X 
X 
X 
X 
X 
X 
CBC/differential * 
X 
X X X X X X X* X 
X 
X 
X 
Serum chemistries panel4 
X 
X X X X X X X 
X 
X 
X 
X 
CT/PET 
X 
Infectious disease screen ǂ 
X 
Β-HCG serum pregnancy test 5 
X 
X 
CMV/EBV6 
X 
X 
X 
X 
PFT7 
X 
X 
X 
X 
Echo or MUGA 
X 

Version No.: 3 
Version Date: 10-14-2022
 
MCW Protocol No: Hamadani-Flu-MEL-TBI 
 
8 
 
Study Assessment 
Baseline1 PG-free Mel/Flu/TBI 
Days Post-Transplant (~ ±14 days up to day 365 and then 
±28 days)13 
 
 
- 6 - 5 - 4 - 3 - 2 - 1 0 
30 
60 
100 
180 
1 year 
2 years 
Sorted chimerisms (or FISH XX/XY as 
appropriate) 12 
X 
X 
 
 
 
Quantitative immunoglobulins8 
 
X 
X 
X 
X 
Immune reconstitution panel9 
 
X 
X 
X 
X 
X 
CD34/CD3 cell dose infused [PB] 
X 
Acute GVHD assessment 
X 
X 
X 
X 
X 
X 
Chronic GVHD assessment 
X 
X 
X 
X 
X 
X 
Toxicity assessment 
X 
X 
X 
X 
ANC and platelet recovery10 
X 
Disease Response11 
 
X 
X 
Notes: 
H & PE= history and physical examination. 
* CBC will be drawn at least weekly until engraftment. 
ǂ ID screening will be done per standard institutional practices 
1 Baseline refers to the period prior to enrolling on trial. Assessments should be made within 60 days prior to start of conditioning. 
2 History and height are only required at baseline. 
3 Vital signs: blood pressure, pulse rate, respiratory rate and temperature. 
4 Serum chemistries panel: electrolytes, BUN, ALT, AST, creatinine, bilirubin. Electrolytes to include sodium, potassium. Creatinine clearance to be 
calculated at baseline, using Cockcroft-Gault calculation. Comprehensive Metabolic Panel/Basic metabolic panel will be performed based on institutional 
standard. 
5 Females of reproductive potential only. Will be repeated on day of admission for potential childbearing females. 

Version No.: 3 
Version Date: 10-14-2022
 
MCW Protocol No: Hamadani-Flu-MEL-TBI 
 
9 
 
6 CMV NAAT weekly (duration per BMT SOP), EBV NAAT every two weeks through D +100. 
7 PFTs (DLCO, FEV1, FVC [adjusted for hemoglobin]) recommended at 100, 180 and 365 days but are not mandatory and ordered at the discretion of the 
treating physician. 
8 IgG, IgM and IgA. 
9 Peripheral blood flow cytometry to assess recipient immune reconstitution, using standard MCW panel (includes CD3, CD4, CD8, CD20, CD56 and 
Treg assessment).  
10 Record time to neutrophil engraftment, defined as first of three consecutive days with ANC ≥ 500 x 109/L, and platelet engraftment, defined as first day of 
platelet count ≥ 20,000 x 109/L, without transfusion for seven consecutive days. 
11 Leukemia and Myelodysplastic Syndrome: Bone marrow aspirate and biopsy to be recorded within three to four months of HCT and at one year postHCT. After 
one year, it will be up to the discretion of the treating physician, as indicated clinically. Lymphomas: A PET/CT or CT scan to be recorded around day +100 (±30 
days) postHCT. Subsequent need for imaging studies will be up to the discretion of the treating physician as indicated clinically. Myelomas: myeloma panel and 
bone marrow aspirate and biopsy to be recorded around day +100 post HCT. Subsequent need for bone marrow biopsy and/or myeloma panel will be 
performed, per the discretion of the treating physician, as indicated clinically. 
12 After 30 days, chimerisms can be checked per physician discretion. 
13 Or until progression.

Version No.: 3 
Version Date: 10-14-2022 
 
 
MCW Protocol No: Hamadani-Flu-MEL-TBI 
 
10 
 
 
 
TABLE OF CONTENTS 
PROTOCOL SUMMARY ..................................................................................................... 3 
STUDY CALENDAR ............................................................................................................ 7 
TABLE OF CONTENTS ..................................................................................................... 10 
LIST OF ABBREVIATIONS ............................................................................................... 13 
1  INTRODUCTION ........................................................................................................... 15 
1.1  Background ........................................................................................................... 15 
1.2  Nonclinical Experience ......................................................................................... 17 
1.2.1 Melphalan .......................................................................................................................... 17 
1.2.2  Captisol® .......................................................................................................................... 18 
1.3  Previous Clinical Experience ............................................................................... 18 
1.4  Rationale for Study................................................................................................ 19 
2  STUDY OBJECTIVES ................................................................................................... 19 
2.1  Primary Objective .................................................................................................. 19 
2.2  Secondary Objectives ........................................................................................... 20 
3  SELECTION OF SUBJECTS ......................................................................................... 20 
3.1 Inclusion criteria ..................................................................................................... 20 
3.2  Exclusion Criteria .................................................................................................. 21 
4.  STUDY ENTRY AND WITHDRAWAL; STUDY PROCEDURES .................................. 22 
4.1  Study Entry Procedures ........................................................................................ 22 
4.1.1  Required Preregistration Screening Tests and Procedures ............................................... 22 
4.1.2  Registration Process ....................................................................................................... 22 
4.1.3  Pretreatment Period ......................................................................................................... 22 
4.2  Study Procedures during Treatment ................................................................... 23 
4.2.1  Day -6 through Day -1 ...................................................................................................... 23 
4.2.2  Day 0 ................................................................................................................................. 23 
4.2.3  Follow-Up Visits Post-transplant Evaluations ..................................................................... 24 
4.3  Duration of Therapy .............................................................................................. 24 
4.4  Withdrawal Criteria ................................................................................................ 24 
4.5  End Point Analysis ................................................................................................ 25 
5  TREATMENT PLAN ...................................................................................................... 25 
5.1  Administration Schedule to Transplant Recipients............................................ 26 
5.2  Conditioning Regimen .......................................................................................... 27 
5.2.1  Propylene Glycol-Free Melphalan for Injection (EVOMELA®) ........................................... 27 
5.2.2  Fludarabine ...................................................................................................................... 27 
5.2.3  Total Body Irradiation ...................................................................................................... 28 
5.3  Transplantation Procedure ................................................................................... 28 
5.4  Post-transplantation Immunosuppression ............................................................... 28 
5.4.1  Cyclophosphamide .......................................................................................................... 28 
5.4.2  Mesna ................................................................................................................................ 28 
5.4.3  Mycophenolate Mofetil .................................................................................................... 28 
5.4.3.1  Guidelines for MMF Dose Adjustment and Monitoring .......................................... 29 
5.4.3.2  Maintaining MMF ....................................................................................................... 29 
5.4.3.3  Guidelines for MMF Dose Adjustment, Based on Toxicity .................................... 29 
5.4.3.4  Gastrointestinal Toxicity........................................................................................... 29 
5.4.3.5  Neutropenia ............................................................................................................... 29 
5.4.4  Tacrolimus ........................................................................................................................ 30 

Version No.: 3 
Version Date: 10-14-2022 
 
 
MCW Protocol No: Hamadani-Flu-MEL-TBI 
 
11 
 
5.4.4.1 Guidelines for Tacrolimus Dose Adjustment and Monitoring ................................ 30 
5.5  Growth Factor Support ......................................................................................... 31 
6  DISEASE ASSESSMENT .............................................................................................. 31 
6.1  Leukemias and Myelodysplastic Syndrome ....................................................... 31 
6.2  Lymphomas ........................................................................................................... 31 
6.3  Myelomas ............................................................................................................... 32 
6.4  Graft Failure and Rejection ................................................................................... 32 
6.4.1  Graft Failure ..................................................................................................................... 32 
6.4.2  Graft Rejection ................................................................................................................. 32 
6.5  Acute and Chronic GVHD ..................................................................................... 32 
6.5.1  Acute GVHD ..................................................................................................................... 32 
6.5.2  Chronic GVHD .................................................................................................................. 32 
6.5.3  Clinical Grading of Chronic GVHD (According to Appendix 6) ........................................... 32 
7  PHARMACEUTICAL INFORMATION ........................................................................... 33 
7.1  Investigational Product (EVOMELA®) ................................................................. 33 
7.1.1  Description ....................................................................................................................... 33 
7.1.2  Storage and Administration ............................................................................................ 33 
7.1.3  Assigning Subjects to Treatment Group ............................................................................ 34 
7.1.4  Study Medication Accountability ........................................................................................ 34 
7.1.5  Blinding/Masking of Treatments ......................................................................................... 34 
7.1.6  Treatment Administration ............................................................................................... 34 
7.2  Fludarabine ............................................................................................................ 34 
7.2.1  Description ....................................................................................................................... 34 
7.2.2  Dosage and Administration ............................................................................................ 35 
7.2.3  Side Effects and Toxicities ................................................................................................. 35 
7.3  Total Body Irradiation ........................................................................................... 35 
7.4  Cyclophosphamide ............................................................................................... 35 
7.4.1  Description ....................................................................................................................... 35 
7.4.2  Storage and Administration ............................................................................................ 35 
7.4.3  Side Effects and Toxicity ................................................................................................ 36 
7.4.4  Precautions ...................................................................................................................... 36 
7.5  Mesna ..................................................................................................................... 36 
7.5.1  Description ....................................................................................................................... 36 
7.5.2  Storage and Administration ............................................................................................ 36 
7.5.3  Side Effects and Toxicity ................................................................................................ 36 
7.6  Tacrolimus ............................................................................................................. 36 
7.6.1  Description ....................................................................................................................... 36 
7.6.2  Dosage and Administration ............................................................................................ 37 
7.6.3  Side Effects and Toxicities ................................................................................................. 37 
7.7  Mycophenolate Mofetil (MMF) .............................................................................. 37 
7.7.1  Description ....................................................................................................................... 37 
7.7.2  Storage and Administration ............................................................................................ 38 
7.7.3  Side Effects and Toxicity ................................................................................................ 38 
7.8  Prophylaxis and Other Therapy ........................................................................... 38 
7.8.1  Hematopoietic Growth Factors .......................................................................................... 38 
7.8.2  Prophylactic Treatment for Opportunistic Infections........................................................... 38 
7.8.3  Antiemetics ...................................................................................................................... 38 
7.8.4  Blood Products ................................................................................................................ 38 
8.  STATISTICAL METHODS ............................................................................................ 39 

Version No.: 3 
Version Date: 10-14-2022 
 
 
MCW Protocol No: Hamadani-Flu-MEL-TBI 
 
12 
 
8.1  Study Design ......................................................................................................... 39 
8.2  Safety/Stopping Rules .......................................................................................... 39 
8.2.1  Stopping Rule for Excess NRM.......................................................................................... 39 
8.2.2  Stopping rule for excess primary graft rejection ................................................................. 39 
8.3  Accrual Estimate ................................................................................................... 39 
8.4  Accrual and Follow-up Period .............................................................................. 39 
8.5  Sample Size Estimates .......................................................................................... 39 
8.6  Data Collection Methods ....................................................................................... 40 
9  ADVERSE EVENTS:  DEFINITIONS AND REPORTING REQUIREMENTS ................ 40 
9.1  Adverse Event (AE) and Serious Adverse Events (SAE) ................................... 40 
9.2  Unanticipated Problem Involving Risk to Subject or Other (UPIRSO) .............. 41 
9.3  AE Attribution and Grading .................................................................................. 41 
9.4  Adverse Event Attribution .................................................................................... 41 
9.5  Relationship Assessment:  In-depth Definitions ................................................ 42 
9.6  Time Period and Grade of AE Capture ................................................................ 43 
9.7  Monitoring and Recording an Adverse Event ..................................................... 43 
9.8  Follow-up of Adverse Events ............................................................................... 43 
9.9  Procedure for Reporting Drug Exposure during Pregnancy and Birth Events 43 
9.10  Reporting of SAEs ............................................................................................... 44 
9.11  Reporting to the Data and Safety Monitoring Committee ................................ 44 
9.12  Reporting to MCW Committee Institutional Review Board .............................. 44 
9.13  Reporting to Spectrum Pharmaceuticals, Inc. .................................................. 45 
10.  REGULATORY COMPLIANCE, ETHICS, AND STUDY MANAGEMENT .................. 45 
10.1  Ethical Standard .................................................................................................. 45 
10.2  Regulatory Compliance ...................................................................................... 45 
10.3  Prestudy Documentation .................................................................................... 45 
10.4  Institutional Review Board ................................................................................. 45 
10.5  Informed Consent Process ................................................................................. 45 
10.6  Subject Confidentiality and Access to Source Documents/Data .................... 46 
10.7  Protection of Human Subjects ........................................................................... 47 
10.7.1  Protection from Unnecessary Harm ................................................................................. 47 
10.7.2  Protection of Privacy ..................................................................................................... 47 
10.7.3  Changes in the Protocol ................................................................................................ 48 
10.7.4  Investigator Compliance ............................................................................................... 48 
10.7.5  Data and Safety Monitoring Committee ........................................................................... 48 
REFERENCES .................................................................................................................. 50 
APPENDICES .................................................................................................................... 52 
Appendix 1  Response Assessment in Leukemia, Lymphoma & Multiple Myeloma52 
Appendix 2 Revised Criteria for Lymphoma Response Assessment ...................... 54 
Appendix 3 International Myeloma Working Group Uniform Response Criteria .... 55 
Appendix 4 Assessment of Acute GVHD ................................................................... 56 
Appendix 5 Staging/Grading of Acute GVHD ............................................................. 57 
Appendix 6 Grading of Chronic GVHD (NIH Criteria) ................................................ 58 
 
 
 
 
 

Version No.: 3 
Version Date: 10-14-2022 
 
 
MCW Protocol No: Hamadani-Flu-MEL-TBI 
 
13 
 
LIST OF ABBREVIATIONS 
 
ABW 
Actual Body Weight 
AjBW 
Adjusted Body Weight 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
ANC 
Absolute Neutrophil Count 
ASBMT 
American Society of Blood and Marrow Transplantation 
AST 
Aspartate Aminotransferase 
ß-HC 
Beta Human Chorionic Gonadotropin 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CMV 
Cytomegalovirus 
CPK 
Creatinine Phosphokinase 
CRF 
Case Report Form 
DLCO 
Diffusing Capacity of the Lung for Carbon Monoxide 
EBV 
Epstein-Barr Virus 
ECG 
Electrocardiogram 
FACT 
Foundation for the Accreditation of Cellular Therapy 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume in One Second 
FLU 
Fludarabine 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GVHD 
Graft-Versus-Host Disease 
HAPLO HCT 
Haplo Identical Hematopoietic Cell Transplantation 
HCL 
Hydrochloride 
HCT-CI 
Hematopoietic Cell Transplant Co-morbidity Index 
HCT 
Hematopoietic Cell Transplantation 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
IBW 
Ideal Body Weight 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMWG 
International Myeloma Working Group 
IRB 
Institutional Review Board 
IWG 
International Working Group 
LDH 
Lactic Dehydrogenase 
LV 
Left Ventricular 
MEL 
Melphalan 
MM 
Multiple Myeloma 
MMF 
Mycophenolate Mofetil 
MPA 
Mycophenolic Acid 
MRI 
Magnetic Resonance Imaging 
MUGA 
Multigated Acquisition Scan 
NCCN 
National Comprehensive Cancer Network 

Version No.: 3 
Version Date: 10-14-2022 
 
 
MCW Protocol No: Hamadani-Flu-MEL-TBI 
 
14 
 
 NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
 NMA 
Non-Myeloablative 
 NRM 
Non-Relapse PFS Mortality 
 OS 
Overall Survival 
 PBSC 
Peripheral Blood Stem Cell 
 PFS 
Progression-free Survival 
 PFT 
Pulmonary Function Tests 
 PG 
Propylene Glycol-Free 
 RBC 
Red Blood Cell 
 RIC 
Reduced-intensity Conditioning 
 RPR 
Rapid Plasma Regain 
 SAE 
Serious Adverse Event 
 SAP 
Statistical Analysis Plan 
 SAS 
Statistical Analysis System 
 SC 
Subcutaneous 
 SGOT 
Serum Glutamic Oxaloacetic Transaminase 
 SGPT 
Serum Glutamic Pyruvic Transaminase 
 TBI 
Total Body Irradiation 
 TID 
Three Times Daily 
 TRM 
Transplant-related Mortality 
 ULN 
Upper Limit of Normal 
 WBC 
White Blood Cell 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
15 
Version No.: 3 
Version Date: 10-14-2022
 
1 INTRODUCTION 
 
1.1 Background 
 
Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative modality for a 
variety of malignant and benign hematological disorders. However, the vast majority of elderly 
and infirm patients with advanced hematological malignancies are not candidates for 
myeloablative allogeneic HCT due to unacceptably high rates of toxicities and nonrelapse 
mortality (NRM), associated with higher-intensity conditioning allografts. During the last two 
decades, the observed improved rates of NRM in patients receiving non-myeloablative (NMA) or 
reduced-intensity conditioning (RIC) transplantation have spurred a dramatic increase in the 
application of RIC allogeneic transplantation in elderly and unfit patients with hematological 
malignancies. Clinicians using these regimens seek to reduce early transplant-related mortality 
(TRM), while maintaining reliable rates of hematopoietic and donor-immune cell engraftment to 
exert a graft-versus-leukemia (GVL) effect. (1) 
 
The decision to use RIC regimens for patients undergoing transplantation is often empirical, and 
significant variation exists in the selection criteria used by transplant centers. (2) While poor 
outcomes for elderly patients, following myeloablative transplantation, are well known, (3) Sorror 
et al. evaluated the impact of medical comorbidities on transplant outcomes by using the 
Hematopoietic Cell Transplantation - Comorbidity Index (HCT-CI) and reported significantly 
higher NRM rates and inferior OS in patients with an HCT-CI score of ≥ 3. (4, 5) Based on these 
data, it is common practice to offer RIC HCT to patients with advanced age (generally > 50–55 
years), HCT-CI > 2 (regardless of age), history of prior autologous transplantation or to patients 
with recent or active invasive fungal infections. 
 
Owing to the plasma half-life of fludarabine (allowing once-daily administration), RIC regimens 
often use this agent as the lymphocyte-depleting component to facilitate donor-cell engraftment. 
In the RIC setting, fludarabine is often combined with either busulfan or melphalan. Fludarabine 
/ busulfan-based conditioning (depending on dose intensity) is, however, often complicated by 
busulfan-related pulmonary toxicity, neurological toxicity (e.g., seizures) and veno-occlusive 
disease. An M.D. Anderson Cancer Center group pioneered the use of fludarabine melphalan 
(Flu/Mel) conditioning, which since has gained wide usage. (6) The use of melphalan for 
conditioning in allogeneic transplantation is based on its convenience, its broad antitumor 
activity in hematologic malignancies and its immunosuppressive effects, initially described in 
animal models, but subsequently confirmed by empirical clinical observations. (7) Fludarabine 
was added to this conditioning regimen because of its potent immunosuppressive effects and its 
potential synergism with alkylators. The Flu/Mel conditioning regimen can provide long-term 
disease control, especially in the subset of patients with chemosensitive disease. (6) 
Recently, TBI (200 cGy) was used in combination with Flu/Mel for patients with advanced 
lymphoma (n=22) treated with haploidentical HCT (haplo-HCT). With a median follow-up time 
close to two years, the survival of these mostly advanced, relapsed/refractory patients was very 
encouraging with OS of 54% and PFS of 54% for the entire group. (8) TRM was low at day 100 
(9.1%) and two years (19%) after transplantation, with stable engraftment achieved in the great 
majority of patients. Two of four CLL/SLL patients experienced secondary-graft rejection, 
suggesting that these patients may have a higher risk of engraftment failure and should be 
closely monitored in the early post-transplantation period. Although the numbers were low, the 
results were comparable with the NMA Flu/Cy/TBI (Table 1). 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
16 
Version No.: 3 
Version Date: 10-14-2022 
 
TABLE 1: Comparison of Haploidentical Transplantation Outcomes for Lymphoma 
Author 
Regimen 
Lymphoma Type 
N 
2-yr 
PFS 
1-yr 
NRM 
Brammer et al. (8) 
Flu/Mel/Tt/TBI 
Hodgkin and NHL 
22 
54% 
19% 
Burroughs et al. (9) 
Flu/Cy/TBI 
Hodgkin 
28 
51% 
05% 
Raiola et al. (10) 
Flu/Cy/TBI 
Hodgkin and NHL 
26 
63% 
04% 
Castagna et al. (11) 
Flu/Cy/TBI 
Hodgkin and NHL 
49 
65% 
16% 
Kanakry et al. (12) 
Flu/Cy/TBI 
NHL 
69 
63% 
10% 
Kanate et al. (13) 
Flu/Cy/TBI 
Hodgkin and NHL 
185 
50% 
11% 
 
In theory, intensifying the dose of melphalan in Flu/Mel conditioning could provide better 
disease control post-HCT, allowing more time for curative GVL effects to emerge. Attempts to 
escalate the dose intensity of Flu/Mel conditioning (to melphalan doses >140mg/m2), however, 
have been complicated by melphalan-related renal, hepatic, pulmonary and gastrointestinal 
toxicities.(6) Moreover, the current commercial formulation of melphalan (Alkeran®), used off- 
label as part of autologous and allogeneic HCT, has several limitations when given at these 
higher doses, based on its marginal solubility that prevents the solution from being administered 
as a longer infusion. The commercial Alkeran® product must be reconstituted with a sterile 
diluent that contains propylene glycol, a substance that has been associated with toxic side 
effects (e.g., hyperosmolality, increased anion gap metabolic acidosis [due to lactic acidosis], 
acute kidney injury, sepsis-like syndrome, allergic contact dermatitis, hemolysis, central nervous 
system depression, seizures, arrhythmias and nephrotoxicity).(14–16). After reconstitution of 
Alkeran®, an impurity (citrate derivative of melphalan) can develop in < 30 minutes and, when 
further diluted, the potency of melphalan is rapidly lost over time. A single dose of Alkeran®, 
which is administered at 200 mg/m2, contains 24 g/m2 of propylene glycol. Hence, this dose of 
Alkeran® would include a propylene glycol dose of about 45 g for a 70 kg patient (Alkeran® for 
injection PI, 2008). If this dose of Alkeran®  is infused into the body for myeloablative 
conditioning in as little time as 15 minutes, due to the limited stability of the product after 
reconstitution, then, the infusion rate of propylene glycol would be high at 180 g/h, or nearly 60 
times faster than the recommended rate. As stated above, such doses of propylene glycol may 
be associated with renal toxicity and metabolic acidosis. 
 
A number of studies designed to assess the efficacy of high-dose melphalan, followed by 
autologous HCT have included information regarding dose-limiting toxicities, but not necessarily 
information about common adverse effects. Despite hematopoietic progenitor cell rescue, 
myelosuppression with neutropenia and thrombocytopenia occur in all patients. (17, 18) Both 
the severity and duration of myelosuppression are dose dependent. Gastrointestinal toxicity is 
the major non-hematological toxicity of high-dose melphalan; it includes mucositis, nausea, 
vomiting and diarrhea. Although melphalan does not appear to be cardiotoxic like other 
alkylating agents, atrial fibrillation has been reported after high-dose melphalan administration, 
particularly in elderly patients. In addition, pulmonary toxicities, such as pulmonary fibrosis, are 
a rare and late complication of melphalan. 
 
The substitution of Captisol® in propylene glycol-free melphalan for injection (EVOMELA®) for 
injection (Spectrum Pharmaceuticals, Inc.) for the excipients found in Alkeran® directly 
overcomes the formulation limitations noted with Alkeran®. Captisol® is a substituted ß-

MCW Protocol No: Hamadani-Flu-MEL-TBI 
17 
Version No.: 3 
Version Date: 10-14-2022 
 
cyclodextrin that serves as the major functional excipient in (EVOMELA®). When the formulation 
is administered intravenously, the equilibrium between melphalan and melphalan-Captisol® 
complex rapidly shifts in favor of melphalan, due to its dilution by blood and the distribution and 
binding of melphalan to body tissues and blood components. Moreover, melphalan for injection 
(propylene glycol free) has been shown to be stable for 10 to 24 hours once reconstituted. It 
may be refrigerated (which extends the use time). 
 
1.2  Nonclinical Experience 
 
1.2.1 Melphalan 
 
Spectrum conducted one nonclinical study to support the use of melphalan for injection 
(propylene glycol free). The only difference between the Alkeran® for injection formulation and 
the proposed EVOMELA® is Captisol®. Therefore, the pharmacokinetics (PK) of melphalan were 
evaluated, following intravenous administration in Sprague-Dawley® rats of a nominal 2 mg/kg 
melphalan dose, prepared in either a Captisol® or nonCaptisol® (propylene glycol) formulation. 
(19). There were no significant differences in the mean whole-blood and plasma AUC profiles or 
in the urinary excretion of melphalan, following intravenous administration, suggesting that the 
change from a propylene glycol to Captisol® formulation does not affect melphalan PK. 
Melphalan is an older drug with a history of clinical use since the 1960s. Approved labeling for 
both the oral and intravenous formulations of melphalan (Alkeran®) support the relatively low 
clinical doses of melphalan used in multiple cycles of induction chemotherapy for MM. While 
Alkeran®  for injection has not been approved for high-dose (200 mg/m2 or 100 mg/m2/day for 
two days) conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation, it 
has been successfully used and is the standard of care in the clinic for this indication. The 
nonclinical data in the paragraphs below are excerpted from the current Alkeran® labeling. 
Melphalan is a bifunctional (interstrand and intrastrand) alkylating agent that is noncell-cycle 
specific. It is actively transported into cells by the high-affinity L-amino acid transport system. It 
exerts an intracellular cytotoxic effect through the formation of interstrand or intrastrand DNA; 
cross-links or DNA protein cross-links via the two chlorethyl groups of the molecule (alkylation). 
This leads to impairment of DNA replication and mitotic division and eventually cell death. Like 
other bifunctional alkylating agents, it is active against both resting and rapidly dividing tumor 
cells (PACKAGE INSERT DATA: Alkeran® [melphalan hydrochloride] kit. GlaxoSmithKline LLC, 
Research Triangle Park, North Carolina). 
 
Melphalan acute toxicity, following intravenous administration, was evaluated in the rat and 
following oral and intraperitoneal administration in mouse and rat. The intravenous median 
lethal dose (LD50) was determined to be 5.1 and 6.6 mg/kg in male and female rats, 
respectively. These doses are equivalent to 30.6 and 39.6 mg/m2 in the male and female rat, 
respectively, indicating that in animal studies melphalan cannot be administered at doses high 
enough to support melphalan high-dose conditioning treatment prior to hematopoietic progenitor 
(stem) cell transplantation in humans. Melphalan has been shown to cause chromatid or 
chromosome damage in humans and was considered to be carcinogenic because chronic 
administration by intraperitoneal injection produced lymphosarcomas and dose-related increase 
in lung tumors in mice and peritoneal tumors in rats. Melphalan was embryolethal and 
teratogenic in rats, following oral and intraperitoneal administration. It has been reported that 
Alkeran®  for injection may cause local tissue damage should extravasation occur, and 
melphalan was determined to be a mild irritant, following topical application (PACKAGE INSERT 
DATA: Alkeran® [Melphalan hydrochloride] kit. GlaxoSmithKline LLC, Research Triangle Park, 
North Carolina). 
 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
18 
Version No.: 3 
Version Date: 10-14-2022 
 
,
The acute LD50 and chronic administration data indicate that nonclinical species demonstrate 
toxicity consistent with that seen in humans but at lower doses. Nonclinical studies could not be 
conducted at dose levels equivalent to the anticipated daily human dose of 100 mg/m2, based 
on the observed intravenous LD50 values of 5.1 and 6.6 mg/kg (equivalent to 30.6 and 
39.6 mg/m2) in male and female rats, respectively. The primary dose-limiting toxicity of therapy 
relates to the myeloablative pharmacological effect of melphalan — the desired 
pharmacological activity in the clinical patient population. The high-dose melphalan clinical data 
(20–22) support the conduct of well-controlled clinical trials with high-dose melphalan for 
conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation in patients 
with MM. 
 
1.2.2  Captisol® 
 
Captisol® is the major excipient in the propylene glycol-free melphalan for injection 
(EVOMELA®) formulation. There was no mortality or other evidence of toxicity observed in 
the single-dose intravenous toxicity studies in which 2,000 mg/kg Captisol® was 
administered over 10 or 20 seconds in the mouse and rat, respectively. In repeat-dose 
toxicity studies, vacuolation of renal tubular epithelium cells was observed in rats, dogs and 
monkeys. This type of vacuolation is commonly seen in animals given substituted 
ßcyclodextrins. There was no evidence of degeneration, necrosis or pseudocrystal 
formation in the epithelial cells at doses ≤1,000 mg/kg/day for one month in rats, ≤1,500 
mg/kg/day for one month in dogs or ≤5,600 mg/kg/day for 14 days in monkeys. There was 
no evidence to suggest a deterioration of renal function, and vacuolation was largely 
reversible. There was no evidence of mutagenicity and no effects on the reproductive 
function of rats or rabbits were observed in the studies conducted with Captisol®. (23) In 
conclusion, intravenous toxicity studies with Captisol® doses as high as 1,000 mg/kg/day 
(equivalent to 6,000 mg/m2/day) in rats, 1,500 mg/kg/day (equivalent to 30,000 mg/m2/day) 
in dogs and 5,600 mg/kg/day (equivalent to 67,200 mg/m2/day) in monkeys did not produce 
toxicologically significant findings suggestive of a risk to humans. The recommended dose 
for EVOMELA® is 200 mg/m2 which is equivalent to 5,400 mg/m2/day, based on a 70-
kilogram patient with a BSA of 1.8 m2). 
 
1.3  Previous Clinical Experience 
 
EVOMELA® has been analyzed in humans in two studies to date. The first clinical study of 
EVOMELA®, Study CDX-353-001, established bioequivalence to Alkeran® for Injection. (24) 
Based on a noncompartmental analysis, the geometric mean ratios for estimated Cmax, AUC0-∞, 
and AUC0-t for EVOMELA® to Alkeran® for injection at high dose (100 mg/m2) were 112.00%, 
110.90% and 110.77%, respectively; and the associated 90% confidence intervals were 
contained within the 80% to 125% bioequivalence guidelines established by FDA. Myeloablation 
and engraftment rates were measured in all patients as a measurement of efficacy in this 
preliminary efficacy study. All 24 patients exhibited myeloablation and engraftment after 
administration of the two doses of melphalan at 100 mg/m2. The median times to myeloablation 
and engraftment were three days (postgraft) and 11 days (postgraft), respectively.(24) The 
safety profile was consistent with that already established for high-dose melphalan when given 
as a conditioning regimen with autologous HCT [Ligand Pharmaceuticals, Inc. Investigational 
Drug Brochure v3 August 2012]. The phase II, open-label study was the only one where 200 
mg/m2 dose of EVOMELA® was administered to MM patients.(25) This study enrolled 61 MM 
patients, who received 200 mg/m2  of CE-melphalan (100 mg/m2/day x 2), followed by ASCT. 
The majority of the subjects were male (57%) with a median age of 62 years (range 32–73) and 
included 56 (92%) subjects receiving upfront auto-HCT and five (8%) after relapse. Median lines 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
19 
Version No.: 3 
Version Date: 10-14-2022 
 
of prior therapy were three (range 2–16). All subjects achieved myeloablation, followed by 
successful engraftment. Median time to neutrophil engraftment was 12 days post-HCT (range: 
10–12); time to platelet engraftment was 13 days (range 10–28). There was no mortality by 
day100, and as expected, the most common Grade 3 and 4 toxicities were hematologic. Severe 
mucositis was reported in few patients (Grades 3/4; 10%). At day 100 post-HCT, all patients 
(100%) had a response with 82% of subjects achieving a >= very good partial response (VGPR) 
response, including stringent CR in 13%, CR in 8% and VGPR in 61%. (25) Notably, the dosage 
schema reported did not use the more common approach of a single infusion of melphalan of 
200 mg/m2. 
 
The EVOMELA® formulation does not need a second vial of solvent for reconstitution and can 
be dissolved directly, using saline with relatively small volumes of infusate required to deliver a 
given high dose. Moreover, it is stable at room temperature for at least four hours upon 
reconstitution, followed by immediate dilution. This leads to less handling of this cytotoxic agent 
by pharmacy and nursing staff with a concomitant decrease in exposure risks and an increase 
in convenience, as well as administration flexibility. 
 
1.4  Rationale for Study 
 
The preliminary data suggest that the substitution of Captisol® in EVOMELA® for the excipients 
found in Alkeran® directly overcomes the formulation limitations and provides a potentially safer 
melphalan formulation for administration at higher doses used in HCT conditioning regimens. 
Based on these observations, we now propose a phase II study of a RIC regimen, consisting of 
EVOMELA,® in combination with fludarabine and TBI for patients undergoing haplo-HCT. The 
study will investigate the safety and tolerability of this conditioning approach. While the FDA 
indication for EVOMELA® is for myeloablative conditioning prior to autologous HCT in patients 
with multiple myeloma, we anticipate our study will provide critical preliminary data to explore 
this formulation in allogeneic HCT conditioning. 
 
Given the bioequivalence between Alkeran® and Captisol®, as detailed in section 3.3 (24), 100 
mg/m2 or 140 mg/m2 of propylene glycol-free melphalan for Injection (EVOMELA®) on day -6 
were selected as the dose for the study drug in this study. Fludarabine (40 mg/ m2/day 
intravenously on days -5,-4, -3, -2) and TBI (200 cGy; day -1 [or 200 cGy on days -2 and -1]) 
are administered, based on current clinical practice. Because of observed mucosal toxicity 
(nausea, vomiting, diarrhea and mucositis) with Flu/Mel-100/400 cGY TBI conditioning option 
in elderly patients (n=2) enrolled to date (as of 5/22/2018), we decided to amend the protocol 
to reduce melphalan and TBI does for elderly and frail patients to Flu/Mel-70/200 cGY TBI.  
This study will be conducted in compliance with the protocol, good clinical practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonization (ICH) 
guidelines. 
 
2  STUDY OBJECTIVES 
 
2.1  Primary Objective 
 
1. To assess one-year progression-free survival (PFS) of patients with hematological 
malignancies undergoing propylene glycol-free melphalan for Injection (EVOMELA®), 
fludarabine, (FLU) and total-body irradiation-based reduced-intensity conditioning (RIC) 
for haploidentical hematopoietic cell transplantation (haplo-HCT). 
2. To determine the safety of EVOMELA®/Flu/TBI-based RIC haplo-HCT. 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
20 
Version No.: 3 
Version Date: 10-14-2022 
 
 
2.2  Secondary Objectives 
 
1. To assess OS following RIC haplo HCT at one year and two years. 
 
2. To assess NRM following RIC haplo-HCT at day +100 and one year. 
 
3. To assess relapse rate following RIC haplo-HCT at day +100 and one year. 
 
4. To assess time from RIC haplo-HCT to neutrophil and platelet recovery. 
 
5. To assess rates of acute graft-versus-host disease (GVHD) at day +100 and +180. 
 
6. To assess rates of chronic GVHD at 1-year post-transplantation. 
 
7. To assess lineage specific chimerism kinetics of donor cells (or FISH XX/XY per 
physician discretion) following PG-Mel/Flu/TBI-based RIC haplo-HCT at baseline 
(approximately day +30), and day +100. 
8. To determine kinetics of immune reconstitution following RIC haplo-HCT at baseline 
(approximately day +30), day +100, day +180, day +365. 
9. To assess rates of primary graft failure. 
 
10. To assess rates of primary and secondary graft rejection. 
 
3  SELECTION OF SUBJECTS 
3.1 Inclusion criteria 
 
1. Patients with a diagnosis of hematological malignancy undergoing a related-donor 
haploidentical HCT. (Haplo-identical donor is defined as below:  
 
Patients must be HLA typed at high resolution, using DNA-based typing at the 
following HLA loci: HLA-A, -B, -C and DRB1 and have available: 
A related haploidentical donor with two, three or four HLA-mismatches.  
An unidirectional mismatch in either the graft-versus-host or host-versus-graft 
direction is considered a mismatch. The donor and recipient must be HLA 
identical for at least one antigen (using high-resolution DNA-based typing) at the 
following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1. Fulfillment of this 
criterion shall be considered sufficient evidence that the donor and recipient 
share one HLA haplotype and typing of additional family members is not required.   
2. Patients ≥18 are eligible. 
 
3. Bilirubin ≤ 2 x the ULN. For patients with Gilbert’s syndrome or suspected mild veno- 
occlusive disease, bilirubin ≤ 3 x ULN is permitted. 
4. Adequate renal function, as defined by a serum creatinine clearance of > 30 mL/min, 
calculated by Cockcroft-Gault equation. 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
21 
Version No.: 3 
Version Date: 10-14-2022 
 
5. Left ventricular ejection fraction ≥40%. No uncontrolled arrhythmias or New York Heart 
Association class III-IV heart failure. 
6. FEV1 or DLCO (diffusion capacity; corrected for hemoglobin) ≥ 50% of predicted. 
 
7. Karnofsky Performance Status Scale Index score > 60. 
 
8.   Graft source of either peripheral blood (the infused CD34+ cell dose will be capped at 5 
x 106 CD 34+ cells/kg recipients actual body weight) or bone marrow (the ideal infused 
TNC dose will be targeted at 4 x 108/kg recipient actual body weight) at the discretion of 
the transplant physician. 
9.    A negative pregnancy test will be required for all women of childbearing potential. 
Females of childbearing potential should agree to practice two effective methods of 
contraception, from the time of signing the informed consent form through 90 days after 
the last dose of study drug. They must adhere to the guidelines of any treatment-
specific pregnancy prevention program, if applicable, or agree to practice true 
abstinence when this is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] 
and withdrawal are not acceptable methods of contraception.). Breast-feeding is not 
permitted. 
10. Male patients, even if surgically sterilized (i.e., status postvasectomy), must agree to one 
of the following: practice effective barrier contraception during the entire study treatment 
period and through 90 days after the last dose of study drug, or must also adhere to the 
guidelines of any treatment-specific pregnancy prevention program, if applicable, or 
agree to practice true abstinence when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable methods of contraception.) 
11. No evidence of uncontrolled bacterial, viral or fungal infections at the time of enrollment. 
 
12. Transplant recipient able to give informed consent. 
 
 
3.2  Exclusion Criteria 
 
1. Patient must not have a healthy, eligible and readily available HLA-identical sibling donor 
or a volunteer adult unrelated donor (matched at allele-level at HLA-A, -B, -C and - 
DRB1). 
2. No serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 
3. Presence of active disease in AML/MDS: patients with active disease defined as >5% 
blasts in bone marrow and/or circulating leukemic blasts in peripheral blood, patients 
with known active central nervous disease involvement with leukemia/lymphoma or 
lymphoma patients with progressive disease on clinical and/or radiographic assessment 
are not eligible for this study. 
 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
22 
Version No.: 3 
Version Date: 10-14-2022 
 
4. STUDY ENTRY AND WITHDRAWAL; STUDY PROCEDURES 
 
4.1  Study Entry Procedures 
 
4.1.1  Required Preregistration Screening Tests and Procedures 
 
A written, signed informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated. A signed ICF copy will be given to the subject and a copy will be filed 
in the medical record. The original will be kept on file with the study records. 
 
The following procedures will be performed at specified intervals; please refer to the study 
calendar . Screening assessments must be performed < 60 days prior to planned initiation of 
conditioning. Any results falling outside of the reference ranges may be repeated at the 
investigator’s discretion. Treatment or visit delays for public holidays or weather conditions do 
not constitute a protocol violation. 
 
4.1.2  Registration Process 
 
-  All patients who are consented will be registered in OnCore®, the MCW Cancer Center 
clinical trial management system. The system is password protected and meets HIPAA 
requirements. 
-  Eligible patients will be identified by the Clinical Trials Office, which will register the 
patients. 
-  All source documents that support eligibility include a signed informed consent/HIPAA 
and signed eligibility checklist. These must be available for review and verification. 
 
4.1.3  Pretreatment Period 
 
Baseline Assessments 
After a patient signs the consent form, the baseline procedures and assessments must be 
completed within ≤60 days from the planned initiation of conditioning, unless otherwise 
indicated. 
 
- 
Complete medical history (only required at baseline), physical examination, height and 
weight. 
- 
Vital signs: blood pressure, pulse rate, respiratory rate and temperature. 
 
- 
Karnofsky Performance Status Scale score. 
 
- 
Complete blood count (CBC) with differential. 
 
- 
Serum Chemistries 
- 
CT/PET. 
- 
Infectious disease markers: HIV, EBV, CMV, hepatitis B surface antigen and HCV. If the 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
23 
Version No.: 3 
Version Date: 10-14-2022 
 
HCV antibody is positive, a screening HCV RNA by any RT-PCR or bDNA assay must 
be performed. Patients with HIV or Hep B positivity will be excluded from the study. 
- 
B-HCG serum pregnancy test for females of childbearing potential. 
 
- 
Additional viral testing (EBV/Adeno/CMV) will be performed at the discretion of the 
treating physicians. 
- 
Pulmonary function tests (PFT), including DLCO (adjusted for hemoglobin) and FEV1. 
 
- 
Echo or MUGA. 
 
- 
Sorted chimerisms (or FISH XX/XY per physician discretion). 
 
 
4.2  Study Procedures during Treatment 
 
4.2.1  Day -6 through Day -1 
 
- 
Physical examination. 
 
- 
Vital signs: blood pressure, pulse rate, respiratory rate and temperature. 
 
- 
Complete blood count (CBC) with differential. 
- 
Serum Chemistries  
For patients <60 years old: 
 
 
-  Melphalan: 140 mg/m2/day IV on Day -6. 
 
 
-  Fludarabine: 40 mg/ m2/day IV Days -5, -4, -3, -2. 
 
 
-  Total-body irradiation: 200 cGy on Day -1. 
 
 
For patients with age ≥60 years and/or HCT-CI score of >3 will have the option of receiving 
the following regimen: 
 
 
-  Melphalan:  70 mg/m2/day IV on Day -6. 
 
 
-  Fludarabine: 40 mg/m2/day IV Days -5, -4, -3, -2. 
 
 
- Total-body irradiation: 200 cGy on Day -1.   
 
4.2.2  Day 0 
 
- 
Physical exam. 
 
- 
Vital signs: blood pressure, pulse rate, respiratory rate and temperature. 
 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
24 
Version No.: 3 
Version Date: 10-14-2022 
 
- 
Complete blood count (CBC) with differential. 
 
- 
Serum Chemistry  
- 
CD34/CD3 cell dose infused (peripheral blood or bone marrow graft). 
- 
CMV and EBV. 
 
4.2.3  Follow-Up Visits Post-transplant Evaluations 
 
Patients will be followed for two years post-transplant or until disease progression. The 
following procedures will be performed at specified intervals; please refer to the study 
calendar. 
 
- 
Physical examination, including weight and review of adverse events. 
- 
Vital signs: blood pressure, temperature, respiratory rate, pulse. 
 
- 
CBC with differential. 
 
- 
Serum Chemistry  
 
- 
Bone marrow transplant markers. 
 
- 
Quantitative immunoglobulins (IgG, IgM, and IgA). 
- 
Bone marrow biopsy and aspirate (to be performed as determined by treating physician 
to meet standard-of-care clinical needs). 
 
- 
Chimerisms. 
 
- 
CMV/EBV/Adeno. 
 
- 
Acute and chronic GVHD. 
 
- 
PFTs (DLCO and FEV1, adjusted for hemoglobin). 
 
- 
Karnofsky Performance Status. 
 
- 
Assessment of ANC and platelet recovery. 
 
4.3  Duration of Therapy 
We plan to accrue a total of 43 haploidentical transplant patients in two and a half years with two 
years additional follow-up. The study will be closed to accrual after the last patient is enrolled. 
 
4.4  Withdrawal Criteria 
 
The subject has the right to withdraw from the study at any time. 
The subject will be withdrawn from the study if: 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
25 
Version No.: 3 
Version Date: 10-14-2022 
 
- 
There is deterioration in the subject’s signs/symptoms and/or the subject develops a 
disease or condition that, in the opinion of the Investigator, would compromise the 
subject’s safety by continuing in the study. 
- 
In the investigator’s judgment, it is in the subject’s best interest. 
If a subject withdraws prematurely from the trial due to the above criteria or any other reason, 
study staff should make every effort (at withdrawal) to complete the full set of evaluations 
scheduled for the end-of-study evaluation. The reason for subject withdrawal must be 
documented in the CRF. 
 
If a subject withdraws from the study due to an AE (e.g., clinical signs, symptoms or clinically 
significant laboratory abnormality), the subject will be asked to return to the clinic for the 
evaluations scheduled for the post-treatment follow-up period, at a minimum. If the AE has still 
not resolved, additional follow-up will be performed, as appropriate and documented in the 
subject’s medical records. As a minimum requirement, AEs should be followed for seven days 
after the date of engraftment or until any treatment-emergent AE or laboratory abnormality has 
resolved or is otherwise explained. 
 
In the case of a subject lost to follow-up, attempts to contact the subject must be made and 
documented in the subject’s medical records. 
 
Withdrawn subjects will not be replaced. 
 
4.5  End Point Analysis 
 
Response assessments for leukemia will be based on the International Working Group (IWG) 
response criteria (26) (see Appendix 1). Lymphoma response assessments will be performed 
based on the revised response criteria (27) (see Appendix 2). Treatment responses in 
multiple myeloma will be assessed based on International Myeloma Working Group (IMWG) 
response criteria (28) (see Appendix 3). 
 
5  TREATMENT PLAN 
All patients may undergo conditioning and post-transplant treatments either as an inpatient or 
outpatient, as medically appropriate. See the below table for more information. 
 
HLA-Haploidentical, RIC HCT Treatment Plan 
Days 
−6 
−5 
−4 
−3 
−2 
−1 
Conditioning 
Evomela 
140mg/m2 
● 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
26 
Version No.: 3 
Version Date: 10-14-2022 
 
FLU 40 
mg/m2/day 
● 
● 
● 
● 
TBI 200 cGy 
● 
HCT  
0 
Post-Transplantation 
+3 
+4 
+5 
+35 
+100 
+180 
CY 50 mg/kg 
● 
● 
MESNA (dosed 100% CY dose) 
● 
● 
MMF 
Start 
Stop* 
Tacrolimus 
Start 
→ 
Taper* 
Stop* 
G-CSF 5μg/kg/day 
Start^ 
Conditioning consists of Evomela 140 mg/m2, FLU 40 mg/m2, and 200 cGy TBI. 
Stem cell infused on Day 0. 
^G-CSF begins day +5 after stem cell infusion and continues until engraftment is seen. 
Post-transplantation immunosuppression consists of CY (day +3 and +4), MMF and tacrolimus that must 
begin at least 24 hours after the CY infusion in order to prevent blunting of the alloreactive response needed 
for effective CY targeting of proliferating lymphocytes. 
*If there is no evidence of GVHD. 
Please note that patients who are ≥60 years and/or with an HCT-CI >3 can have the option to receive 
PG-free MEL 70 mg/m2 IV on day -6, FLU 40 mg/m2 IV days -5 to -2 and TBI dose of 200cGy on day -1. 
 
 
5.1  Administration Schedule to Transplant Recipients 
 
For patients who are <60 years of age. 
EVOMELA®: 140 mg/ m2/day IV on day -6. 
Fludarabine: 40 mg/ m2/day IV days -5, -4, -3, -2. 
TBI: 200 cGy; day -1. 
Stem Cell infusion on day 0. 
Cyclophosphamide: 50 mg/ kg IV on days +3, +4. 
Mesna: 50 mg/kg IV, divided into three doses IV on cyclophosphamide days +3, +4. 
Tacrolimus: Dosed per institutional standards starting day +5 to +90, target level 5-10  
ng/ml. Mycophenolate mofetil: 15 mg/kg PO three times daily (max dose 1gram TID) starting 
day +5. MMF will be stopped on day +35, if there is no evidence of GVHD. 
G-CSF: 5 µg/kg subcutaneously daily, starting day +5 until neutrophil recovery. 
 
For patients with age ≥60 years and/or HCT-CI score of >3 will have the option of receiving 
the following regimen: 
EVOMELA®: 70 mg/ m2/day IV on day -6. 
Fludarabine: 40 mg/ m2/day IV days -5, -4, -3, -2. 
TBI: 200 cGy; days -1  
Stem Cell infusion on day 0. 
Cyclophosphamide: 50 mg/ kg IV on days +3, +4. 
Mesna: 50 mg/kg IV, divided into three doses IV on cyclophosphamide days +3, +4. 
Tacrolimus: Dosed per institutional standards starting Day +5 to +90, target level 5-10 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
27 
Version No.: 3 
Version Date: 10-14-2022 
 
ng/mL Mycophenolate mofetil: 15 mg/kg PO three times daily (max dose 1gram TID) starting 
day +5. MMF will be stopped on day +35, if there is no evidence of GVHD. 
G-CSF: 5 µg/kg subcutaneously daily, starting day +5 until neutrophil recovery. 
 
 
 
 
 
5.2  Conditioning Regimen 
 
5.2.1  Propylene Glycol-Free Melphalan for Injection (EVOMELA®) 
 
EVOMELA® will be administered at 140 mg/m2/day IV on day -6. In patients who are 60 years 
and older or have an HCT-CI score of >3, EVOMELA® may be administered at 70 mg/m2 on 
day -6 (optional). 
 
It will be dosed according to the adjusted body weight, if the patient’s actual body weight is 
greater than the ideal body weight. 
If the ideal body weight (IBW) > actual body weight, then, actual body weight will be used. 
 
For the calculation of BSA, actual body weight should be used for patients who weigh less than 
their IBW. For patients who weigh more than their IBW, BSA should be calculated, based on 
adjusted body weight. 
 
BSA (m2) = SQR RT ([Height (cm) x Weight (kg)]/ 3600). 
Adjusted body weight= IBW + 0.4(actual weight - IBW). 
Institutional standard of care rounding policies may be followed for calculating the final dose of 
melphalan. 
 
5.2.2  Fludarabine 
- Fludarabine dose is based on estimated creatinine clearance. 
- Adults: creatinine clearance may be estimated by the Cockcroft-Gault Formula, using 
actual body weight: CrCl = [(140-age) x weight (kg) x 0.85 (for women only)]/ [72 x creat 
(mg/dl)]. 
- Fludarabine will be administered by IV infusion over 30 minutes in a dose of 40 
mg/m2/day on days -5 to -2. 
- The dose of fludarabine will be based on actual body weight. 
 
 
Fludarabine dose, based on creatinine clearance 
Creatinine Clearance ml/min 
Daily Fludarabine Dose (mg/m2) 
> 60 
40 
46–60 
32 (80% of full dose) 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
28 
Version No.: 3 
Version Date: 10-14-2022 
 
31–45 
30 (75% of full dose) 
21–30 
26 (65% of full dose) 
 
5.2.3  Total Body Irradiation 
 
200 cGy TBI will be given on day -1 at a rate of 6–15 cGy/minutes per radiation oncology 
standard guidelines.  
 
5.3  Transplantation Procedure 
 
Both peripheral blood and bone marrow graft sources are acceptable for transplantation and 
will be decided in advance by the transplant physician. Infused peripheral blood product dose 
will be capped at 5 x 106 CD34+ cell/kg recipient actual body weight. (30) Unmanipulated stem 
cells will be infused on day 0, per Foundation for the Accreditation of Cellular Therapy (FACT) 
guidelines. Donor bone marrow will be harvested with a target yield of 4 x 108 nucleated 
cells/kg recipient actual body weight. In addition to calculating the total nucleated cell dose, 
CD34+ cell content in the graft will be calculated by flow cytometry. Unprocessed marrow will 
be infused on day 0 unless there is a major and/or minor ABO incompatibility, in which case red 
blood cells and/or plasma will be depleted from the donor marrow in accordance with the 
institutional practices.  
 
5.4  Post-transplantation Immunosuppression 
 
Immunosuppression to permit engraftment and provide GVHD prophylaxis will be performed 
with cyclophosphamide (CY), mycophenolate mofetil (MMF) and tacrolimus. 
 
5.4.1  Cyclophosphamide 
 
- On Days +3 and Day +4, CY will be given as a single dose of 50 mg/kg IV. 
- Use adjusted body weight. 
- Adjusted body weight = IBW + 0.4 (actual weight — IBW). 
- If actual body weight is less than ideal body weight, use actual body weight. Post-transplant - - 
- CY will be given within 48–72 hours of peripheral blood or bone marrow stem cell infusion 
as a one-hour infusion with MESNA prophylaxis and IV hydration. 
- Refer to standard practice guidelines. 
- Urine output and signs of hematuria will be monitored closely. 
- To maximize the effectiveness of post-transplant CY, it is critical that immunosuppressive 
agents are avoided FROM THE MORNING OF STEM CELL INFUSION until 24 
hours AFTER the completion of the post-transplant CY, unless there is medical necessity. This 
includes corticosteroids as anti-emetics. Standard of care fluids should be used for Cytoxan. 
 
5.4.2  Mesna 
 
Mesna dose will be administered IV at 50 mg/kg based on adjusted body weight, divided into 3 
doses (first dose 30 min prior, second dose 4 hours after completion, and 3rd dose 8 hours after 
completion of Cy) on cyclophosphamide days +3, +4. 
 
 
5.4.3  Mycophenolate Mofetil 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
29 
Version No.: 3 
Version Date: 10-14-2022 
 
 
Starting on Day +5 (24–36 hours after last dose of CY), MMF will be given orally at a 
dose of 15 mg/kg based on adjusted body weight every eight hours. 
 
MMF will be stopped on day +35 if there is no evidence of GVHD. 
 
 
 
5.4.3.1  Guidelines for MMF Dose Adjustment and Monitoring 
 
- Initiating MMF therapy: Oral administration of MMF will be at 15 mg/kg orally every eight hours 
(45 mg/kg/day), starting on Day +5. 
- Maximum dose will be capped at 1 gm TID. 
- If there is nausea and vomiting at any time preventing the oral administration of MMF, MMF 
should be administered intravenously at the appropriate dose. 
 
5.4.3.2  Maintaining MMF 
 
- Markedly low (<40%) donor T-cell chimerism after HCT may indicate impending graft rejection. 
- MMF should be continued at full dose or if the MMF taper has been initiated, reinstitution of full 
dose MMF should occur. 
- If MMF has been discontinued, MMF should be reinitiated at full dose. 
 
5.4.3.3  Guidelines for MMF Dose Adjustment, Based on Toxicity 
 
If, in the clinical judgment of the attending physician, the observed toxicity is related to MMF 
administration, a dose adjustment may occur. The discontinuation of MMF at any point should 
be discussed with the Study PI and should be documented in the permanent medical record and 
all Case Report Forms (CRF). 
 
5.4.3.4  Gastrointestinal Toxicity 
 
- Severe gastrointestinal toxicities, such as gastrointestinal hemorrhage, have been very rare 
after non-myeloablative HCT. 
- In the event of gastrointestinal toxicity that requires medical intervention, including medication 
for control of persistent vomiting or diarrhea that is considered to be due to MMF after day 28, a 
20% dose reduction will be made or the drug may be given IV. 
- If severe refractory diarrhea or overt gastrointestinal bleeding occurs, MMF may be temporarily 
stopped. 
- The MMF should be restarted at 20% reduced dose when the underlying toxicity subsides. 
 
5.4.3.5  Neutropenia 
 
Based on previous experience in patients after non-myeloablative HCT, dose adjustments are 
likely to occur because of hematopoietic adverse effects, in particular neutropenia. 
- A thorough evaluation of neutropenia should occur, including peripheral blood 
chimerism studies, marrow aspiration and review of marrow-suppressive medications. 
 
- If all other potential causes of marrow toxicity are ruled out, dose adjustments will only 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
30 
Version No.: 3 
Version Date: 10-14-2022 
 
be made for severe, prolonged neutropenia (ANC <500/ul for 5 days or more) that 
persists after day +21 post-transplant. Dose reductions should be conservative (20%). 
- After day +21, the use of G-CSF will be permitted for severe neutropenia. For severe 
hematological toxicity related to MMF (neutropenia > 5 days refractory to G-CSF), MMF 
may be temporarily stopped. The MMF should be restarted at 20% reduced dose, when 
the underlying toxicity subsides. The discontinuation of MMF at any point should be 
discussed with the study principal investigator and should be documented in the 
permanent medical record and all CRFs. 
 
5.4.4  Tacrolimus 
 
- Starting on Day +5 (24-36 hours after last dose of CY), tacrolimus will be dosed  
per institutional standards starting Day +5 to +90, target level 5-10 ng/ml  
- Serum levels of tacrolimus should be measured on Day +8 and then at least weekly until 
Day +30 and the dose adjusted to maintain a level of 5-10 ng/ml. 
  - Dose reduction should be made if toxicity is present, or if whole blood levels are above the 
therapeutic range, in the absence of toxicity. 
- Tacrolimus will be tapered after Day +100 (adapted dose-reduction to be discontinued by day 
+180) if there is no evidence of GVHD. 
 
5.4.4.1 Guidelines for Tacrolimus Dose Adjustment and Monitoring 
 
- If there are nausea and vomiting, which prevent oral intake at any time during tacrolimus 
treatment, the drug should be given intravenously at the appropriate dose that was used to 
obtain a therapeutic level. (IV: PO ratio = 1: 4). 
- Whole-blood trough levels of tacrolimus (i.e., just prior to the next dose) should be obtained on 
Day +8, and then, twice weekly until the taper is initiated, unless high levels (>20 ng/ml) are 
detected or toxicity is suspected, in which case more frequent monitoring will be performed, as 
clinically indicated. The dose should be adjusted accordingly to maintain a level of 5–15 ng/ml. 
- Dose reductions should only be made if tacrolimus toxicity is present or levels exceed 20ng/ml, 
in the absence of toxicity. 
- Dose reductions of tacrolimus for high levels without toxicity should be conservative, e.g. 25%, 
to avoid inadequate immunosuppression. 
- If creatinine is greater or equal to two times the baseline level, then the tacrolimus dose will be 
reduced by 25%. 
 
 
Medications that Affect Tacrolimus Levels (use with caution) 
Decrease Tacrolimus Levels 
Increase Tacrolimus Levels 
Dilantin 
Steroids 
Phenobarbital 
Fluconazole 
Carbamazepine 
Ketoconazole 
Rifampin 
Itraconazole 
Caspofungin 
Voriconazole* 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
31 
Version No.: 3 
Version Date: 10-14-2022 
 
Cimetidine 
Macrolide antibiotics 
Calcium channel blockers 
Danazol 
Metoclopramide 
* When initiating therapy with voriconazole in patients already receiving tacrolimus, it is recommended 
that the tacrolimus dose be reduced to one-third of the original dose, (a 67% reduction) and followed 
with frequent monitoring of the tacrolimus blood levels. Increased tacrolimus levels have been 
associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus levels should be carefully 
monitored, and the dose increased as necessary. 
 
- Blood pressure, renal function tests (creatinine, BUN), electrolytes and magnesium need to be 
followed at least two to three times per week, while receiving tacrolimus to full dose, and then, 
twice weekly or per attending, until tacrolimus is discontinued. 
- Tacrolimus levels should be performed more frequently when 
o drug is converted from oral to IV or IV to oral. 
o dose adjustments are made due to levels outside the therapeutic range. 
o voriconazole (see table below) is initiated or withdrawn, if toxicity is suspected. 
o steady-state levels will not be achieved for at least 72 hours after any change in dosing, 
i.e., levels determined earlier may not reflect an accurate steady state concentration. 
- Patients requiring hemodialysis should have tacrolimus levels maintained in the therapeutic 
range (5 to15 ng/ml). 
- Grapefruit and grapefruit juice affect the metabolism of tacrolimus and should be avoided. Oral 
tacrolimus should be taken consistently with or without food. 
 
5.5  Growth Factor Support 
 
Patients will receive G-CSF at 5ug/kg/day SC starting at day +5 and continuing until the ANC 
>500/uL for three days. 
 
6  DISEASE ASSESSMENT 
The team will follow standard institutional guidelines for post HCT disease assessment. The 
following time periods are suggestions, and disease assessments may be performed earlier or 
later at the discretion of the treating physician. 
 
6.1  Leukemias and Myelodysplastic Syndrome 
 
Bone marrow aspirate and biopsy to be recorded within three to four months of HCT and at one 
year post HCT. After one year, it will be up to the discretion of the treating physician, as 
indicated clinically. 
 
6.2  Lymphomas 
 
A PET/CT or CT scan to be recorded around day +100 (±30 days) post HCT. Subsequent 
need for imaging studies will be up to the discretion of the treating physician as indicated 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
32 
Version No.: 3 
Version Date: 10-14-2022 
 
clinically. 
 
6.3  Myelomas 
 
- Myeloma panel and bone marrow aspirate and biopsy to be recorded approximately  
day +100 post HCT. 
- Subsequent need for bone marrow biopsy and/or myeloma panel will be performed, per the 
discretion of the treating physician, as indicated clinically. 
 
6.4  Graft Failure and Rejection 
 
6.4.1  Graft Failure 
 
Primary graft failure is defined as the absence of absolute neutrophil count (ANC) recovery after 
HCT nadir to ≥500/µL by day +35 post HCT. 
 
6.4.2  Graft Rejection 
 
Primary graft rejection is defined as the failure to demonstrate donor-derived hematopoiesis 
after haplo-HCT (i.e., no evidence of donor-cell chimerisms of ≥5% on unsorted or lineage- 
specific chimerism analysis [LSCA] at any time point post HCT), while complete loss of 
donor- cell chimerism (i.e., <5% donor-cells on chimerism analysis) after demonstrating 
evidence of donor-derived hematopoiesis is termed secondary graft rejection. 
 
6.5  Acute and Chronic GVHD 
 
6.5.1  Acute GVHD 
 
Diagnosis of acute GVHD will ideally require biopsy confirmation in at least one involved organ. 
When more than one organ is involved, biopsy confirmation of all involved organs is 
recommended, but not necessary. Liver-only GVHD must be confirmed by biopsy. Acute GVHD 
will be assessed by consensus criteria (Appendix 4) and graded on Blood Marrow Transplant 
Clinical Trials Network Manual of Procedures-suggested grading sheets (Appendix 5). Acute 
GVHD assessment and grading will be performed by treating physicians. 
 
6.5.2  Chronic GVHD 
 
Chronic GVHD diagnosis and grading will be according to NIH Criteria. Please see the 
appendix. 
 
6.5.3  Clinical Grading of Chronic GVHD (According to Appendix 6) 
 
- None 
- Mild chronic GVHD involves only one or two organs or sites (except the lung: see below ‡), 
with no clinically significant functional impairment (maximum score of 1 in all affected organs or 
sites). 
- Moderate chronic GVHD involves: (1) at least one organ or site with clinically significant but no 
major disability (maximum score of 2 in any affected organ or site) or (2) three or more organs 
or sites with no clinically significant functional impairment (maximum score of 1 in all affected 
organs or sites). 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
33 
Version No.: 3 
Version Date: 10-14-2022 
 
 
‡A lung score of 1 will also be considered moderate chronic GVHD. Severe chronic GVHD 
indicates major disability caused by chronic GVHD (score of 3 in any organ or site). 
‡A lung score of 2 or greater will also be considered severe chronic GVHD. 
Presence of limited or extensive chronic GVHD will be also recorded. 
 
7  PHARMACEUTICAL INFORMATION 
For the calculation of body surface area, the most recent height and weight available on day -6 
will be used. Institutional standard-of-care rounding policies may be followed for calculating the 
final dose of administered medications. 
 
7.1  Investigational Product (EVOMELA®) 
 
7.1.1  Description 
 
EVOMELA® is a white lyophilized powder containing 56 mg of melphalan for Injection 
(equivalent to 50 mg of melphalan free base) and 2,700 mg sulfobutylether-beta-cyclodextrin 
Captisol®. There is also sodium hydroxide and hydrochloric acid, if necessary, present in the 
product that is used to adjust the pH of the solution prior to lyophilization to a physiologically 
well-tolerated range of 
pH 5.0 ± 1.0. Evomela® will be supplied by the sponsor. 
 
7.1.2  Storage and Administration 
 
Normal saline solution (0.9% sodium chloride injection, USP) is used to reconstitute (8.6 mL) 
and dilute (for infusion) the product prior to clinical use. After reconstitution with 0.9% normal 
saline, the concentration of the diluted vial is 5 mg/mL. Immediately, further dilute with 0.9% 
normal saline to a final concentration equal to 2 mg/mL. EVOMELA® is stable at room 
temperature for at least four hours after reconstitution, if followed by immediate dilution. 
EVOMELA® will be supplied by Spectrum in a 20-mL glass vial, Type I, with a 20-mm finish, a 
20-mm lyophilization type rubber stopper and a crimp seal. EVOMELA® vials should be stored 
protected from light and at a controlled room temperature of 20–25 °C (68–77 °F) with 
excursions permitted between 15 and 30 °C (59 and 86 °F). 
Below is an example of the information that may appear on the label of the study medication: 
 
- 
Spectrum 
- 
EVOMELA® lyophilized powder containing 56 mg melphalan for Injection (equivalent 
to 50 mg melphalan free base) 
- 
Each vial contains melphalan for Injection, Captisol® and sodium hydroxide 
- 
Reconstitute with normal saline prior to infusion 
- 
Protocol Number IIT-MEL-MCW-001 
- 
Lot number 
- 
Manufacture date 
- 
Manufactured by DSM Pharmaceuticals, Inc., Greenville, North Carolina, 
- 
U.S.A; for Spectrum Pharmaceuticals, Inc., USA 
- 
Storage conditions 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
34 
Version No.: 3 
Version Date: 10-14-2022 
 
 
7.1.3  Assigning Subjects to Treatment Group 
 
All patients will receive 140 mg/m2 of EVOMELA® on day -6 administered over 30±5 minutes as 
a 2-mg/ml solution, followed by fludarabine (40 mg/m2 IV days -5 to -2) and TBI (200 cGy on 
day -1). In patients who are 60 years and older, and/or have an HCT-CI score of >3, 
EVOMELA® may be administered at 70 mg/m2 on day -6 (optional). 
 
7.1.4  Study Medication Accountability 
 
The investigator/pharmacist must maintain accurate records of study drug disposition, patient 
administration (including date and time), in addition to noting any accidentally destroyed drugs. 
At the end of the study, information describing study drug supplies (e.g., lot numbers) and 
disposition of supplies for each patient must be provided, signed by the investigator. If any 
errors or irregularities in any shipment of study medication to the site are discovered at any 
time, Spectrum must be contacted immediately. 
 
At the end of the study, all medication not dispensed or administered, and packaging materials 
will be collected with supervision of the monitor and returned to Spectrum or destroyed on site, 
as dictated by the appropriate SOP at this institution. 
 
7.1.5  Blinding/Masking of Treatments 
 
This is an open-label study. All patients enrolled in the study will receive EVOMELA® on day -6 
prior to haplo-HCT. No blinding or masking of the study drug will occur. 
 
7.1.6  Treatment Administration 
 
EVOMELA® will be infused over 30±5 minutes in a 2-mg/mL solution via a central venous 
catheter by a trained health care professional. Records of study medication administered (date, 
time and dose administered relative to reconstitution time) will be recorded in the patient’s CRF. 
 
EVOMELA® will be administered at 140 mg/m2/day IV on day -6. In patients who are 60 
years and older, and/or have an HCT-CI score of >3, EVOMELA® may be administered at 70 
mg/m2 on day -6 (optional). It will be dosed according to the adjusted body weight, if the 
patient’s actual body weight is >100% of the ideal body weight. 
 
If the ideal body weight (IBW) > actual body weight, then, actual body weight will be used. For 
the calculation of BSA, actual body weight should be used for patients who weigh less than their 
IBW. For patients who weigh more than their IBW, BSA should be calculated, based on 
adjusted body weight. 
 
BSA (m2) = SQR RT ([Height (cm) x Weight (kg)]/ 3600).  
Adjusted body weight= IBW + 0.4(actual weight IBW). 
 
7.2  Fludarabine 
 
7.2.1  Description 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
35 
Version No.: 3 
Version Date: 10-14-2022 
 
 
Fludarabine’s active metabolite 2-fluoro-ara-A is an antimetabolite that inhibits DNA primase, 
DNA polymerase alpha and ribonucleotide nuclease. This is commercially available. 
 
7.2.2  Dosage and Administration 
 
Fludarabine monophosphate is commercially available as a 50-mg vial, which is reconstituted 
with 2 ml of sterile water, resulting in a 25-mg/ml solution. The desired dose is further diluted 
to concentrations of 0.04–1 mg/ml in normal saline or 5% dextrose (50–100ml) for injection 
and will be administered by IV infusion over 30 minutes or longer. 
 
Fludarabine will be administered by IV infusion over 30 minutes in a dose of 40 mg/m2/day on 
days -5 to -2. The dose of fludarabine is based on actual body weight. 
 
7.2.3  Side Effects and Toxicities 
 
- The dose of fludarabine used in this protocol is nonmyeloablative; however, it can cause 
severe immunosuppression, particularly in the CD4+ T-cell compartment. Immunosuppression 
increases the risk of infection, which can be life threatening. Immunosuppression observed with 
the use of fludarabine increases the risk of infection, which can be life threatening. 
 
- In addition, clinical toxicities of fludarabine monophosphate include myelosuppression, 
primarily lymphopenia and granulocytopenia, alopecia, rash, dermatitis, nausea, vomiting, 
anorexia, stomatitis, diarrhea, somnolence, fatigue, peripheral neuropathy, mental status 
changes, cortical blindness, hepatocellular toxicity with elevation in serum transaminases, 
neurotoxicity and interstitial pneumonitis. These effects are reversible when the drug is 
discontinued. 
 
7.3  Total Body Irradiation 
 
- TBI, given at high doses in conventional transplants, may cause nausea, vomiting, diarrhea, 
temporary hair loss and painful swelling of the salivary glands for a few days. 
- TBI may destroy normal marrow cells, in addition to the cancer cells. The dose of TBI (200 
cGy,) used in this protocol is about one-sixth of that used in conventional transplant protocols 
and severe acute side effects have so far not been observed. TBI has been associated with 
causing sterility and there is a risk of major genetic damage to any children conceived after 
transplantation. There is a risk that a small percentage of patients may develop a secondary 
cancer resulting from this treatment. 
 
7.4  Cyclophosphamide 
 
7.4.1  Description 
 
Cyclophosphamide is an alkylating agent, which prevents cell division primarily by cross-linking 
DNA strands. Cyclophosphamide is cell-cycle nonspecific. Cyclophosphamide is not stem cell 
toxic. 
 
7.4.2  Storage and Administration 
 
Cyclophosphamide for injection is commercially available in 2000-mg vials, which are 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
36 
Version No.: 3 
Version Date: 10-14-2022 
 
reconstituted with 100-ml sterile water for injection. The concentration of the reconstituted 
product is 20 mg/ml. The calculated dose will be diluted further in 250–500 ml of dextrose 5% in 
water. Each dose will be infused over one to two hours (depending on the total volume). 
 
Cyclophosphamide 50 mg/ kg IV will be administered on days +3 and +4. 
 
 
7.4.3  Side Effects and Toxicity 
 
Clinical toxicities of cyclophosphamide include alopecia, nausea and vomiting, headache and 
dizziness, hemorrhagic cystitis, cardiotoxicity, immunosuppression, myelosuppression, 
pulmonary fibrosis, increased hepatic enzymes and syndrome of appropriate antidiuretic 
hormone (SIADH). 
 
7.4.4  Precautions 
 
Avoid steroids (>10 mg prednisone/equivalent) from day 0 until 24 hours after completion of 
cyclophosphamide. 
 
7.5  Mesna 
 
7.5.1  Description 
 
Mesna is a prophylactic agent used to prevent hemorrhagic cystitis induced by the 
oxazaphosphorine (cyclophosphamide and iphosphamide). It has no intrinsic cytotoxicity and no 
antagonistic effects on chemotherapy. Mesna binds with acrolein, the urotoxic metabolite 
produced by oxazaphosphorine, to produce a nontoxic thioether and slows the rate of acrolein 
formation by combining with 4-hydroxy metabolites of oxazaphosphorine. 
 
7.5.2  Storage and Administration 
 
Mesna is commercially available in 200-mg, 400-mg and 1000-mg vials containing a 100-mg/ml 
solution. Each dose of mesna will be diluted further in 50 ml of normal saline to be infused over 
15 minutes. Mesna dose will be administered IV at 50 mg/kg, divided into three doses on 
cyclophosphamide days +3 and +4. 
 
7.5.3  Side Effects and Toxicity 
 
At the doses used for uroprotection, Mesna is virtually non-toxic. However, adverse effects, 
which may be attributable to mesna, include nausea and vomiting, diarrhea, abdominal pain, 
altered taste, rash, urticaria, headache, joint or limb pain, hypotension and fatigue. 
 
7.6  Tacrolimus 
 
7.6.1  Description 
 
Tacrolimus, also known as FK-506, is a macrolide immunosuppressive agent and is 
commercially available. Tacrolimus inhibits lymphocytes by forming a complex with FKBP-12, 
calcium and calmodulin, leading to the decrease in the phosphatase activity of calcineurin. 
Calcineurin mediates the first intracellular signal required for T-cell activation after antigen 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
37 
Version No.: 3 
Version Date: 10-14-2022 
 
recognition by the T-cell receptor. This drug is used with corticosteroids for prophylaxis of organ 
rejection in patients receiving allogeneic liver transplants and for prophylaxis of GVHD in the 
setting of HCT. It also is used for immunosuppression after kidney, cardiac, pancreas, pancreatic 
islet cell and small bowel transplantation. This drug is well absorbed orally. It is metabolized in the 
liver by unknown mechanisms, but demethylation and hydroxylation have been proposed based on 
in vitro studies. The metabolized products are excreted in the urine. 
 
7.6.2  Dosage and Administration 
  
Oral 
Tacrolimus 0.06 mg/kg, PO every 12 hours starting day +5 to +90. Target level 5 to 15 ng/ml. 
For better absorption, it is recommended that tacrolimus capsules be taken on an empty 
stomach. 
 
Tacrolimus should not be taken with grapefruit juice as it may increase blood levels. If a 
patient vomits within one hour of oral administration, repeat the dose. If vomiting persists, 
switch to IV administration. 
 
Conversion from IV to PO dosing of tacrolimus. 
Patients should be converted to an oral dose at four times the IV dose to be given in divided 
(Q 12 hour) doses. 
 
7.6.3  Side Effects and Toxicities 
 
- Renal – Rise in serum creatinine, hemolytic uremic syndrome. 
- Neurological – Peripheral: paresthesia, tremor. Central: seizures, headache, 
insomnia, dizziness, depression, confusion, hallucinations, psychosis, myoclonus, 
neuropathy, agitation. 
- Gastrointestinal – Nausea, vomiting, anorexia, constipation, diarrhea. 
- Cardiovascular – Hypertension, myocardial hypertrophy. 
- Endocrine – Hyperglycemia, hyper/hypokalemia, hypophosphatemia, 
hypomagnesemia. 
- Integument – Itching, rash. 
- Hematologic – Leukocytosis, thrombocytopenia, leukopenia, anemia, PTLD, 
thrombotic microangiopathy. 
- Liver – Abnormal liver function tests. 
- Ocular – Blurred vision, photophobia. 
- Respiratory – Pleural effusion, atelectasis, cough, dyspnea. 
- Musculoskeletal – Arthralgia. 
 
7.7  Mycophenolate Mofetil (MMF) 
 
7.7.1  Description 
 
MMF is the morpholinylethylester of mycophenolic acid (MPA) and reversibly inhibits inosine 
monophosphate dehydrogenase, particularly the type II isoform that is more prominent in 
activated lymphocytes. As a result of the inhibition of de novo purine synthesis, proliferation of B 
and T lymphocytes is blocked, and antibody production is inhibited. MMF is commercially 
available. 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
38 
Version No.: 3 
Version Date: 10-14-2022 
 
 
7.7.2  Storage and Administration 
 
MMF is available in an oral and an intravenous formulation. The oral formulation is supplied in 
250-mg hard gelatin capsules and can be stored at room temperature. MMF for IV 
administration is supplied as a lyophilized powder in a glass vial containing the equivalent of 
500 mg. Mycophenolate mofetil will be administered at 15 mg/kg PO three times daily (max 
dose 1 gram three times a day) starting day +5 and stopped on day +35, if there is no evidence 
of GVHD. 
 
7.7.3  Side Effects and Toxicity 
 
MMF has been studied extensively among patients after non-myeloablative HCT. Previous 
clinical studies in patients after allografting suggest that the principal adverse reactions 
associated with the administration of MMF include nausea, vomiting, neutropenia, diarrhea and 
on one occasion bloody diarrhea. In the setting of marrow transplantation, several etiologic 
factors may contribute to alterations in gastrointestinal and hematologic parameters. MMF has an 
increased incidence of digestive system adverse events, including GI tract ulceration, and 
hemorrhage (3% of patients receiving MMF). GI tract perforations have rarely been observed. 
Most patients in these studies were also on other drugs known to be associated with these 
complications. Up to 2% of patients receiving MMF for prevention of rejection developed severe 
neutropenia (ANC <500). The development of neutropenia may be related to MMF itself, 
concomitant medications, viral infections or some combination of these causes. MMF dose 
adjustments will be made if clinically indicated if in the opinion of the attending physician, no 
other cause is thought to be responsible for the abnormality. These adjustments should be 
discussed with the principal investigator and documented in the medical records and the clinical 
reporting form (CRF). 
 
7.8  Prophylaxis and Other Therapy 
 
7.8.1  Hematopoietic Growth Factors 
 
Filgrastim is required. Administer filgrastim 5 micrograms/kg/day subcutaneous (SC) (may be 
rounded to the nearest vial), based on actual body weight, beginning on Day +5. In the 
absence of toxicity, continue filgrastim until the postnadir ANC is ≥ 500 / µL on three 
consecutive measurements over different days. 
 
7.8.2  Prophylactic Treatment for Opportunistic Infections 
 
All patients will receive prophylaxis against bacterial, fungal and viral infections during the peri- 
transplant period, according to institutional guidelines. 
 
7.8.3  Antiemetics 
 
Patients will receive antiemetics with conditioning regimen in accordance with institutional 
guidelines. 
 
7.8.4  Blood Products 
 
Transfusion thresholds for blood-product support will be in accordance with institutional 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
39 
Version No.: 3 
Version Date: 10-14-2022 
 
guidelines. 
 
8. STATISTICAL METHODS 
Descriptive statistical methods will be used to summarize the data from this study. Unless stated 
otherwise, the term “descriptive statistics” refers to number of subjects (n), mean, median, 
standard deviation, minimum and maximum for continuous data and frequencies and 
percentages for categorical data. The progression-free survival (PFS) and overall survival (OS) 
postHCT will be calculated, using the Kaplan-Meier estimator and the probabilities of NRM, 
relapse, neutrophil and platelet recovery, acute and chronic GVHD will be calculated, using 
cumulative incidence curves to accommodate competing risks, and treating withdrawn subjects 
as censored subjects. Approximately 95% confidence interval of estimated probability will be 
reported. 
 
All statistical analyses will be conducted with the SAS® System, Version 9.1.3 or higher. 
 
8.1  Study Design 
 
This is an open-label, single-arm, phase II study. The primary end point of the study is one-year 
PFS and safety of EVOMELA®/Flu/TBI-based RIC haplo-HCT. 
 
8.2  Safety/Stopping Rules 
 
8.2.1  Stopping Rule for Excess NRM 
 
NRM rate will be the key end point to monitor safety of this approach. Based on historical 
control data, an NRM rate at day 100 of ≥15% in the current study will be considered 
unacceptable. We will evaluate and monitor TRM after the first 15 and 25 patients enrolled 
the study. Assuming 15% of TRM occurring will stop the enrollment for protocol review. A 
Pocock- type boundary with the lower limit of 95% confidence interval will be used for 
monitoring TRM. At planned interim monitoring points, if no more than six or seven TRMs 
occur, the study will continue to its full enrollment of 43. 
 
8.2.2  Stopping rule for excess primary graft rejection 
 
Primary graft rejection rate of ≥20% by day +45 would be considered unacceptable. 
 
8.3  Accrual Estimate 
 
We plan to accrue 43 haploidentical transplant patients in two and a half years. 
 
8.4  Accrual and Follow-up Period 
 
The expected accrual period is two and a half years with two years additional follow-up. The 
study will be closed to accrual after the last patient is enrolled. 
 
8.5  Sample Size Estimates 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
40 
Version No.: 3 
Version Date: 10-14-2022 
 
 
The primary end point of the study is one-year PFS. The historical one-year PFS since 
transplant under standard treatment is 45%. Assuming one-year PFS for haploidentical 
transplant is 59%. We plan to accrue haploidentical transplant patients in two and a half years 
with two years additional follow-up. The study will be closed to accrual after the last patient has 
been enrolled. 
 
Based on exponential distribution and on a one-sided test with significance level of 5%, we will 
have 80% power to detect at least a 14% increase in one-year PFS for 41 patients. Allowing 5% 
subjects to be lost to follow-up or withdrawn, we plan to accrue 43 patients in the final study. 
 
8.6  Data Collection Methods 
 
The data will be recorded on the OnCore® CRF. The clinical research coordinator must submit a 
completed CRF for each subject who signs an informed consent form (ICF), regardless of 
duration. All documentation supporting the CRF data, such as laboratory or hospital records, 
must be readily available to verify entries in the CRF. 
 
9  ADVERSE EVENTS:  DEFINITIONS AND REPORTING 
REQUIREMENTS 
 
9.1  Adverse Event (AE) and Serious Adverse Events (SAE) 
 
The investigator and his or her team will follow the Medical College of Wisconsin policies related 
to adverse event reporting. This information may be found on the Human Research Protection 
Program website. (http://www.mcw.edu/hrpp/InvestigatorsandStudyStaff.htm). 
 
Serious AE (SAE) means any untoward occurrence that at any dose: 
 
Definitions 
 
An SAE is defined as any untoward medical occurrence at any dose that: 
 
• Death. Results in death.  
• Life threatening. Is life threatening (refers to an AE in which the patient was at risk of death at 
the time of the event. It does not refer to an event which hypothetically might have caused death if 
it were more severe).  
• Hospitalization. Requires inpatient hospitalization or prolongation of an existing hospitalization 
(see clarification in the paragraph below on planned hospitalizations).  
• Disability/incapacity. Results in persistent or significant disability or incapacity. (Disability is 
defined as a substantial disruption of a person’s ability to conduct normal life functions).  
• Medically important event. This refers to an AE that may not result in death, be immediately life 
threatening, or require hospitalization, but may be considered serious when, based on appropriate 
medical judgment, may jeopardize the patient, require medical or surgical intervention to prevent 1 
of the outcomes listed above, or involves suspected transmission via a medicinal product of an 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
41 
Version No.: 3 
Version Date: 10-14-2022 
 
infectious agent. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization; any organism, virus, or infectious particle (e.g., prion protein 
transmitting Transmissible Spongiform Encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent.  
Clarification should be made between a serious AE (SAE) and an AE that is considered severe 
in intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous. The 
general term severe is often used to describe the intensity (severity) of a specific event; the 
event itself, however, may be of relatively minor medical significance (such as a Grade 3 
headache). This is NOT the same as serious, which is based on patient/event outcome or action 
criteria described above and is usually associated with events that pose a threat to a patient’s life 
or ability to function. A severe AE (Grade 3 or 4) does not necessarily need to be considered 
serious. Seriousness (not intensity) serves as a guide for defining regulatory reporting 
obligations. Planned hospitalizations will not be considered an adverse event. 
 
9.2  Unanticipated Problem Involving Risk to Subject or Other (UPIRSO) 
 
The investigator and his or her team will follow the Medical College of Wisconsin policies related 
to unanticipated problems involving risks to subjects or others. This information may be found on 
the Human Research Protection Program website. 
(http://www.mcw.edu/hrpp/InvestigatorsandStudyStaff.htm) 
 
 
 
9.3  AE Attribution and Grading 
 
Adverse Event Grading 
 
Grade 
Description 
0 
No AE (or within normal limits). 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
2 
Moderate; minimal, local or noninvasive intervention (e.g., packing cautery) indicated; limiting 
age-appropriate instrumental activities of daily living (ADL). 
3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to AE 
 
9.4  Adverse Event Attribution 
 
Attribution is an assessment of the relationship between the AE and the medical intervention. 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
42 
Version No.: 3 
Version Date: 10-14-2022 
 
 
 
 
 
 
 
 
 
Relationship 
Attribution 
Description 
Unrelated to investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related to the 
intervention 
Unlikely 
The AE is doubtfully related to the 
intervention 
Related to investigational 
agent/intervention 
Possible 
The AE may be related to the 
intervention 
Probable 
The AE is likely related to the 
intervention 
Definite 
The AE is clearly related to the 
intervention 
 
 
9.5  Relationship Assessment:  In-depth Definitions 
 
For all collected AEs, the clinician who examines and evaluates the subject will determine the 
adverse event’s causality, based on temporal relationship and his/her clinical judgment. The 
degree of certainty about causality will be graded using the categories below: 
 
- 
Definitely Related: There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to drug administration and cannot 
be explained by concurrent disease or other drugs or chemicals. The response to withdrawal 
of the drug (dechallenge) should be clinically plausible. The event must be pharmacologically 
or phenomenologically definitive, with use of a satisfactory rechallenge procedure, if 
necessary. 
- 
Probably Related: There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time sequence to administration of the drug, is unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (dechallenge). Rechallenge information is not required to 
fulfill this definition. 
- 
Possibly Related: There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). However, 
the influence of other factors may have contributed to the event (e.g., the subject’s clinical 
condition, other concomitant events). Although an adverse drug event may rate only as 
“possibly related” soon after discovery, it can be flagged as requiring more information and 
later be upgraded to “probably related” or “definitely related”, as appropriate. 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
43 
Version No.: 3 
Version Date: 10-14-2022 
 
 
- 
Unlikely: A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to drug administration makes a causal relationship improbable (e.g., the event did 
not occur within a reasonable time after administration of the trial medication) and in which  
other drugs or chemicals or underlying disease provides plausible explanations (e.g., the 
subject’s clinical condition, other concomitant treatments). 
 
- 
Unrelated: The AE is completely independent of study drug administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
9.6  Time Period and Grade of AE Capture 
 
AEs will be captured from signing the informed consent through 30 days after last dose of 
Evomela. CTCAE v4.0 will be used to grade and report AEs. 
 
9.7  Monitoring and Recording an Adverse Event 
 
Definition. Any clinically relevant deterioration in laboratory assessments or other clinical 
finding is considered an AE. 
Reporting source. AEs may be spontaneously reported by the patient and/or in response to an 
open question from study personnel or revealed by observation, physical examination or other 
diagnostic procedures. 
Prior to the trial. Planned hospital admissions or surgical procedures for an illness or disease 
that existed before the patient was enrolled in the trial are not to be considered AEs unless the 
condition deteriorated in an unexpected manner during the trial (e.g., surgery was performed 
earlier or later than planned). 
Pretreatment events following signed informed consent. For serious pretreatment events, 
the investigator must determine both the intensity of the event and the relationship of the event 
to study procedures. 
Treatment events. For serious AEs, the investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. 
Not serious AEs. For non-serious AEs, the investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. 
 
9.8  Follow-up of Adverse Events 
 
All adverse events will be followed with appropriate medical management 30 days following the 
last dose of the Evomela or until they are resolved, if they are related to the study treatment. 
 
9.9  Procedure for Reporting Drug Exposure during Pregnancy and Birth Events 
 
If a woman becomes pregnant, or suspects that she is pregnant, while participating in this study, 
she must inform the investigator immediately and permanently discontinue the study drug. The 
sponsor-investigator must notify the DSMC by email. The pregnancy must be followed for the 
final pregnancy outcome. 
 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor-investigator must also immediately notify the DSMC by email. Every effort 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
44 
Version No.: 3 
Version Date: 10-14-2022 
 
should be made to follow the pregnancy for the final pregnancy outcome. 
 
Routine Reporting Procedures for AEs 
Signs or symptoms reported as adverse events will be graded and recorded by the investigator, 
according to the CTCAE. When possible, signs and symptoms indicating a common underlying 
pathology should be noted as one comprehensive event. 
 
The investigator will assess all adverse events and determine reporting requirements to the 
MCWCC Data and Safety Monitoring Committee (DSMC) and MCW’s Institutional Review 
Board. 
 
The DSMC will review unexpected grade 3, as well as all grade 4 and 5 adverse events. 
Nonhematological grade 4 and all grade 5 events must be reported to the DSMC via email 
within five calendar days of study staff’s knowledge. Hematological grade 4 events may be 
routine reported. 
 
All adverse events, whether or not unexpected, and whether or not considered to be associated 
with the use of the study drug, will be entered into OnCore®. 
 
9.10  Reporting of SAEs 
 
Since this is an investigator-initiated study, the principal investigator, also referred to as the 
sponsor-investigator, is responsible for reporting serious adverse events (SAEs) to any 
regulatory agency, the sponsor- investigator’s IRB, and Spectrum Pharmaceuticals, Inc. 
 
 
9.11  Reporting to the Data and Safety Monitoring Committee 
 
Regardless of expectedness or causality, all SAEs (including serious pretreatment events) must 
also be reported to the DSMC as soon as possible, but no later than five calendar days of the 
sponsor-investigator’s observation or awareness of the event. 
 
As noted, the DSMC will review unexpected grade 3, as well as all grade 4 and 5 adverse 
events. Nonhematological grade 4 and all grade 5 events must be reported to the DSMC via 
email within five calendar days of study staff’s knowledge. Hematological grade 4 events may 
be routine reported. 
 
Report Method: The investigator will use email to report SAEs to the DSMC. The SAE report 
must include event term(s), serious criteria and the sponsor-investigator’s or sub-investigator’s 
determination of both the intensity of the event(s) and the relationship of the event(s) to study 
drug administration. Intensity for each SAE, including any lab abnormalities, will be determined 
by using the NCI CTCAE as a guideline whenever possible. The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 
 
9.12  Reporting to MCW Committee Institutional Review Board 
 
The principal investigator must report events to the MCW IRB within five business days of 
his/her awareness of the event. [Guidance on Adverse Event Reporting to the IRB is available 
online at MCW IRB Policies and Procedures.] 
 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
45 
Version No.: 3 
Version Date: 10-14-2022 
 
9.13  Reporting to Spectrum Pharmaceuticals, Inc. 
 
When study staff becomes aware of a SAE, they will report to Spectrum Pharmaceuticals, Inc. 
within 24 hours of his/her awareness of the event. [Guidance on Adverse Event Reporting to 
Spectrum Pharmaceuticals, Inc. is available in the contract] 
 
 
10. REGULATORY COMPLIANCE, ETHICS, AND STUDY MANAGEMENT 
 
10.1  Ethical Standard 
 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
 
 
10.2  Regulatory Compliance 
 
This study will be conducted in compliance with: 
▪ 
The protocol 
▪ 
Federal regulations, as applicable, including: 21 CFR 50 (Protection of Human 
Subjects/Informed Consent); 21 CFR 56 (Institutional Review Boards) and §312 
(Investigational New Drug Application; and 45 CFR 46 Subparts A (Common Rule), B 
(Pregnant Women, Human Fetuses and Neonates), C (Prisoners) and D (Children), 
GCP/ICH guidelines, and all applicable regulatory requirements. The IRB must comply 
with the regulations in 21 CFR §56 and applicable regulatory requirements. 
 
10.3  Prestudy Documentation 
 
Prior to implementing this protocol at Froedtert & the Medical College of Wisconsin, the 
protocol, informed consent form, HIPAA authorization and any other information pertaining to 
participants must be approved by the MCW IRB. 
 
 
10.4  Institutional Review Board 
 
The protocol, the proposed informed consent form and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) will be reviewed and 
approved by the MCW Institutional Review Board. Prior to obtaining MCW approval, the 
protocol must be approved by the Medical College of Wisconsin Cancer Center Scientific 
Review Committee. The initial protocol and all protocol amendments must be approved by the 
IRB prior to implementation. 
 
10.5  Informed Consent Process 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of this therapy will be provided to the subjects and their families. 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
46 
Version No.: 3 
Version Date: 10-14-2022 
 
Consent forms describing in detail the study interventions/products, study procedures and risks 
are given to the subject and written documentation of informed consent is required prior to 
starting intervention/administering study product. 
 
Potential subjects will be told and a statement will be included that this study is designed to 
determine both safety and effectiveness. The consent forms will include the approved MCW IRB 
template language. 
 
Consent forms will be IRB approved and the subject (and legally authorized representative, if 
necessary) will be asked to read and review the document. Upon reviewing the document, the 
investigator will explain the research study to the subject and answer any questions that may 
arise. In accordance with 46 CR 46.111, the subject will sign and date the informed consent 
document prior to any procedures being done specifically for the study. 
 
A witness should only sign when required, per FH/MCW IRB policy. If a witness signs the 
document when not required, the study staff should document in the legal medical record (or 
note to file) the relationship to the patient and why a witness signed. (i.e., “Although not 
required, the subject’s spouse was present during the consenting process and signed as the 
witness.” Or “Although not required, hospital staff was present for consenting process and 
signed as a witness.”) 
 
The subjects will have the opportunity to discuss the study with their surrogates or think about it 
prior to agreeing to participate. The subjects may withdraw consent at any time throughout the 
course of the trial. 
 
A copy of the informed consent document will be given to the subjects for their records. The 
rights and welfare of the subjects will be protected by emphasizing to them that the quality of 
their medical care will not be adversely affected if they decline to participate in this study. If 
there are changes to the consent form, all revisions will be reviewed with study subject at the 
next appropriate opportunity. Patients that require reconsenting will be defined in the IRB 
approved amendment submission. The process for obtaining informed consent will again be 
performed. Study subjects will not be reconsented for continuing reviews. The MCWCC CTO 
will follow the MCW/FH IRB’s policy for subjects who demonstrate limited English proficiency 
or limited literacy. 
 
After the subject’s visit in which the consent is signed, it is documented in the clinic chart that the 
consent has been signed and that all questions have been answered to the subject’s satisfaction 
after adequate time for review of the consent. It is also documented that a copy of the consent is 
given to the subject. The original consent is kept with the subject’s study file, and a copy of the 
consent is sent to the OCRICC office, which will then submit to HIM a copy of the signed consent 
to be scanned into EPIC, the legal medical record. 
 
10.6  Subject Confidentiality and Access to Source Documents/Data 
 
Subject confidentiality is strictly held in trust by the sponsor-investigator, participating 
investigators, and any staff, [and the sponsor(s) and their agents]. This confidentiality includes 
the clinical information relating to participating subjects, as well as any genetic or biological 
testing. 
 
The study protocol, documentation, data and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
47 
Version No.: 3 
Version Date: 10-14-2022 
 
third party without prior written approval of the principal investigator. 
 
The conditions for maintaining confidentiality of the subjects’ records are required for the life of 
the data. These rules apply equally to any and all MCWCC projects. 
 
One risk of taking part in a research study is that more people will handle the personal health 
information collected for this study. The study team will make every effort to protect the 
information and keep it confidential, but it is possible that an unauthorized person might see it. 
Depending on the kind of information being collected, it might be used in a way that could 
embarrass the subject or affect his/her ability to get insurance. 
 
While data are being collected and after all data have been collected but are still in the process of 
being analyzed, the subject’s data/PHI are stored in the locked clinical research office in the 
Clinical Trials Office. Databases in which the study subject information is stored and accessed 
are password protected, allowing for limited access by authorized personnel only. Data/PHI kept 
in the case report forms contain the study identifiers, subject initials, date of birth and date of 
service. 
 
Personal identifiers, such as name and medical record number, will be removed from 
accompanying lab reports and test results. Any data/PHI that are not stored for the purposes of 
the study are shredded in the Clinical Trials Office. 
 
After all study queries and analyses are completed, the data/PHI will not be destroyed but will be 
archived in a secure long-term storage site in order to keep an accurate record of screened and 
enrolled subjects for the sponsor and potential audit purposes only specific for this study. 
Data/PHI would not be destroyed until permission is granted by the sponsor to destroy the 
records. 
The principal investigator will allow access to all source data and documents for the purposes of 
monitoring, audits, IRB review, and regulatory inspections. 
 
The study monitor or other authorized representatives of the principal investigator may inspect 
all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the subjects in 
this study. The clinical study site will permit access to such records. 
 
10.7  Protection of Human Subjects 
 
10.7.1  Protection from Unnecessary Harm 
 
Each clinical site is responsible for protecting all subjects involved in human experimentation. 
This is accomplished through the IRB mechanism and the informed consent process. The IRB 
reviews all proposed studies involving human experimentation and ensures that the subject’s 
rights and welfare are protected and that the potential benefits and/or the importance of the 
knowledge to be gained outweigh the risks to the individual. The IRB also reviews the informed 
consent document associated with each study in order to ensure that the consent document 
accurately and clearly communicates the nature of the research to be done and its associated 
risks and benefits. 
 
10.7.2  Protection of Privacy 
 
As noted, patients will be informed of the extent to which their confidential health information 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
48 
Version No.: 3 
Version Date: 10-14-2022 
 
generated from this study may be used for research purposes. Following this discussion, they 
will be asked to sign informed consent documents. The original signed document will become 
part of the patient’s medical records, and each patient will receive a copy of the signed 
document. 
 
 
 
10.7.3  Changes in the Protocol 
 
Once the protocol has been approved by the MCW IRB, any changes to the protocol must be 
documented in the form of an amendment.  
 
The IRB may provide, if applicable regulatory authority (ies) permit, expedited review and 
approval/favorable opinion for minor change(s) in ongoing studies that have the approval 
/favorable opinion of the IRB. The investigator will submit all protocol modifications to the 
sponsor and the regulatory authority (ies) in accordance with the governing regulations. 
 
Changes to the protocol may require approval from Spectrum Pharmaceuticals, Inc. 
 
Any deviations from the protocol must be fully documented in the source documents. 
 
10.7.4  Investigator Compliance 
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB and the appropriate regulatory authority (ies). 
 
Onsite Audits 
 
Auditing is essential to ensure that research conducted at the Medical College of Wisconsin 
(MCW) Cancer Center is of the highest quality and meets MCW and regulatory agency 
standards. 
 
Regulatory authorities, the IRB and/or sponsor may request access to all source documents, 
data capture records and other study documentation for on-site audit or inspection. Direct 
access to these documents must be guaranteed by the investigator, who must provide support 
at all times for these activities. 
 
High-risk trials are reviewed every six months. Approximately 30% of subject files will be selected 
randomly for review (a maximum of 10 subjects at each monitoring timepoint). Consent/eligibility 
and objective-based data will be reviewed for those files selected. One file will be selected 
randomly for a comprehensive review at each monitoring time point. Regulatory documents (IRB 
submissions, reportable events, etc.) will be reviewed at each monitoring timepoint. 
 
10.7.5  Data and Safety Monitoring Committee 
 
This study will be reviewed by the Medical College of Wisconsin Cancer Center Data and Safety 
Monitoring Committee (MCWCC DSMC). Information on the DSMC is available online 
(https://www.mcw.edu/Cancer-Center/Clinical-Trials-/Starting-a-Cancer-Clinical-Trial.htm). A 
summary of the MCWCC DSMC activities are as follows: 
 
- Review the clinical trial for data integrity and safety. 
- Review all unexpected grade 3, and all grade 4, and 5 adverse events, as well as any others 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
49 
Version No.: 3 
Version Date: 10-14-2022 
 
requiring expedited reporting as defined in this protocol. (Grades 4 & 5 events must be 
reported to the DSMC within five calendar days of study staff’s knowledge.) 
- Review all DSM reports. 
- Submit a summary of any recommendations related to study conduct. 
- Terminate the study if deemed unsafe for patients. 
 
The committee will review reports from the study PI twice annually (or more frequently if 
needed) and provide recommendations on trial continuation, suspension or termination as 
necessary. 
 
Any available DSMC letters will be submitted to the IRB of record, as required. 
 
 
 
 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
50 
Version No.: 3 
Version Date: 10-14-2022 
 
 
REFERENCES 
 
1. 
Baron F, Maris MB, Sandmaier BM, Storer BE, Sorror M, Diaconescu R, et al. Graft- 
versus-tumor effects after allogeneic hematopoietic cell transplantation with 
nonmyeloablative conditioning. J Clin Oncol. 2005;23(9):1993-2003. 
2. 
Hamadani M, Craig M, Awan FT, Devine SM. How we approach patient evaluation for 
hematopoietic stem cell transplantation. Bone Marrow Transplant. 2010;45(8):1259-68. 
3. 
Ringden O, Horowitz MM, Gale RP, Biggs JC, Gajewski J, Rimm AA, et al. Outcome 
after allogeneic bone marrow transplant for leukemia in older adults. JAMA. 1993;270(1):57-60. 
4. 
Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, et al. 
Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk 
assessment before allogeneic HCT. Blood. 2005;106(8):2912-9. 
5. 
Sorror ML, Giralt S, Sandmaier BM, De Lima M, Shahjahan M, Maloney DG, et al. 
Hematopoietic cell transplantation specific comorbidity index as an outcome predictor for 
patients with acute myeloid leukemia in first remission: combined FHCRC and MDACC 
experiences. Blood. 2007;110(13):4606-13. 
6. 
Van Besien K, Devine S, Wickrema A, Jessop E, Amin K, Yassine M, et al. Regimen- 
related toxicity after fludarabine-melphalan conditioning: a prospective study of 31 patients with 
hematologic malignancies. Bone Marrow Transplant. 2003;32(5):471-6. 
7. 
Van Besien K, Demuynck H, Lemaistre CF, Bogaerts MA, Champlin R. High-dose 
Melphalan allows durable engraftment of allogeneic bone marrow. Bone Marrow Transplant. 
1995;15(2):321-3. 
8. 
Brammer JE, Khouri I, Gaballa S, Anderlini P, Tomuleasa C, Ahmed S, et al. 
Outcomes of Haploidentical Stem Cell Transplantation for Lymphoma with Melphalan-Based 
Conditioning. Biol Blood Marrow Transplant. 2016;22(3):493-8. 
9. 
Burroughs LM, O'Donnell PV, Sandmaier BM, Storer BE, Luznik L, Symons HJ, et al. 
Comparison of outcomes of HLA-matched related, unrelated, or HLA-haploidentical related 
hematopoietic cell transplantation following nonmyeloablative conditioning for relapsed or 
refractory Hodgkin lymphoma. Biol Blood Marrow Transplant. 2008;14(11):1279-87. 
10. 
Raiola A, Dominietto A, Varaldo R, Ghiso A, Galaverna F, Bramanti S, et al. 
Unmanipulated haploidentical BMT following non-myeloablative conditioning and post- 
transplantation CY for advanced Hodgkin's lymphoma. Bone Marrow Transplant. 
2014;49(2):190-4. 
11. 
Castagna L, Bramanti S, Furst S, Giordano L, Crocchiolo R, Sarina B, et al. 
Nonmyeloablative conditioning, unmanipulated haploidentical SCT and post-infusion CY for 
advanced lymphomas. Bone Marrow Transplant. 2014;49(12):1475-80. 
12. 
Kanakry JA, Gocke CD, Bolanos-Meade J, Gladstone DE, Swinnen LJ, Blackford AL, et 
al. Phase II Study of Nonmyeloablative Allogeneic Bone Marrow Transplantation for B Cell 
Lymphoma with Post-Transplantation Rituximab and Donor Selection Based First on Non-HLA 
Factors. Biol Blood Marrow Transplant. 2015;21(12):2115-22. 
13. 
Kanate AS, Mussetti A, Kharfan-Dabaja MA, Ahn KW, DiGilio A, Beitinjaneh A, et al. 
Reduced-intensity transplantation for lymphomas using haploidentical related donors vs HLA- 
matched unrelated donors. Blood. 2016;127(7):938-47. 
14. 
Zar T, Graeber C, Perazella MA. Recognition, treatment, and prevention of 
propylene glycol toxicity. Semin Dial. 2007;20(3):217-9. 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
51 
Version No.: 3 
Version Date: 10-14-2022 
 
15. 
Wilson KC, Reardon C, Theodore AC, Farber HW. Propylene glycol toxicity: a severe 
iatrogenic illness in ICU patients receiving IV benzodiazepines: a case series and 
prospective, observational pilot study. Chest. 2005;128(3):1674-81. 
16. 
Yaucher NE, Fish JT, Smith HW, Wells JA. Propylene glycol-associated renal toxicity 
from lorazepam infusion. Pharmacotherapy. 2003;23(9):1094-9. 
17. 
Moreau P, Kergueris MF, Milpied N, Le Tortorec S, Mahe B, Bulabois CE, et al. A pilot 
study of 220 mg/m2 Melphalan followed by autologous stem cell transplantation in patients with 
advanced haematological malignancies: pharmacokinetics and toxicity. Br J Haematol. 
1996;95(3):527-30. 
18. 
Sarosy G, Leyland-Jones B, Soochan P, Cheson BD. The systemic administration 
of intravenous Melphalan. J Clin Oncol. 1988;6(11):1768-82. 
19. 
Koltun M, Morizzi J, Katneni K, Charman SA, Shackleford DM, McIntosh MP. Preclinical 
comparison of intravenous Melphalan pharmacokinetics administered in formulations containing 
either (SBE)7 m-beta-cyclodextrin or a co-solvent system. Biopharm Drug Dispos. 2010;31(8-
9):450-4. 
20. 
Lazarus HM, Herzig RH, Graham-Pole J, Wolff SN, Phillips GL, Strandjord S, et al. 
Intensive Melphalan chemotherapy and cryopreserved autologous bone marrow 
transplantation for the treatment of refractory cancer. J Clin Oncol. 1983;1(6):359-67. 
21. 
Selby PJ, McElwain TJ, Nandi AC, Perren TJ, Powles RL, Tillyer CR, et al. Multiple 
myeloma treated with high dose intravenous Melphalan. Br J Haematol. 1987;66(1):55-62. 
22. 
Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, et al. High-dose 
chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 
2003;348(19):1875-83. 
23. 
Stella VJ, He Q. Cyclodextrins. Toxicol Pathol. 2008;36(1):30-42. 
24. 
Aljitawi OS, Ganguly S, Abhyankar SH, Ferree M, Marks R, Pipkin JD, et al. Phase IIa 
cross-over study of propylene glycol-free Melphalan (LGD-353) and alkeran in multiple 
myeloma autologous transplantation. Bone Marrow Transplant. 2014;49(8):1042-5. 
25. 
Hari P, Aljitawi OS, Arce-Lara C, Nath R, Callander N, Bhat G, et al. A Phase IIb, 
Multicenter, Open-Label, Safety, and Efficacy Study of High-Dose, Propylene Glycol-Free 
Melphalan Hydrochloride for Injection (EVOMELA) for Myeloablative Conditioning in 
Multiple Myeloma Patients Undergoing Autologous Transplantation. Biol Blood Marrow 
Transplant. 2015;21(12):2100-5. 
26. 
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised 
recommendations of the International Working Group for Diagnosis, Standardization of 
Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in 
Acute Myeloid Leukemia. J Clin Oncol. 2003;21(24):4642-9. 
27. 
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. 
Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-86. 
28. 
Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. 
International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9):1467-73. 
29. 
Bashir Q, Khan H, Thall PF, Liu P, Shah N, Kebriaei P, et al. A randomized phase II trial 
of Fludarabine / Melphalan 100 versus Fludarabine / Melphalan 140 followed by allogeneic 
hematopoietic stem cell transplantation for patients with multiple myeloma. Biol Blood Marrow 
Transplant. 2013;19(10):1453-8. 
30. 
Raj K, Pagliuca A, Bradstock K, Noriega V, Potter V, Streetly M, et al. Peripheral blood 
hematopoietic stem cells for transplantation of hematological diseases from related, 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
52 
Version No.: 3 
Version Date: 10-14-2022 
 
haploidentical donors after reduced-intensity conditioning. Biol Blood Marrow Transplant. 
2014;20(6):890-5. 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
52 
Version No.: 3 
Version Date: 10-14-2022 
 
 
 
APPENDICES 
 
Appendix 1  Response Assessment in Leukemia, Lymphoma & Multiple Myeloma 
 
Category 
Definition 
Complete remission (CR)1 
Bone marrow blasts <5 percent; absence of blasts with Auer rods; absence of extramedullary 
disease; absolute neutrophil count >1.0 x 109/L (1000/µL); platelet count >100 x 109/L (100,000/µL); 
independence of red cell transfusions. 
CR with incomplete recovery (CRi)2 
All CR criteria except for residual neutropenia (<1.0 x 109/L (1000/µL)) or thrombocytopenia (<100 x 
109/L (100,000/µL). 
Morphologic leukemia-free state 3 
Bone marrow blasts <5 percent; absence of blasts with Auer rods; absence of extramedullary 
disease; no hematologic recovery required. 
Partial remission (PR) 
Relevant in the setting of phase I and II clinical trials only; all hematologic criteria of CR; decrease of 
bone marrow blast percentage to 5 to 25 percent and decrease of pretreatment bone marrow blast 
percentage by at least 50 percent. 
Cytogenetic CR (CRc) 
Reversion to a normal karyotype at the time of morphologic CR (or CRi) in cases with an abnormal 
karyotype at the time of diagnosis; based on the evaluation of 20 metaphase cells from bone 
marrow. 
Molecular CR (CRm)4 
No standard definition; depends on molecular target. 
Treatment Failure 
Resistant disease (RD) 
Patient survives ≥ seven days post-CT; persistent AML in blood or bone marrow. 
Death in aplasia 
Patient survives ≥ seven days post-CT; death while cytopenic, with aplastic bone marrow. 
 
 
 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
53 
Version No.: 3 
Version Date: 10-14-2022 
 
 
Death from indeterminate cause 
Patients who die < seven days posttherapy; Patients who die > seven days posttherapy with no PB 
blasts, but no bone marrow examination; Patients who do not complete the first course of therapy. 
Relapse5 
Bone marrow blasts ≥5 percent; or reappearance of blasts in the blood; or development of 
extramedullary disease. 
1. All criteria need to be fulfilled; marrow evaluation should be based on a count of 200 nucleated cells in an aspirate with spicules; if ambiguous, 
consider repeat exam after five to seven days; flow cytometric evaluation may help to distinguish between persistent leukemia and regenerating 
normal marrow; a marrow biopsy should be performed in cases of dry tap, or if no spicules are obtained; no minimum duration of response 
required. 
2. The criterion of CRi is of value in protocols using intensified induction or double-induction strategies in which hematologic recovery is not 
awaited and intensive therapy will be continued. In such protocols, CR may even not be achieved in the course of the entire treatment plan. In 
these instances, the overall remission rate should include CR and CRi patients. Some patients may not achieve complete hematologic recovery 
upon longer observation times. 
3. This category may be useful in the clinical development of novel agents within phase I clinical trials in which a transient morphologic leukemia- 
free state may be achieved at the time of early response assessment. 
4. As an example, in CBF AML, low-level PCR-positivity can be detected in patients, even in long-term remission. Normalizing to 104 copies of 
ABL1, in accordance with standardized criteria, transcript levels below 10 to 12 copies appear to be predictive for long-term remission. 
5. In cases with low-blast percentages (5 to 10 percent), a repeat marrow should be performed to confirm relapse. Appearance of new dysplastic 
changes should be closely monitored for emerging relapse. In a patient who has been recently treated, dysplasia or a transient increase in blasts 
may reflect a chemotherapy effect and recovery of hematopoiesis. Cytogenetics should be tested to distinguish true relapse from therapy-related 
MDS/AML. 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
54 
Version No.: 3 
Version Date: 10-14-2-22 
 
Appendix 2 Revised Criteria for Lymphoma Response Assessment 
 
Response Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance 
of all evidence 
of disease. 
(a) FDG-avid or PET 
positive prior to therapy; 
mass of any size permitted, 
if PET negative 
(b) Variably FDG-avid or 
PET negative; regression to 
normal size on CT 
Not palpable, 
nodules 
disappeared. 
Infiltrate cleared on repeat 
biopsy; if indeterminate by 
morphology, 
immunohistochemistry 
should be negative. 
PR 
Regression of 
measurable 
disease and no 
new sites. 
≥50% decrease in SPD of 
up to 6 largest dominant 
masses; no increase in size 
of other nodes. 
(a) FDG-avid or PET 
positive prior to therapy; 
one or more PET positive at 
previously involved site. 
(b) Variably FDG-avid or 
PET negative; regression 
on CT. 
≥50% 
decrease in 
SPD of 
nodules (for 
single nodule 
in greatest 
transverse 
diameter); no 
increase in 
size of liver or 
spleen. 
Irrelevant if positive prior 
to therapy; cell type 
should be specified. 
SD 
Failure to attain 
CR/PR or PD. 
(a) FDG-avid or PET 
positive prior to therapy; 
PET positive at prior sites of 
disease and no new sites 
on CT or PET. 
(b) Variably FDG-avid or 
PET negative; no change in 
size of previous lesions on 
CT. 
Relapsed 
disease 
or PD 
Any new lesion 
or increase by 
≥50% of 
previously 
involved sites 
from nadir. 
Appearance of a new 
lesion(s) 1.5 cm in any axis, 
≥50% increase in SPD of 
more than one node, or 
≥50% increase in longest 
diameter of a previously 
identified node 1 cm in 
short axis. 
Lesions PET positive if 
FDG-avid lymphoma 
or PET positive prior to 
therapy. 
>50% increase 
from nadir in 
the SPD of 
any previous 
lesions 
New or recurrent 
involvement 
Abbreviations: CR, complete remission; FDG, [18F] fluorodeoxyglucose; PET, positron emission 
tomography; CT, computed tomography; PR, partial remission; SPD, sum of the product of the 
diameters; SD, stable disease; PD, progressive disease. 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
55 
Version No.: 3 
Version Date: 10-14-2-22 
 
Appendix 3 International Myeloma Working Group Uniform Response Criteria 
 
Response 
subcategory 
Response criteria1 
CR 
Negative immunofixation on the serum and urine and 
Disappearance of any soft tissue plasmacytomas and 
5% plasma cells in bone marrow 2 
sCR 
CR as defined above plus 
Normal FLC ratio and 
Absence of clonal cells in bone marrow b by immunohistochemistry or 
immunofluorescence 3 
VGPR 
Serum and urine M-component detectable by immunofixation but not on 
electrophoresis or 
90 or greater reduction in serum M-component plus urine M-component 
<100 mg per 24 h 
PR 
≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥ 
90% or to <200 mg per 24 h 
If the serum and urine M-protein are unmeasurable, a ≥ 50% decrease in the 
difference between involved and uninvolved FLC levels is required in place of the 
M-protein criteria 
If serum and urine M-protein are unmeasurable, and serum free light assay is 
also unmeasurable, ≥50% reduction in plasma cells is required in place of M- 
protein, provided baseline bone marrow plasma cell percentage was ≥30% 
In addition to the above listed criteria, if present at baseline, a ≥50% reduction in 
the size of soft tissue plasmacytomas is also required 
SD 
Not meeting criteria for CR, VGPR, PR or progressive disease 
Abbreviations: CR, complete response; FLC, free light chain; PR, partial response; SD, stable disease; 
sCR, stringent complete response; VGPR, very good partial response. 
1. All response categories require two consecutive assessments made at any time before the institution 
of any new therapy; complete and PR and SD categories also require no known evidence of progressive 
or new bone lesions if radiographic studies were performed. Radiographic studies are not required to 
satisfy these response requirements. 
2. Confirmation with repeat bone marrow biopsy not needed. 
3. Presence/absence of clonal cells is based upon the k/ ratio. An abnormal k/ ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for 
analysis. An abnormal ratio reflecting presence of an abnormal clone is k/ of >4:1 or <1;2. Alternatively, 
the absence of clonal plasma cells can be defined based on the investigation of phenotypically aberrant 
PC. The sensitivity level is 10-3 (less than one phenotypically aberrant PC within a total of 1000 Pc). 
Examples of aberrant phenotypes include (1) CD38 +dim and CD56+ strong and CD19- and CD45-; (2) 
CD38+dim and CD138+ and CD56++ and CD28+; (3) CD138+, CD19- CD56++, CD117+. 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
56 
Version No.: 3 
Version Date: 10-14-2-22 
 
 
 
 
Appendix 4 Assessment of Acute GVHD 
 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
57 
Version No.: 3 
Version Date: 10-14-2-22 
 
Appendix 5 Staging/Grading of Acute GVHD 
 
 
 
 
 
Consensus GVHD Grading (PRZEPIORKA, ET AL., 
GVHD STAGING 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
58 
Version No.: 3 
Version Date: 10-14-2-22 
 
Appendix 6 Grading of Chronic GVHD (NIH Criteria) 
 
 

MCW Protocol No: Hamadani-Flu-MEL-TBI 
59 
Version No.: 3 
Version Date: 10-14-2-22