A Pilot Trial of Using Pre-Transplant Risk Stratification and Prophylactic Defibrotide to Prevent Serious Thrombotic Microangiopathy in High-Risk Hematopoietic Stem Cell Transplant Patients
Phase: PHASE2
Conditions: Thrombotic Microangiopathies
Sponsor: University of California, San Francisco

 
 
 
A Pilot Trial of Using Pre-Transplant Risk Stratification and Prophylactic Defibrotide to Prevent 
Serious Thrombotic Microangiopathy in High-Risk Hematopoietic Stem Cell Transplant Patients 
 
 
 
 
NCT03384693 
 
 
 
 
IRB Last Approval Date: 8/4/2020 

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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 that it should not be further disclosed. 
A Pilot Trial of Using Pre-Transplant Risk Stratification and Prophylactic Defibrotide to 
Prevent Serious Thrombotic Microangiopathy in High-Risk Hematopoietic Stem Cell 
Transplant Patients 
 
Protocol Number:  #      
Study Drug:  Defibrotide (Jazz Pharmaceuticals) 
Version Number:  1.3 
Version Date:  9/18/2018 
IND Number:        
Principal Investigator (Sponsor-Investigator) 
Christine Higham, MD   
University of California San Francisco 
550 16th Street, 4th floor 
  San Francisco, CA 94143 
Telephone:  415-476-2188 
Fax:  415-502-4867 
E-mail:   Christine.Higham@ucsf.edu 
Co-Investigators 
Jasmeen Dara, MD 
Chris Dvorak, MD 
Craig Forester, MD 
James Huang, MD   
Sandhya Kharbanda, MD 
 Alexis Melton, MD 
Kristin Shimano, MD 
Jennifer Willert, MD 
 
Clinical Research Coordinator 
Kevin Magruder   
University of California San Francisco 
550 16th Street, 4th floor 
  San Francisco, CA 94143 
Telephone:  415-476-2188 
Fax:  415-502-4867 
Revision History 
 Version 1.0  
8/1/2017   
 Version 1.1 
9/5/2017 
 Version 1.2  
 Version 1.3 
2/27/2018 
9/18/2018 
   
 

 
Version date:  2/27/2018 
Protocol #: 
Phase II – Study drug(s) 
Protocol Signature Page 
Protocol No.:       
Version Date:       
1. I agree to follow this protocol version as approved by the UCSF Committee on Human 
Research (CHR)  
2. I will conduct the study in accordance with applicable CHR requirements, Federal 
regulations, and state and local laws to maintain the protection of the rights and welfare of 
study participants.  
3. I certify that I, and the study staff, have received the requisite training to conduct this 
research protocol.  
4. I have read and understand the information in the Investigators’ Brochure (or Manufacturer’s 
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in 
accordance with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the 
Statement of Investigator (Form FDA 1572), and with local regulatory requirements. In 
accordance with the FDA Modernization Act, I will ensure the registration of the trial on the 
www.clinicaltrials.gov website.  
5. I agree to maintain adequate and accurate records in accordance with CHR policies, 
Federal, state and local laws and regulations. 
UCSF Principal Investigator / Study Chair 
 
 
Printed Name 
 
 
Signature 
 
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Version date:  2/27/2018 
Protocol #: 
Phase II – Study drug(s) 
Abstract 
 
Title 
A Pilot Trial of Using Pre-Transplant Risk Stratification and Prophylactic 
Defibrotide to Prevent Serious Thrombotic Microangiopathy in High-Risk 
Hematopoietic Stem Cell Transplant Patients 
Patient 
population 
Pediatric patients age 0-30 years receiving autologous or allogeneic HSCT 
meeting TMA high risk criteria. 
Rationale for 
Study 
TMA is a common complication in the stem cell transplant population.  Certain 
populations within the HSCT population are at a higher risk than others.  
Defibrotide is an endothelial stabilizing agent which may prevent the 
endothelial damage that triggers TMA in HSCT patients.  The feasibility, 
safety, and efficacy of defibrotide prophylaxis in a pediatric transplant 
population is unknown. 
Primary 
Objective 
To determine the feasibility and safety of defibrotide in children receiving 
HSCT. 
Secondary 
Objectives 
To determine the efficacy of defibrotide prophylaxis in preventing severe TMA 
in pediatric patients receiving HSCT. 
Study Design 
Single arm non-randomized Phase II safety and feasibility trial of un-blinded 
defibrotide prophylaxis. 
Number of 
patients 
25 
Duration of 
Therapy 
Patients may continue treatment for 28-35 days from time of study drug 
initiation. 
Duration of 
Follow up 
Follow up for 6 months post-HSCT per HSCT standard of care. 
Duration of 
study 
The study will reach completion 30 months from the time the study opens to 
accrual. 
Study Drugs 
Defibrotide 6.25mg/kg IV Q6h for 28-35 days.  
Safety 
Assessments 
Weekly inpatient assessments of administration feasibility, hypersensitivity 
reaction, and bleeding while defibrotide is administered. This includes all 
HSCT SOC evaluations including routine clinical evaluations and laboratory 
assessments.  
Efficacy 
Assessments 
Efficacy will be based on overall incidence of TMA as well as incidence of 
severe TMA within 6 months post-HSCT, as defined in the protocol. 

 
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Phase II – Study drug(s) 
Unique 
Aspects of 
this Study 
This is the first study to evaluate safety and efficacy of defibrotide in pediatric 
patients for prevention of severe TMA. 

 
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Protocol #: 
Phase II – Study drug(s) 
 
List of Abbreviations 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
ANG-2 
absolute neutrophil count 
angiopoietin 2 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical (Classification System) 
AUC 
BCH-SF 
BMT 
area under the curve 
Benioff Children’s Hospital- San Francisco 
bone marrow transplant 
BUN 
blood urea nitrogen 
CBC 
CH50 
complete blood cell (count) 
complement activity 
CHR 
Committee on Human Research (UCSF IRB) 
CR 
complete response 
CRC 
Clinical Research Coordinator 
CRF 
case report form 
CSF 
cerebral spinal fluid 
CT 
computerized tomography 
CTCEA 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTMS 
Clinical Trial Management System 
DFS 
disease-free survival 
DLT 
dose limiting toxicity 
DSMP 
Data and Safety Monitoring Plan 
FCBP 
female of childbearing potential 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HCT 
HSCT 
hematocrit 
hematopoietic stem cell transplant 
HCV 
hepatitis C virus 
HGB 
hemoglobin 
HIV 
human immunodeficiency virus 

 
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Protocol #: 
Phase II – Study drug(s) 
List of Abbreviations 
ICH 
International Conference on Harmonization 
IND 
investigational new drug application 
IP 
investigational product 
IRB 
Institutional Review Board 
IV 
intravenous 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
ORR 
PAI-1 
overall response rate 
plasminogen activator inhibitor – 1 
PD 
disease progression 
PK 
pharmacokinetics 
PO 
per os (by mouth, orally) 
PR 
PRES 
partial response 
posterior reversible encephalopathy syndrome 
PRC 
PT 
PTT 
Protocol Review Committee (UCSF) 
prothrombin time 
partial thromboplastin time 
QOL 
Quality of Life 
RBC 
SAE 
red blood cell (count) 
serious adverse event 
SD 
stable disease 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
ST2 
TBI 
serum glutamic pyruvic transaminase 
suppression of tumorigeneicity  
total body irradiation 
TMA 
TRM 
ULN 
WBC 
thrombotic microangiopathy 
treatment related mortality 
upper limit of normal 
white blood cell (count)      

 
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Protocol #: 
Phase II – Study drug(s) 
Table of Contents 
Protocol Signature Page ............................................................................................................... 1 
List of Abbreviations ...................................................................................................................... 4 
Table of Contents .......................................................................................................................... 6 
1 
Introduction ............................................................................................................ 9 
1.1 
Background on Indication .................................................................................... 9 
1.2 
Background on the Compounds ........................................................................ 10 
1.3 
Rationale for the Proposed Study ...................................................................... 10 
1.4 
Correlative Studies ............................................................................................. 11 
2 
Objectives of the Study ....................................................................................... 11 
2.1 
Primary ............................................................................................................... 11 
2.2 
Secondary .......................................................................................................... 11 
2.3 
Exploratory Objectives, Other Assessments ...................................................... 12 
2.4 
Endpoints ........................................................................................................... 12 
2.4.1 
Primary Endpoints .......................................................................................... 12 
2.4.2 
Secondary Endpoints ..................................................................................... 12 
2.4.3 
Exploratory Endpoints .................................................................................... 12 
3 
Study Design ....................................................................................................... 12 
3.1 
Characteristics ................................................................................................... 12 
3.2 
Number of Subjects ........................................................................................... 12 
3.3 
Eligibility Criteria ................................................................................................ 12 
3.3.1 
Inclusion Criteria ............................................................................................ 13 
3.3.2 
Exclusion Criteria ........................................................................................... 13 
3.4 
Duration of Therapy ........................................................................................... 14 
3.5 
Duration of Follow Up ........................................................................................ 14 
3.6 
Study Timeline ................................................................................................... 14 
3.6.1 
Primary Completion ........................................................................................ 14 
3.6.2 
Study Completion ........................................................................................... 14 
4 
Study Drugs ......................................................................................................... 14 
4.1 
Description, Supply and Storage of Investigational Drugs ................................. 14 
4.1.1 
Investigational Drug #1 .................................................................................. 14 
4.2 
Drug Accountability ............................................................................................ 15 
4.3 
Drug Ordering .................................................................................................... 15 
4.4 
Packaging and Labeling of Study Drugs ............................................................ 15 
5 
Treatment Plan .................................................................................................... 15 
5.1 
Dosage and Administration ................................................................................ 15 
5.1.1 
Dose Modifications and Dosing Delays Tables for Specific Adverse Events . 16 
5.2 
Monitoring and Toxicity Management ................................................................ 16 
5.2.1 
Other toxicities: .............................................................................................. 16 
6 
Study Procedures and Observations ................................................................... 17 
6.1 
Schedule of Procedures and Observations ....................................................... 17 
6.1.1 
Pretreatment Period ....................................................................................... 17 
6.1.2 
Treatment Period ........................................................................................... 18 
6.1.3 
Post-treatment/Follow Up Visits ..................................................................... 18 
6.1.4 
Discontinuation of Therapy ............................................................................ 19 
6.2 
Usage of Concurrent/Concomitant Medications ................................................ 21 

 
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Table of Contents 
6.3 
Dietary Restrictions ............................................................................................ 21 
6.4 
Prohibited Medications ....................................................................................... 21 
7 
Reporting and Documentation of Results ............................................................ 21 
7.1 
Evaluation of Efficacy (or Activity) ...................................................................... 21 
7.2 
Definitions .......................................................................................................... 21 
7.2.1 
Definition of TMA ............................................................................................ 21 
7.2.2 
Definition of Severe TMA ............................................................................... 23 
7.3 
Evaluation of Safety and Toxicity ....................................................................... 23 
7.4 
Definitions of Adverse Events ............................................................................ 23 
7.4.1 
Adverse Event ................................................................................................ 23 
7.4.2 
Adverse reaction ............................................................................................ 23 
7.5 
Recording of an Adverse Event ......................................................................... 25 
7.6 
Follow-up of Adverse Events ............................................................................. 25 
7.7 
Adverse Events Monitoring ................................................................................ 26 
7.8 
Expedited Reporting .......................................................................................... 26 
8 
Statistical Considerations and Evaluation of Results .......................................... 27 
8.1 
Study Endpoints ................................................................................................. 27 
8.1.1 
Study Design .................................................................................................. 28 
8.1.2 
Randomization ............................................................................................... 28 
8.1.3 
Unblinding Subjects ....................................................................................... 28 
8.1.4 
Stratification Factors ...................................................................................... 28 
8.2 
Determination of Sample Size and Accrual Rate ............................................... 28 
8.2.1 
Sample Size and Power Estimate .................................................................. 29 
8.2.2 
Replacement Policy ....................................................................................... 29 
8.2.3 
Accrual estimates ........................................................................................... 29 
8.3 
Interim Analyses and Stopping Rules ................................................................ 29 
8.4 
Analyses Plans .................................................................................................. 29 
8.4.1 
Analysis Population ........................................................................................ 29 
8.4.2 
Primary Analysis (or Analysis of Primary Endpoints) ..................................... 29 
8.4.3 
Secondary Analysis (or Analysis of Secondary Endpoints) ............................ 29 
8.4.4 
Other analyses/Assessments ......................................................................... 29 
8.5 
Evaluation of Safety ........................................................................................... 29 
8.6 
Study Results ..................................................................................................... 30 
9 
Study Management ............................................................................................. 30 
9.1 
Pre-study Documentation .................................................................................. 30 
9.2 
Institutional Review Board Approval .................................................................. 30 
9.3 
Informed Consent .............................................................................................. 30 
9.4 
Changes in the Protocol ..................................................................................... 30 
9.5 
Handling and Documentation of Clinical Supplies ............................................. 31 
9.6 
Case Report Forms (CRFs) ............................................................................... 31 
9.7 
Oversight and Monitoring Plan ........................................................................... 31 
9.8 
Coordinating Center Documentation of Distribution ........................................... 31 
9.9 
Regulatory Documentation ................................................................................ 32 
10 
Protection of Human Subjects ............................................................................. 32 
10.1 
Protection from Unnecessary Harm ................................................................... 32 
10.2 
Protection of Privacy .......................................................................................... 32 

 
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Table of Contents 
References 
33 
11 
Appendices .......................................................................................................... 35 
Appendix 1 
Performance Status Criteria ................................................................................ 35 
Appendix 2 
Prohibited Medications ........................................................................................ 36 
List of Tables 
Table 5.1 
Regimen Description ............................................. Error! Bookmark not defined. 
Table 5.1.1     Adverse events: bleeding or hypersensitivty reaction ........... Error! Bookmark not 
defined. 
Table 6.1         Schedule of Study Procedures and Assessments Error! Bookmark not defined. 
Table 7.2 
Clinical criteria ....................................................... Error! Bookmark not defined. 
 
 
 
 
 

 
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Protocol #: 
Phase II – Study drug(s) 
1 
Introduction 
1.1 
Background on Indication 
Hematopoietic stem cell transplant (HSCT) is associated with an appreciable degree of 
transplant-related (i.e. toxic) mortality (TRM). The incidence of TRM at 1-year post-HSCT 
ranges from 5-15% depending upon the stem cell source utilized (Wingard, J Clin Oncol 2011). 
The UCSF BCH-SF BMT program has reviewed all cases of non-relapse related death from 
2012-2015 and identified a complication of endothelial injury known as transplant associated 
thrombotic microangiopathy (TMA) as the most common cause of TRM in our patient 
population.   
TMA is a multi-system disease in which widespread endothelial injury leads to microangiopathic 
hemolytic anemia, intravascular platelet activation and formation of thrombi within the 
microcirculation.  The endolethial injury then promotes the complement cascade leading to 
additional injury to the endothelium further propagating the disorder.    
TMA predominantly occurs in the kidneys but can affect the liver, lungs, intestines and brain.  
The risk factors for the development of TMA include myeloablative and reduced intensity 
conditioning regimens, calcineurin inhibitors (tacrolimus, cyclosporine), mTOR inhibitors 
(sirolimus), and infections.  Additional risk factors include mismatched donors, ABO mismatch, 
and non-Caucasian patients.  When genetic testing was performed looking at seventeen genes 
involved in the pathogenesis of other thrombotic microangiopathies, non-Caucasian patients 
with TMA were found to have more genetic variations when compared Caucasian patients 
(Jodele, Blood 2016).   
Diagnosis of TMA can be difficult as systemic signs and symptoms of TMA are often similar to 
other common transplant complications, such as medication induced hypertension and 
cytopenias.  Unlike in thrombocytopenic purpura, patients with TMA have normal ADAMTS13 
activity.   A renal biopsy would be useful in diagnosis however is often not possible given the 
risk factors of the procedure in a transplant patient.   
The reported prevalence of TMA is varied likely due to diagnostic uncertainty and center 
expertise, but large retrospective studies have reported it as 10-39%, with the majority of cases 
occurring in the first 100 days after transplant.  Of the patients who develop TMA, approximately 
half of them will develop severe disease.  Outcomes are poor with a reported 30-50% mortality 
rate and as high as 80% in patients with severe disease. Furthermore, survivors of TMA may 
have significant morbidity (e.g. renal failure and need for long-term dialysis, heart failure, and 
significantly prolonged hospital admission).  
There is no gold standard of treatment for TMA.  Supportive care including renal support, 
discontinuation of calcineurin inhibitors and treatment of infections.  Treatment options include 
plasma exchange, complement cascade blockade, and defibrotide.  Early treatment is crucial to 
decrease morbidity and mortality.    
Interestingly, our most severe cases of TMA have occurred in patients NOT receiving 
calcineurin inhibitors or sirolimus.  Despite the early recognition and treatment of TMA, we have 
continued to see poor outcomes treating with complement blockade alone. This suggests that 
complement activation may trigger a complex cascade of parallel inflammatory mediators that 
lead to end organ damage independent of the complement pathway. Therefore, our goal is to 
prevent TMA whenever possible via augmentation of endothelial repair. 
 

 
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Protocol #: 
Phase II – Study drug(s) 
1.2 
Background on the Compounds 
Refer to the Investigator’s Brochure/approved labeling for detailed background information on 
defibrotide. 
 
1.3 
Rationale for the Proposed Study 
Upon retrospective review of our cases of TMA and the medical literature, we are now 
classifying patients as either standard-risk for the development of TMA, or high-risk, based on 
the following clinical criteria:  
1. Patients undergoing tandem autologous transplant with thiotepa in one or more of the 
conditioning regimens.  
 
OR: 
 
2. Patients with at least 3 of the following characteristics: 
a) 
>10 years of age 
b) 
Non-Caucasian race/ Hispanic ethnicity 
c) 
Undergoing haploidentical transplant 
d) 
Minor ABO Mismatch 
 
Using these criteria, we retrospectively reviewed 160 transplants performed from 1/1/13 to 
9/30/16. There were 13 cases of TMA total (8.1%), with 7 cases (4.4%) deemed severe by the 
onset of renal failure, development of pericardial effusion, and/or death. In the 138 standard-risk 
patients, there were 6 total cases of TMA, but only 1 was severe (0.7%). Conversely, in the 22 
high-risk patients there were 7 total TMA cases, 6 of which were severe (27.3%). Most cases 
showed evidence of evolving TMA before Day +100 post-HCT, and some cases of TMA were 
evident within a week following HCT.  
 
Several groups have demonstrated that the onset of endothelial injury and clinical TMA typically 
begins within 4-6 weeks following HCT (Jodele Blood Rev 2015, Obut BMT 2016). Therefore, 
the hypothesis is that in high-risk patients the administration of certain combinations of high-
dose conditioning agents (radiation and/or chemotherapy) and/or post-HSCT inflammatory 
events initiate the complement pathway to aberrantly attack the endothelium.  Although the 
current standard treatment for post-transplant microangiopathic processes involves targeting 
inflammatory mediators with complement blockade and plasmapheresis, these therapies do not 
address the prevention or treatment of the initial pathologic trigger, namely, endothelial damage. 
 
Defibrotide is an anticoagulant and fibrinolytic agent that has been shown to be an effective 
treatment in other endothelial disorders such as hepatic veno-occlusive disease (Richardson 
Blood 2002).  It is a polydeoxyribonucleotide salt that blocks plasminogen activator inhibitor-1 
(PAI-1) and attenuates the effect of tumor necrosis factor.  It also increases prostaglandin E2 
and prostacyclin levels which alters the platelet activity adhesion and aggregation and relaxes 
the smooth muscle of blood vessel walls.  All of this likely protects the endothelium from 
damage. Yeates et al have shown that patients with TMA who were treated with defibrotide had 
a 77% response rate. (Yeates et al, Bone Marrow Transplantation, 2017).   
 
The use of defibrotide in the context of VOD treatment and prevention has been studied 
extensively.  A landmark report showed that defibrotide given to children during stem cell 

 
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Protocol #: 
Phase II – Study drug(s) 
transplant conditioning is safe and effective in the prevention of veno-occlusive disease and, 
incidentally, acute graft-versus-host disease (Corbacioglu, Lancet 2012).  However, there has 
not been a prospective study to show that such prophylaxis is effective in the prevention of 
TMA. 
 
1.4 
Correlative Studies 
Biomarkers indicative of endothelial damage and TMA activity will be drawn to assess 
subclinical TMA activity as well as risk for subsequent development of TMA while on defibrotide.  
These include plasma free hemoglobin (UCSF clinical lab), suppression of tumorigeneicity (ST2, 
Viracor), angiopoietin 2 (Ang2, Myriad), and plasminogen activator inhibitor – 1 (PAI-1, Quest).  
Study labs will be assessed at 4 time points prior to Day +21, and at diagnosis of TMA.   
Hypothesis:  
1. The incidence of TMA will correlate with increases in one or more of these 
biomarkers over baseline at any time post-HSCT.   
2. The severity of TMA will correlate with a maximum increase in one or more of 
these biomarkers. 
This will provide a predictive basis for future patients who may require preemptive treatment of 
early / preclinical TMA. 
 
2 
Objectives of the Study 
2.1 
Primary 
• 
To determine the safety and feasibility of administering prophylactic Defibrotide 
(provided by Jazz Pharmaceuticals) to a pilot population of patients at clinical high-risk 
for the development of severe TMA following HSCT.  Safety to be determined with 
regard to bleeding risk and risk of hypersensitivity reaction. Feasibility to be determined 
with regard to administration concurrently with chemotherapy and supportive 
medications before, during, and after stem cell infusion 
2.2 
Secondary 
• 
To determine if administration of prophylactic Defibrotide will prevent the development of 
TMA in clinically high-risk patients compared to historic controls.  
o Incidence of TMA in the first 6 months post-HSCT will be compared to incidence 
in a similar cohort of historical controls.  
o Incidence of severe TMA as defined by any TMA with the following 
complications: 
▪ 
Renal dysfunction requiring dialysis 
▪ 
Pleural or pericardial effusion requiring any medical or surgical 
intervention 
▪ 
CNS dysfunction including seizure, PRES 
▪ 
Death 
 

 
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Phase II – Study drug(s) 
2.3 
Exploratory Objectives, Other Assessments 
• 
Biomarker specimens will be drawn at 4 time points prior to development of TMA.  
Values will be analyzed to determine whether any one biomarker or a combination of 
biomarkers may be predictive of TMA development or severity. 
 
2.4 
Endpoints 
2.4.1 Primary Endpoints 
• 
Incidence of missed doses of defibrotide 
• 
Incidence of reportable SAE’s  
• 
Incidence of clinically significant bleeding requiring discontinuation of therapy 
• 
Incidence of hypersensitivity reaction requiring discontinuation of therapy 
 
2.4.2 Secondary Endpoints 
• 
Incidence of TMA as diagnosed by criteria listed in section 7.2.1. 
• 
Incidence of severe TMA as diagnosed by criteria listed in 7.2.2. 
2.4.3 Exploratory Endpoints 
• 
Incidence of elevation of single or combination of biomarkers predictive of development 
of TMA  
 
3 
Study Design 
3.1 
Characteristics 
This is an open-label, single arm pilot study of defibrotide given as prophylaxis to patients 
receiving a conditioned stem cell transplant for the purpose of preventing post-transplant 
microangiopathy. 
3.2 
Number of Subjects 
25 patients are expected to be enrolled. 
3.3 
Eligibility Criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria.  In addition, each patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required evaluations and all 
regulatory requirements for informed consent.  The written informed consent must be obtained 
from the patient prior to enrollment.  The following criteria apply to all patients enrolled onto the 
study unless otherwise specified. 

 
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Protocol #: 
Phase II – Study drug(s) 
3.3.1 Inclusion Criteria 
1. 
Age 0-30 years of age 
2. 
Life expectancy > 6 months 
3. 
ECOG or Karnofsky Performance Status >40 
4. 
Meets minimum organ function requirements per institutional SOC guiding clearance for 
autologous or allogeneic stem cell transplantation. 
5. 
Patients must meet TMA High-Risk criteria  
A. Patients undergoing tandem autologous transplant with thiotepa in one or 
more of the conditioning regimens.  
 
OR: 
B. . Patients with at least 3 of the following characteristics: 
a. >10 years of age 
b. Non-Caucasian race/ Hispanic ethnicity 
c. Undergoing haploidentical transplant 
d. Minor ABO Mismatch 
 
6. 
The effects of defibrotide on the developing human fetus are unknown.  For this reason 
and because other therapeutic drugs used as a part of transplant are known to be 
teratogenic, women of child-bearing potential and men must agree to use adequate 
contraception: abstinence per institutional stem cell transplantation guidelines, for the 
duration of study participation and for a minimum of 2 weeks after last dose of study 
drug.  Should a woman become pregnant or suspect she is pregnant while she or her 
partner is participating in this study, she should inform her treating physician 
immediately.  Men treated or enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study participation, and 2 weeks after 
last dose of study drug.  
7. 
Ability to understand a written informed consent document, and the willingness to sign it 
 
3.3.2 Exclusion Criteria 
1. Age >30 years 
2. Life expectancy < 6 months 
3. Known bleeding diathesis or bleeding risk deemed by the treating physician to be a 
contraindication to administration of anticoagulants. 
4. Known hypersensitivity reaction to defibrotide 
5. Any patient not meeting TMA High-Risk criteria as defined in section 1.3 
6. Pregnant women are excluded from this study because they will be receiving teratogenic 
therapy as part of the stem cell transplant.  

 
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Protocol #: 
Phase II – Study drug(s) 
3.4 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment should begin the day prior 
to initiation of conditioning and continue until Day +21 post-HSCT, or: 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patients decides to withdraw from the study 
• 
Significant patient non-compliance with protocol 
• 
General or specific changes in the patients’ condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
3.5 
Duration of Follow Up 
Patients will be followed for 6 months post-HSCT, or until death, whichever occurs first.  
Patients removed from study for unacceptable treatment related adverse event(s) will be 
followed until resolution or stabilization of all treatment-related adverse events to Grade 2 or 
lower. 
3.6 
Study Timeline 
Accrual is estimated to begin in Fall 2017 and continue through Fall 2019.  Patients will be 
followed for safety and efficacy through Spring 2020.   
3.6.1 Primary Completion 
The study will reach primary completion 24 months from the time the study opens to accrual. 
3.6.2 Study Completion 
The study will reach study completion 30 months from the time the study opens to accrual. 
4 
Study Drugs 
4.1 
Description, Supply and Storage of Investigational Drugs 
4.1.1 Investigational Drug #1 
Defibrotide is available as a solution, Intravenous, as sodium [preservative free]:  Defitelio: 200 
mg/2.5 mL (2.5 mL).  Refer to the package insert for complete information. 
 
Classification:  
Therapeutic Category: Antiplatelet Agent; Thrombolytic Agent 
 
Mechanism of Action:   
Defibrotide augments plasmin enzymatic activity to hydrolyze fibrin clots. It reduces endothelial 
cell (EC) activation and increases EC-mediated fibrinolysis by increasing tissue plasminogen 
activator and thrombomodulin expression, as well as by decreasing von Willebrand factor and 
plasminogen activator inhibitor-1 expression. 
 

 
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Protocol #: 
Phase II – Study drug(s) 
Metabolism:   
Polynucleotides are metabolized via nucleases, nucleotidases, nucleosidases, deaminases, and 
phosphorylases to oligonucleotides, nucleotides, nucleosides, and then to the free 2’-
deoxyribose sugar, purine and pyrimidine bases 
 
Contraindications:   
Known hypersensitivity to defibrotide or any component of the formulation; concomitant 
administration with systemic anticoagulant or fibrinolytic therapy 
 
Availability:   
FDA approved March 2016 
 
Storage and handling 
Store intact vials at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C 
(59°F to 86°F). Solutions diluted for infusion in D5W or NS should be used within 4 hours if 
stored at room temperature or within 24 hours if refrigerated. Discard partially used vials. Side  
 
Effects 
Complete and updated adverse event information is available in the Investigational Drug 
Brochure and/or product package insert.  
 
4.2 
 Drug Accountability 
The Investigational Pharmacist will manage drug accountability records. 
4.3 
Drug Ordering 
UCSF will obtain defibrotide directly from pharmaceutical company as study supply. 
4.4 
Packaging and Labeling of Study Drugs 
Drugs will be packaged and labeled per UCSF institutional standards, adhering to applicable 
local and federal laws. 
5 
Treatment Plan 
5.1 
Dosage and Administration 
Treatment will be administered on an inpatient basis. 
Table 5.1 
Regimen Description 
Study Drug 
Premedication; 
precautions 
Dose 
Route 
Schedule 
Cycle Length 
Defibrotide 
None 
6.25 mg/kg 
IV over 2 hours 
Q6h 
Day prior to start of 
conditioning through 
Day +21 Post-HSCT 

 
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5.1.1 Dose Modifications and Dosing Delays Tables for Specific Adverse Events 
Adverse Event:  Bleeding or Hypersensitivity reaction 
Grade of Event 
Management 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1 
Resume at same dose level 
Grade 3 
Discontinue therapy 
Grade 4 
Discontinue therapy 
*Patients requiring a delay of > 2 weeks should go off protocol therapy 
 
5.2 
Monitoring and Toxicity Management 
Each patient receiving defibrotide will be evaluable for safety.  The safety parameters include all 
laboratory tests and hematological abnormalities, physical findings, and spontaneous reports of 
adverse events reported to the investigator by patients. 
Each patient will be assessed periodically for the development of any toxicity as outlined in 
Section 6 Study Procedures and Observations. Toxicity will be assessed according to the NCI 
CTCAE v4.0.  Dose adjustments will be made according to the system showing the greatest 
degree of toxicity.  
We will monitor for incidence of clinically significant bleeding and hypersensitivity reactions: 
Hemorrhage: Defibrotide may increase the risk of bleeding (based on increased activity of 
fibrinolytic enzymes in vitro). Do not initiate therapy in patients with active 
bleeding; monitor closely for signs of bleeding. If hemodynamically significant 
bleeding develops while on therapy, discontinue defibrotide, evaluate/treat the 
underlying cause, and provide supportive care until bleeding resolves. 
Hypersensitivity reactions: Hypersensitivity reactions (e.g., rash, urticaria, and 
angioedema) have been reported (rare). One patient with a history of previous 
defibrotide exposure experienced an anaphylactic reaction. Monitor closely for 
hypersensitivity reactions, particularly in patients who have received defibrotide 
previously. Discontinue therapy for severe hypersensitivity reactions and treat 
accordingly; monitor until symptoms resolve. 
Acute toxicity will be managed by immediately stopping infusion of defibrotide and holding 
further doses.  Hypersensitivity reactions will be managed per local protocols and standard of 
care.  Further management will depend upon the judgment of the clinician. 
5.2.1 Other toxicities:  
The toxicities listed below have been reported in patients receiving defibrotide.  None have been 
directly attributable to defibrotide itself. 
Cardiovascular: Hypotension, thrombophlebitis 
Central nervous system: Cerebral hemorrhage, intracranial hemorrhage 
Endocrine & metabolic: Hot flash, hyperuricemia 

 
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Gastrointestinal: Abdominal cramps, abdominal pain, bloody diarrhea, diarrhea, gastrointestinal 
hemorrhage, hematemesis, nausea, vomiting 
Genitourinary: Hematuria 
Hematologic & oncologic: Hemorrhage, oral hemorrhage, pulmonary hemorrhage 
Hypersensitivity: Hypersensitivity reaction 
Immunologic: Graft versus host disease 
Infection: Infection, sepsis 
Renal: Renal failure 
Respiratory: Epistaxis, pneumonia, pulmonary alveolar hemorrhage, pulmonary infiltrates 
Miscellaneous: Fever 
 
6 
Study Procedures and Observations 
6.1 
Schedule of Procedures and Observations 
The study-specific assessments are detailed in this section and outlined in Table 6.1, Schedule 
of Study Procedures and Assessments.  Screening assessments must be performed within 28 
days prior to the first dose of investigational product.  Any results falling outside of the reference 
ranges may be repeated at the discretion of the investigator. All on-study visit procedures are 
allowed a window of ± 2 days unless otherwise noted.  Treatment or visit delays for public 
holidays or weather conditions do not constitute a protocol violation. 
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 copy of the signed ICF 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.   
All patients who are consented will be registered in the study database.  The system is 
password protected and meets HIPAA requirements. 
Patients undergoing tandem autologous transplants will repeat the schedule of procedures and 
assessments on admission for second transplant.   
6.1.1 Pretreatment Period 
6.1.1.1 Screening Assessments  
The Screening procedures and assessments must be completed within 28 days prior to 
admission. 
• 
Physical examination 
• 
Vital signs 
• 
Performance Status 
• 
Patient and donor blood type, if eligible 

 
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6.1.2 Treatment Period 
6.1.2.1 Study Procedures: Treatment (Day of admission through Day +21 post-
HSCT) 
These procedures must be completed weekly starting the day before the start of alkylating 
agents or TBI. 
• 
Defibrotide 6.25mg/kg IV Q6h to start at 9 pm (+/- 3 hours) on the day prior to start of 
conditioning . 
• 
Evaluation of clinical response or deterioration 
• 
Physical examination 
• 
Vital signs 
• 
Performance Status 
• 
Evaluation of adverse events 
• 
Standard labs including  
o CBC with differential and platelet count, reticulocyte count 
o Blood chemistry assessment, including: alkaline phosphatase, ALT/AST, total 
bilirubin, calcium, phosphorus, magnesium, BUN, creatinine, total protein, 
albumin, fasting glucose, potassium, sodium, chloride, bicarbonate 
o Uric acid, LDH 
o Direct antiglobulin test, peripheral smear for RBC morphology,  
o Urine protein concentration, urine protein / creatinine ratio,  
o Complement activity (CH50) 
o Coagulation panel including PT/PTT, d-dimer 
6.1.3 Post-treatment/Follow Up Visits 
Patients will be followed weekly until Day +28 then monthly for up to 6 months after enrollment 
or until disease progression; exception for patients receiving tandem transplants will be followed 
weekly until Day +28 then monthly for up to 6 months after admission from second transplant or 
until disease progression.  The following procedures will be performed at the Follow Up Visit(s): 
• 
Evaluation of clinical response or deterioration 
• 
Physical examination 
• 
Vital signs 
• 
Performance Status 
• 
Evaluation of adverse events 
• 
Standard labs including  
o CBC with differential and platelet count, reticulocyte count 
o Blood chemistry assessment, including: alkaline phosphatase, ALT/AST, total 
bilirubin, calcium, phosphorus, magnesium, BUN, creatinine, total protein, 
albumin, glucose, potassium, sodium, chloride, bicarbonate 
o Uric acid, LDH, haptoglobin 
o Direct antiglobulin test, peripheral smear for RBC morphology  

 
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Phase II – Study drug(s) 
o Urine protein concentration, urine protein / creatinine ratio  
o Complement activity (CH50) 
o Coagulation panel including PT/PTT, d-dimer 
6.1.4 Discontinuation of Therapy 
The Investigator will withdraw a patient whenever continued participation is no longer in the 
patient’s best interests.  Reasons for withdrawing a patient include, but are not limited to, 
disease progression, the occurrence of an adverse event or a concurrent illness, a patient’s 
request to end participation, a patient’s non-compliance or simply significant uncertainty on the 
part of the Investigator that continued participation is prudent.  There may also be administrative 
reasons to terminate participation, such as concern about a patient’s compliance with the 
prescribed treatment regimen 
 

 
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Page 20 of 37 
 
Table 6.1: Schedule of Study Procedures and Assessments4 
 
Screen  
Days Pre-HSCT 
Days Post-HSCT 
Weeks Post-HSCT 
TMA Dx 
(+/- in 
days) 
Admit 
(-28) 
Admit 
 
-7 
(+/- 2) 
-1 
(+/- 1) 
7 
(+/- 2) 
14 
(+/- 2) 
21 
(+/- 2) 
28 
(+/- 2) 
8 
(+/- 7) 
12 
(+/- 7) 
16 
(+/-7) 
20  
(+/- 7) 
24 
(+/-7) 
Dx  
(+/-3) 
Informed 
consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE 
assessment 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Defibrotide 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
+/- 
Physical 
exam * 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs * 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Medical 
History * 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Standard 
Labs1 * 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study Labs2 
 
x3 
 
x 
x 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
Labs per standard of care should include CBC, complete chemistry, LDH, uric acid, haptoglobin, direct antiglobulin test, peripheral smear  
for RBC morphology, urine protein concentration, urine protein / creatinine ratio, CH50, coagulation panel.  
2. 
Study labs to include plasma free Hgb, ST2, Ang-2, PAI-1, and hold specimen.  
3. 
+/- 2 day window 
4. 
Patients undergoing tandem autologous transplants will repeat the schedule of procedures and assessments on admission  
for second transplant, with the exception of screening.   
* 
Standard of care for patients undergoing HSCT 

 
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6.2 
Usage of Concurrent/Concomitant Medications 
 
Patients on the trial will receive the UCSF standard of care for high risk TMA 
• 
Vitamin D started prior to admission with goal levels of vitamin D, 25 hydroxy 
level of 30- 60ng/mL 
• 
Allopurinol on admission and continue until Day 0 if uric acids are normal, or 
longer if uric acids remain high 
• 
Two weeks prior to admission patients will begin Eicosapentaenoic Acid (EPA, a 
component of fish oil). (dosing: < 6 months: 110 mg PO qday, 6 months – 17 
years: 30 mg/kg/day, max 2000 mg/day) divided up to three times per day) which 
will continue until day +100.  EPA will be held when patient is unable to take 
PO, during periods when the patient’s platelet count is < 20 x 10^9/L, for clinical 
bleeding, prior to procedures (hold at least 4 days prior to procedure), and/or 
requiring platelets transfusions.  Clinical trial evidence for EPA does not support 
an increased bleeding risk with fish oil therapy, even when used in combination 
with other agents that may increase bleeding. 
• 
 n-Acetylcysteine (NAC) prophylaxis in addition to those doses given on 
admission, and Day +1 and Day +2 for VOD prophylaxis will be given as 70 
mg/kg (rounded to nearest vial size) every 8 hours IV or PO starting day +3 and 
continued until Day +42 or discharge, whichever comes sooner. 
 
There are no restrictions in concurrent / concomitant medications except per standard of care 
recommendations for use of defibrotide.  Specifically, tissue plasminogen activator (t-PA) is 
contraindicated due to bleeding risk; use of low doses for clearance of IV catheters is permitted. 
Administration of other anticoagulants concurrently with defibrotide is at the discretion of the 
treating physician. 
6.3 
Dietary Restrictions 
None 
6.4 
Prohibited Medications 
Eculizumab if used as prophylaxis for TMA, Ibuprofen or other NSAIDs, aspirin 
7 
Reporting and Documentation of Results 
7.1 
Evaluation of Efficacy (or Activity) 
Incidence of TMA will be calculated on a rolling basis and at completion of the study.  If at any 
time incidence of TMA exceeds 2 patients, the study will be paused and evaluated for futility. 
7.2 
Definitions 
7.2.1 Definition of TMA 
Criteria for diagnosis of TMA for purposes of this study will be as follows: 
• 
Evidence of microangiopathy, with an additional item from Category A or B, OR 
o The presence of schistocytes (>2/HPF) in the peripheral blood, or 
o Histologic evidence of microangiopathy on a tissue specimen, or 

 
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o Undetectable haptoglobin with increased reticulocyte count 
• 
No evidence of microangiopathy but: 
o 1 item from Category A (evidence of organ dysfunction), AND 
o 3 items from Category B (increased TMA biomarkers) 
 
Category A (clinical markers / organ dysfunction) 
Category B (biomarkers) 
• 
Proteinuria 
• 
Hypertension 
• 
Renal dysfunction 
• 
De novo anemia 
• 
Do novo thrombocytopenia 
• 
Elevated LDH  
• 
Terminal Complement Activation 
*Definitions of these criteria are provided below. 
 
Definitions of criteria are adapted from Jodele et al (2015 Blood Rev) and provided below: 
Laboratory or clinical marker 
Description 
1. Lactate dehydrogenase (LDH) 
• Elevated above the upper limit of normal for 
age 
2. Proteinuria 
• A random urinalysis protein concentration of 
≥30 mg/dL or abnormal Pr/Cr Ratio 
3. Hypertension 
• <18 years of age: a blood pressure at the 
95th percentile value for age, sex and 
height. 
• ≥18 years of age: a blood pressure ≥140/90 
mm Hg. 
4. De novo thrombocytopenia 
• Thrombocytopenia with a platelet count <50 
× 109/L or a ≥50% decrease in the platelet 
count 
5. De novo anemia 
• A hemoglobin below the lower limit of 
normal for age anemia requiring transfusion 
support 
6. Evidence of microangiopathy 
• The presence of schistocytes (>2/HPF) in 
the peripheral blood, or 
• histologic evidence of microangiopathy on a 
tissue specimen, or 
• Undetectable haptoglobin with increased 
reticulocyte count 
7. Terminal complement activation 
• Elevated plasma concentration of sC5b-9 
above upper normal laboratory limit 
8. Renal dysfunction 
• Elevated creatinine above upper limit of 
normal not due to alternative cause (e.g., 
drug, fluid status) 

 
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7.2.2 Definition of Severe TMA 
Any TMA meeting criteria described in 7.2.1 with any of the following additional features: 
• 
Renal dysfunction requiring dialysis 
• 
Pleural or pericardial effusion requiring any medical or surgical intervention 
• 
CNS dysfunction including seizure 
• 
Inpatient admission > 90 days duration directly related to TMA management 
 
7.3 
Evaluation of Safety and Toxicity 
Evaluable for toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with the study drug. 
This includes measuring incidence of hemodynamically significant bleeding or bleeding that 
results in life-threatening or permanent clinical sequelae. 
Analyses will be performed for all patients having received at least one dose of study drug.  The 
study will use the CTCAE v4.03 for reporting of non-hematologic adverse events and modified 
criteria for hematologic adverse events. 
 
7.4 
Definitions of Adverse Events 
7.4.1 Adverse Event 
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related.  More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, without any judgment about causality.  An adverse event can arise from any use of the 
drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose.  
7.4.2 Adverse reaction 
An adverse reaction is defined as any adverse event caused by the use of a drug.  Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event. 
7.4.2.1 Suspected  
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship 
between the drug and the adverse event.  A suspected adverse reaction implies a lesser degree 
of certainty about causality than an adverse reaction. 
7.4.2.2 Unexpected  
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in 
the investigator brochure or package insert(s), or is not listed at the specificity or severity that 

 
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has been observed, or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the current 
application.  
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or 
as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure.  For example, a certain number of non-acute deaths in a cancer trial 
would be anticipated as an outcome of the underlying disease, but such deaths would generally 
not be listed as a suspected adverse reaction in the investigator brochure. 
Some adverse events are listed in the Investigator Brochure  as occurring with the same class 
of drugs, or as anticipated from the pharmacological properties of the drug, even though they 
have not been observed with the drug under investigation.  Such events would be considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class 
effect, the first case of angioedema observed with the drug under investigation should be 
considered unexpected for reporting purposes. 
7.4.2.3 Serious 
An adverse event or suspected adverse reaction is considered serious if, in the view of either 
the investigator or sponsor (The University of California, San Francisco), it results in any of the 
following outcomes:  
• 
Death 
• 
Life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function 
• 
Congenital anomaly/birth defect 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  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, or the development of 
drug dependency or drug abuse. 
7.4.2.4 Life-threatening 
An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death.  

 
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7.5 
Recording of an Adverse Event 
All grade 3 and above adverse events will be entered into the study database, whether or not 
the event is believed to be associated with use of the study drug.  Safety data (SAEs) will be 
collected from the time of admission until the day after completion of defibrotide (6-12 times the 
half-life of the study drug). Data about these events and their severity will be recorded using the 
NCI CTCAE v4.0.   
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into the study database using the 
classification system listed below:  
Relationship  
Attribution  
Description  
Unrelated to investigational 
drug/intervention 
Unrelated 
The AE is clearly NOT related to the 
intervention  
Unlikely 
The AE is doubtfully related to the 
intervention  
Related to investigational 
drug/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  
 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE.  When specific adverse events are not listed in the CTCAE they will be 
graded by the Investigator as none, mild, moderate or severe according to the following grades 
and definitions: 
Grade 0 
No AE (or within normal limits) 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL) 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL 
Grade 4: Life-threatening consequences; urgent intervention indicated 
Grade 5: Death related to AE 
 
7.6 
Follow-up of Adverse Events 
All adverse events will be followed with appropriate medical management until resolved.  
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  For selected adverse events for which administration of the 
investigational drug was stopped, a re-challenge of the subject with the investigational drug may 
be conducted if considered both safe and ethical by the Investigator. 

 
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7.7 
Adverse Events Monitoring  
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 the study database, as noted above. 
The Investigator will assess all adverse events and determine reportability requirements to the 
UCSF’s Institutional Review Board, the Committee on Human Research (CHR). 
All adverse events entered into the study database will be reviewed by the Study Committee on 
a monthly basis.  The Study Committee will review and discuss at each meeting the selected 
toxicity, the toxicity grade, and the attribution of relationship of the adverse event to the 
administration of the study drug(s). 
All grade(s) 3-5 adverse events entered into the study database will be reviewed on a monthly 
basis at the Study Committee meetings. The Site Committee will review and discuss the 
selected toxicity, the toxicity grade, and the attribution of relationship of the adverse event to the 
administration of the study drug(s). 
In addition, all suspected adverse reactions considered “serious” entered into the study 
database, will be reviewed and monitored by the study committee on an ongoing basis and 
discussed at study meetings, which take place every eight weeks. 
 
7.8 
Expedited Reporting  
Reporting to the Data and Safety Monitoring Committee 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 
or to a study procedure, the Investigator or his/her designee must notify the study Chair (or 
qualified alternate) within 1 business day of knowledge of the event.  The contact may be by 
phone or e-mail. 
Reporting to UCSF Committee on Human Research (Institutional Review Board) 
The Principal Investigator must report events meeting the UCSF CHR definition of 
“Unanticipated Problem” (UP) within 10 business days of his/her awareness of the event.  
Expedited Reporting to the Food and Drug Administration 
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32).  
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected.  The Sponsor-Investigator needs to ensure that the event meets all 
three definitions:  
• 
Suspected adverse reaction (as defined in 6.1.30) 
• 
Unexpected (as defined in 0) 
• 
Serious (as defined in 6.1.5) 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report. 

 
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The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)).  
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)).  
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)).  
Reporting to Pharmaceutical Companies providing Study Drug 
• 
Reporting to Jazz Pharmaceuticals 
o The SI must send all SAEs (initial and follow-up) that require collection and 
reporting per protocol, and which occur in a subject who received a Jazz 
Pharmaceuticals product as study drug, to the Jazz Pharmaceuticals Drug Safety 
Department within 1 business day of their awareness of the SAE 
(AEreporting@jazzpharma.com). 
o The SI will report the SAEs using a US-FDA Form 3500A (MedWatch form). 
[Note: the MedWatch form, is available at 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadForms/
UCM082728.pdf] 
o The SI must also provide Jazz Pharmaceuticals Drug Safety Department 
(PVcomms@jazzpharma.com) with a copy of all submissions made to the FDA at 
the time the submission is made. 
o In addition, all other adverse events will be reported to the Jazz Pharmaceuticals 
Drug Safety Department in summary or line-item form upon Jazz 
Pharmaceuticals’ request and at the conclusion of the study. 
 
8 
Statistical Considerations and Evaluation of Results 
8.1 
Study Endpoints 
• 
Open label non-randomized un-blinded study to determine feasibility, safety, and 
efficacy. 
• 
Feasibility endpoints; 
o Incidence of discontinuation of defibrotide. Study will be suspended if defibrotide 
is not tolerated as outlined below:  
N (accrued) 
0-6 
7-12 
13-18 
19-24 
Evaluate if discontinued in this many or 
more patients: 
5 
8 
10 
12 
 

 
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• 
Safety endpoints 
o Incidence of reportable SAE’s (possibly drug-related and severe or unexpected).  
Study will be suspended if reportable AE’s 
N (accrued) 
0-6 
7-12 
13-18 
19-24 
Evaluate if drug-related SAE’s occur in 
this many or more patients: 
4 
7 
10 
12 
 
• 
Incidence of TMA 
o Historical incidence: 7 of 22 (31.8%). With N=24, study will have 80% power to 
detect a statistically significant difference if incidence in this treated cohort is 8% 
or less.  
o Study will be re-evaluated if 2 patients develop TMA as this will render the 
secondary endpoint futile. May continue enrollment to determine feasibility and 
safety or expand the patient cohort.    
• 
Incidence of Severe TMA 
o Historical incidence: 6 of 22 (27.3%). With N=24, study will have 70% power to 
detect a statistically significant difference if incidence in this treated cohort is 4% 
or less.  
o Study will be re-evaluated if 1 patient develops severe TMA as this will render the 
secondary endpoint futile. May continue enrollment to determine feasibility and 
safety or expand the patient cohort.    
8.1.1 Study Design 
Single arm un-blinded non-randomized Phase II study.  
8.1.2 Randomization 
No randomization is planned. 
8.1.3 Un-blinding Subjects 
No blinding is planned. 
8.1.4 Stratification Factors 
No stratification is required; all patients will receive the same treatment and follow the same 
assessment procedures.  
8.2 
Determination of Sample Size and Accrual Rate 
Based on historical controls, we estimate accrual of 12 patients per year, with a goal of 24 
patients by 2 years.  

 
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8.2.1 Sample Size and Power Estimate 
Assuming an historical rate of severe TMA of 28%, alpha=5%, and N=24, power to detect a 
statistically significant value of 4% in this cohort is 92%. The minimum number of patients to 
enroll to achieve 80% power to detect a difference, assuming a 4% incidence in this cohort, is 
N=19.  Assuming a sample size of N=24, the study has 80% power to detect a statistically 
significant difference if the incidence of severe TMA in this treated cohort is <5%. Given the 
small sample size, adjustments for multiple comparisons will not be made. 
8.2.2 Replacement Policy 
Patients that discontinue participation for reasons other than direct defibrotide toxicity or failure 
of feasibility will be replaced with additional patients.  This included patients who are no longer 
evaluable for TMA due to mortality prior to week 24.  
8.2.3 Accrual estimates 
Based on historical rates we estimate accrual of 12 patients per year. 
8.3 
Interim Analyses and Stopping Rules 
Stopping rules as described in section 8.1. 
8.4 
Analyses Plans 
8.4.1 Analysis Population 
The analysis population will include all the patients who enroll that receive defibrotide.  
8.4.2 Primary Analysis (or Analysis of Primary Endpoints) 
The primary efficacy analysis will be performed using the ITT population. The primary endpoint 
will assess the safety and feasibility of defibrotide.  It will compare how many patients received 
the drug versus how many were intended to receive it.  It will look into how many patients 
stopped the drug early and reasons for this.   
8.4.3 Secondary Analysis (or Analysis of Secondary Endpoints) 
This will include the incidence of TMA in the patients enrolled on study compared to historical 
controls, including their demographics, underlying diagnosis, conditioning regimens and other 
transplant complications.  Also will compare incidence of severe TMA compared to historical 
controls and the complications.   
8.4.4 Other analyses/Assessments 
Other analysis include incidence of TMA by Day +30 post-HSCT, non-relapse mortality by Day 
+100 and by Day +180 post-HSCT.  Summaries for biomarkers will be provided. Additional 
exploratory analyses may be performed based on incidence of elevation of single or 
combination of biomarkers predictive of development of TMA. 
8.5 
Evaluation of Safety 
Analyses will be performed for all patients having received at least one dose of study drug.  The 
study will use the NCI CTCAE v4.03. 

 
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8.6 
Study Results 
Study results will be made available on ClinicalTrials.gov and will be published once the study 
has completed enrollment and all patients have completed the required follow-up period. 
9 
Study Management 
9.1 
Pre-study Documentation 
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. 
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects.   
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements.  
]The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements. 
9.2 
Institutional Review Board Approval 
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 UCSF CHR (UCSF Institutional Review Board).  The initial protocol and all 
protocol amendments must be approved by the IRB prior to implementation.   
9.3 
Informed Consent 
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants 
must sign the CHR-approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  
The original signed copy of the consent document must be retained in the medical record or 
research file.  
9.4 
Changes in the Protocol 
Once the protocol has been approved by the UCSF CHR, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the Investigator 
and approved by the CHR prior to implementation.   
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to CHR approval.  In this circumstance, however, the 
Investigator must then notify the CHR in writing within five (5) working days after 
implementation.  The Study Chair and the UCSF study team will be responsible for updating any 
participating sites. 

 
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9.5 
Handling and Documentation of Clinical Supplies 
The UCSF Principal Investigator and each participating site will maintain complete records 
showing the receipt, dispensation, return, or other disposition of all investigational drugs.  The 
date, quantity and batch or code number of the drug, and the identification of patients to whom 
study drug has been dispensed by patient number and initials will be included.  The sponsor-
investigator will maintain written records of any disposition of the study drug. 
The Principal Investigator shall not make the investigational drug available to any individuals 
other than to qualified study patients.  Furthermore, the Principal Investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol. 
9.6 
Case Report Forms (CRFs) 
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis.  All study data will be entered into the study database via 
standardized CRFs in accordance with the CTMS study calendar, using single data entry with a 
secure access account.  The Clinical Research Coordinator (CRC) will complete the CRFs as 
soon as possible upon completion of the study visit; the Investigator will review and approve the 
completed CRFs.  
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records maintained by 
UCSF personnel.  All source documentation should be kept in separate research folders for 
each patient. 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate.  
All source documentation and CTMS data will be available for review/monitoring by regulatory 
agencies. 
The Principal Investigator will be responsible for ensuring the accurate capture of study data.  At 
study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked.  Any changes to the data entered into the CRFs after that time can only 
be made by joint written agreement among the Study Chair, the Trial Statistician, and the 
Protocol Project Manager. 
9.7 
Oversight and Monitoring Plan 
The CHR will audit study-related activities to ensure that the study is conducted in accordance 
with the protocol, local standard operating procedures, FDA regulations, and Good Clinical 
Practice (GCP).  Coordinating Center Documentation of Distribution  
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution 
of study documents as well as their receipt (when possible). Correspondence file: should 
contain copies (paper or electronic) of all protocol versions, cover letters, amendment outlines 
(summary of changes), etc., along with distribution documentation and (when available) 
documentation of receipt. 
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received. 

 
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At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its 
updates and safety information are distributed. 
9.8 
Regulatory Documentation  
Prior to implementing this protocol at the protocol, informed consent form, HIPAA authorization 
and any other information pertaining to participants must be approved by the UCSF Committee 
on Human Research (CHR). Prior to implementing this protocol at the participating sites, 
approval for the UCSF CHR approved protocol must be obtained from the participating site’s 
IRB.  
10 
Protection of Human Subjects 
10.1 Protection from Unnecessary Harm  
Each clinical site is responsible for protecting all subjects involved in human experimentation. 
This is accomplished through the CHR mechanism and the process of informed consent. The 
CHR 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 CHR 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.  
10.2 Protection of Privacy 
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and 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. The use and disclosure of protected health information will be limited to the 
individuals described in the informed consent document. 

 
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References 
Cho BS, Yahng SA, Lee SE, et al. Validation of recently proposed consensus criteria for  
thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation. 
Transplantation. 2010; 90(8):918-926. 
 
Choi CM, Schmaier AH, Snell MR, Lazarus HM. Thrombotic microangiopathy in haematopoietic  
stem cell transplantation: diagnosis and treatment. Drugs. 2009; 69(2):183-198. 
 
Corbacioglu S, Cesaro S, Faraci M, et al. Defibrotide for prophylaxis of hepatic veno-occlusive  
disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3,  
randomised controlled trial. Lancet. 2012; 379(9823):1301-1309. 
 
Corti P, Uderzo C, Tagliabue A, et al. Defibrotide as a promising treatment for thrombotic 
thrombocytopenic purpura in patients undergoing bone marrow transplantation. Bone Marrow 
Transplant. 2002; 29(6):542-543 
 
Jodele S, Dandoy CE, Myers KC, et al. New approaches in the diagnosis, pathophysiology, and  
treatment of pediatric hematopoietic stem cell transplantation-associated thrombotic  
microangiopathy. Transfus Apher Sci. 2016; 54(2):181-190. 
 
Jodele S, Davies SM, Lane A, et al. Diagnostic and risk criteria for HSCT-associated thrombotic  
microangiopathy: a study in children and young adults. Blood. 2014; 124(4):645-653. 
 
Jodele S, Laskin BL, Dandoy CE, et al. A new paradigm: Diagnosis and management of HSCT- 
associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev. 2015;  
29(3):191-204. 
 
Jodele S, Zhang K, Zou F, et al. The genetic fingerprint of susceptibility for transplant 
associated thrombotic microangiopathy. Blood. 2016; 127(8):989-996. 
 
Kim SS, Patel M, Yum K, Keyzner A. Hematopoietic stem cell transplant-associated thrombotic  
microangiopathy: review of pharmacologic treatment options. Transfusion. 2015; 55(2):452-458. 
 
Kojouri K, George JN. Thrombotic microangiopathy following allogeneic hematopoietic stem cell  
transplantation. Curr Opin Oncol. 2007; 19(2):148-154. 
 
Laskin BL, Goebel J, Davies SM, Jodele S. Small vessels, big trouble in the kidneys and  
beyond: hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Blood.  

 
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2011; 118(6):1452-1462. 
 
Obut F, Kasinath V, Abdi R. Post-bone marrow transplant thrombotic microangiopathy. Bone  
Marrow Transplant. 2016; 51(7):891-897. 
 
Richardson PG, Murakami C, Jin Z, et al. Multi-institutional use of defibrotide in 88 patients after  
stem cell transplantation with severe veno-occlusive disease and multisystem organ failure:  
response without significant toxicity in a high-risk population and factors predictive of outcome.  
Blood. 2002; 100(13):4337-4343. 
 
Rosenthal J. Hematopoietic cell transplantation-associated thrombotic microangiopathy: a  
review of pathophysiology, diagnosis, and treatment. J Blood Med. 2016; 7:181-186. 
 
Uderzo C, Bonanomi S, Busca A, et al. Risk factors and severe outcome in thrombotic  
microangiopathy after allogeneic hematopoietic stem cell transplantation. Transplantation. 2006;  
82(5):638-644. 
 
Uderzo C, Fumagalli M, De Lorenzo P, et al. Impact of thrombotic thrombocytopenic purpura on  
leukemic children undergoing bone marrow transplantation. Bone Marrow Transplant. 2000;  
26(9):1005-1009. 
 
Wingard JR, Majhail NS, Brazauskas R, et al. Long-term survival and late deaths after  
allogeneic hematopoietic cell transplantation. J Clin Oncol. 2011; 29(16):2230-2239. 
 
Yeates L, Slatter MA, Bonanomi S, et al. Use of defibrotide to treat transplant-associated  
thrombotic microangiopathy: a retrospective study of the Paediatric Diseases and Inborn Errors  
Working Parties of the European Society of Blood and Marrow Transplantation. Bone Marrow  
Transplant. 2017; 52(5):762-764. 
 
 

 
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11 
Appendices 
Appendix 1 Performance Status Criteria 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity 
Fully active, able to carry on all 
pre-disease performance without 
restriction 
100 
Normal, no complaints, no evidence 
of disease 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease 
1 
Symptoms, but ambulatory 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work) 
80 
Normal activity with effort; some 
signs or symptoms of disease 
70 
Cares for self, unable to carry on 
normal activity or to do active work 
2 
In bed < 50% of the time 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities 
Up and about more than 50% of 
waking hours 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs 
50 
Requires considerable assistance 
and frequent medical care 
3 
In bed > 50% of the time 
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization 
indicated 
Death not imminent 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
20 
Very sick, hospitalization indicated 
Death not imminent 
10 
Moribund, fatal processes 
progressing rapidly 
5 
Dead 
0 
Dead 
 

 
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Appendix 2 
Prohibited Medications 
Drug 
Trade name (if applicable) 
aspirin 
alteplase (systemic) 
eculizumab (prophylactic) 
ibuprofen 
naproxen 
 
Activase 
Soliris 
Advil, Motrin 
Aleve