Safety and Efficacy of Miltenyi CliniMACS® CD34 Reagent System for Transplant Protocol Utilizing Haploidentical CD34+ Selected Cells Combined With Single Unit Umbilical Cord Blood Transplant for Treatment of High-risk Hematologic Disorders
Phase: NA
Conditions: Hematologic Disorders
Sponsor: University of Colorado, Denver

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CLINICAL RESEARCH PROTOCOL 
 
Title: Safety and efficacy of Miltenyi CliniMACS® CD34 Reagent System for transplant 
protocol utilizing haploidentical CD34+ selected cells combined with single unit umbilical 
cord blood transplant for treatment of high-risk hematologic disorders. 
 
Version:  February 22, 2021 
COMIRB #:  16-1672 
 
Principal Investigator: 
Jonathan Gutman, MD  
 
 
IDE #: 17240 
 
IDE Holder: Jonathan Gutman, M.D. 
 
Product: Miltenyi CliniMACS® CD34 Reagent System 
 
 
 
Other identifying words: AML, ALL, CML, MDS, MPD, NHL, AA 
 
Estimated duration of study: 8 years 
 
Enrollment:  
 
 
Number 
Sex 
Age Range 
Subjects 
Up to 200 
Either 
≥ 18 - ≤ 80 
 
 
 
 
 
 
 

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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................ 4 
1. 
SUMMARY .......................................................................................................................................... 5 
2. 
OBJECTIVE ........................................................................................................................................ 6 
3. 
BACKGROUND ................................................................................................................................. 6 
3.1. 
Review ............................................................................................................................................. 6 
4. 
SCIENTIFIC AND CLINICAL JUSTIFICATION ............................................................................ 7 
5. 
STUDY DESIGN ................................................................................................................................. 8 
6. 
ELIGIBILITY ASSESSMENT ........................................................................................................... 9 
6.1. 
Inclusion Criteria - Recipient .................................................................................................... 9 
6.2. 
Exclusion Criteria – Recipient (any of the following) ......................................................... 9 
6.3. 
Donor Eligibility ............................................................................................................................ 9 
7. 
CLINICAL EVALUATION OF THE TRANSPLANT RECIPIENT ............................................. 10 
8. 
TREATMENT PLAN ........................................................................................................................ 10 
8.1. 
Preparative Regimens ............................................................................................................... 10 
8.1.1. 
Preparative Regimen for patients with hematologic malignancies .......................... 10 
8.1.2. 
Medium intensity preparative regimen for patients with hematologic 
malignancies ........................................................................................................................................... 10 
8.1.3. 
Reduced intensity conditioning (RIC) preparative regimen for patients with 
hematologic malignancies who cannot tolerate high intensity regimen ................................ 11 
8.1.4. 
Preparative Regimen with high dose total body irradiation (TBI) for patients with 
hematologic malignancies ................................................................................................................... 11 
8.1.5. 
Preparative Regimen for patients with aplastic anemia .............................................. 11 
8.2. 
Stem Cell Transplantation (Day 0) ......................................................................................... 12 
8.2.1. 
Cord blood: .............................................................................................................................. 12 
8.2.2. 
Haploidentical donor:............................................................................................................ 12 
8.3. 
GVHD Prophylaxis: .................................................................................................................... 12 
9. 
BIOSTATISTICAL CONSIDERATIONS ...................................................................................... 13 
9.1. 
Methods of Statistical Analysis .............................................................................................. 13 
9.2. 
Sample Size ................................................................................................................................. 13 
9.3. 
Stopping Rules for Safety ........................................................................................................ 13 
10. 
DATA AND SAFETY MONITORING ........................................................................................ 15 
10.1. 
Safety Monitoring and Oversight ....................................................................................... 15 
11. 
REPORTING ................................................................................................................................. 17 

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11.1. 
Treatment Related Serious Adverse Events ................................................................... 17 
11.2. 
Reports at the time of continuing IRB review................................................................. 17 
11.3. 
Reporting to Miltenyi Biotec, Inc. ...................................................................................... 17 
11.4. 
Reporting to the FDA ............................................................................................................ 17 
11.4.1. 
Expectant Outcomes ......................................................................................................... 18 
11.5. 
Data Management .................................................................................................................. 19 
11.6. 
Protocol Monitoring - Quality Control and Quality Assurance .................................. 20 
12. 
HUMAN SUBJECT PROTECTIONS ........................................................................................ 21 
12.1. 
Rationale for Subject Selection .......................................................................................... 21 
12.2. 
Recruitment ............................................................................................................................. 21 
12.3. 
Participation of Children ...................................................................................................... 21 
12.4. 
Hazards and Discomforts .................................................................................................... 21 
12.5. 
Informed Consent Processes and Procedures .............................................................. 21 
13. 
CliniMACS® CD34 Reagent System (see current Investigator’s Brochure) .................... 22 
13.1. 
Investigational Product ........................................................................................................ 22 
13.2. 
Physical, Chemical and Toxicological Information ....................................................... 23 
13.3. 
Safety Testing of CliniMACS® System Components ................................................... 24 
13.4. 
Overall Safety of the CliniMACS® CD34 Reagent System .......................................... 24 
REFERENCES ......................................................................................................................................... 28 
 
 
 
 
 
 
 
 
 
 

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STATEMENT OF COMPLIANCE 
 
This is an investigator-initiated study.  The principal investigator (PI), Jonathan Gutman, 
MD, is conducting the study.  University of Colorado is acting as the sponsor.   
 
The trial will be carried out in accordance with Good Clinical Practice (GCP) as required 
by applicable United States (US) laws and applications, including but not limited to United 
States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 812).  
 
The PI will assure that no changes to the protocol will take place without documented 
approval from the Institutional Review Board (IRB). All personnel involved in the conduct 
of this study have completed Human Subjects Protection Training.  
 
I agree to ensure that all staff members involved in the conduct of this study are informed 
about their obligations in meeting the above commitments.  
 
 
 
Principal Investigator (Sponsor Investigator):   Jonathan Gutman, MD  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Print/Type Name  
 
 
Signed:   
 
 
 
 
 
 
 
 
 
 
 
 
 
Date:   
 
 
 
 
 
 
 
 
 

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1. SUMMARY 
Allogeneic hematopoietic stem cell transplantation (aHSCT) from an HLA-
matched related donor (MRD) can cure patients with hematologic disorders.  
Unfortunately, many patients with these disorders lack a MRD. For such patients, 
transplantation using unrelated umbilical cord blood (UCB) has been utilized as an 
alternative donor transplant strategy. The advantages of UCB transplant (UCBT) 
include the ease and rapidity of availability, requirement of less than perfect HLA 
match, and lower rates of graft versus host disease compared to bone marrow or 
peripheral blood stem cell transplants.  The major disadvantage of UCB 
transplantation in adults is the limited number of nucleated cells contained within the 
cord unit resulting in prolonged neutropenia which contributes to infection and 
transplant related mortality (TRM). In order to harness the advantage of UCB 
availability and to overcome the disadvantage of delayed neutrophil recovery, co-
administration of unrelated UCB and highly purified haploidentical peripheral blood 
CD34+ cells from a related donor promotes rapid engraftment and reduce TRM 
secondary to prolonged neutropenia associated with conventional UCBT 1-12. 
Miltenyi Biotec’s CliniMACS® CD34 Reagent System was approved as a 
Humanitarian Use Device (HUD) by the U.S. FDA. The approved label indication is 
“The CliniMACS® CD34 Reagent System is indicated for processing hematopoietic 
progenitor cells collected by apheresis (HPC, Apheresis) from an allogeneic, HLA-
identical, sibling donor to obtain a CD34+ cell-enriched population for hematopoietic 
reconstitution following a myeloablative preparative regimen without the need for 
additional graft versus host disease (GVHD) prophylaxis in patients with acute 
myeloid leukemia (AML) in first morphologic complete remission”. While sufficient 
clinical data exists to warrant the use of haploidentical CD34+ selected cells 
combined with single unit umbilical cord blood as a standard of care stem cell 
transplant strategy, the strategy requires CD34+ cells selection using the Miltenyi 
CliniMACS® CD34 Reagent System. Though the Miltenyi CliniMACS® CD34 
Reagent System is used for this purpose at numerous centers1-12, the device is not 
FDA approved for this specific indication. As such this investigational device 
exemption (IDE) protocol supports the use of Miltenyi CliniMACS® CD34 Reagent 
System for preparing CD34+ enriched/T-cell depleted cells from haploidentical 
mobilized peripheral blood. 
The haploidentical donor will be mobilized by G-CSF and undergo apheresis to 
collect CD34+ stem cell product after Miltenyi CD34+ selection. The products will be 
cryopreserved until the time of transplantation. Recipients with hematologic 
malignancies will receive a standard conditioning. After the conditioning regimen, 
subjects will receive an allograft on day 0 containing donor CD34+ cells that have 
been positively selected and T-cell depleted following G-CSF mobilization (goal 
CD34+ cell dose of 3 x 106 CD34+ cells /kg recipient) combined with a single UCB 
unit (serologically matched at ≥ 4/6 HLA loci).  UCB unit will not be manipulated, and 
will be prepared and infused separately following standard of care procedure. 

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This study will evaluate 200 patients with hematologic disorders meeting 
indication for transplant but who do not have MRD. Safety will be monitored 
continuously with a stopping rule for toxicity based on the treatment-related serious 
adverse event rate (TRSAE), defined by failure of Miltenyi CliniMACS® CD34 
Reagent System to select CD34+ cells, and/or failure to engraft that is higher than 
historical control   (<10% for hematologic malignancies and 34% for severe aplastic 
anemia).  
 
2. OBJECTIVE 
To determine safety and efficacy of Miltenyi CliniMACS® CD34 Reagent 
System to select haploidentical CD34+ cells. 
 
3. BACKGROUND 
3.1. 
Review 
Haploidentical donor stem cell transplantation, umbilical cord blood transplant, 
and Haploidentical CD34+ selected cells combined with single unit umbilical cord 
blood transplant: 
Although allogeneic stem cell transplantation (allo-SCT) is a curative option for 
many hematologic disorders, MRD are available for only 30% of the patients needing 
a transplant. Alternative stem cell source includes cord blood or a partially matched 
(haploidentical) family donor. Potential donors for haploidentical stem cell 
transplantation (haplo-SCT) include family members (parents, siblings, or children) 
who share one haplotype with the recipient. Haplo-SCT may have advantages over 
UCBT for the following reasons: 1) higher stem cell dose and rapid hematological 
recovery, 
2) 
feasibility 
of 
repeated 
cell 
collections 
for 
post-transplant 
immunotherapy13,14. The major disadvantage of haploidentical transplant is high rate 
of acute and chronic GVHD without significant immunosuppression, or high rates of 
relapse if significant immunosuppression is administered. 
UCB is also increasingly being used as a source of stem cells, as this allows the 
transplantation of patients without a MRD. Advantages of UCBT include: 1) the 
rapidity by which UCB units can be obtained, 2) low relapse rates, 3) the requirement 
for less than a perfect HLA match, and 4) lower rates of graft versus host disease 
associated with HLA mismatching compared to bone marrow or peripheral blood 
stem cell transplants.  The major disadvantage of UCBT in adults is the limited 
number of nucleated cells contained within the cord unit resulting in prolonged 
neutropenia and failure of engraftment, which contributes to infection and TRM. 
Median time to neutrophil engraftment is prolonged at day 22 (range, 21-25 days), 
with less than 10% graft failure for patients with hematologic malignancies. Median 

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time to neutrophil engraftment for patients with severe aplastic anemia is even 
further prolonged at 42 days (range, 13 to 55 days), with the primary graft failure 
incidence of 34%15-18.  
Engraftment is defined as achievement of absolute neutrophil count (ANC) of 
≥500 cells/μl for three consecutive days.   
Primary graft failure for cord blood transplant (also known as failure to engraft), 
is defined as failure to achieve a neutrophil count (ANC) of ≥500/μl by day 42 post-
transplant and the aplastic appearance of a marrow sample.  
Delayed (secondary) graft failure is defined by failure to achieve a neutrophil 
count (ANC) of ≥500/μl after initial achievement of ANC recovery to >500/μL for three 
consecutive occasions. 
In order to harness the advantage of UCB availability and to overcome the 
disadvantage of delayed neutrophil recovery, co-administration of unrelated 
umbilical cord blood and highly purified haploidentical peripheral blood CD34+ cells 
from a related donor promotes rapid engraftment and reduce TRM secondary to 
prolonged neutropenia associated with conventional UCBT 1-12. 
 
4. SCIENTIFIC AND CLINICAL JUSTIFICATION 
Miltenyi Biotec’s CliniMACS® CD34 Reagent System was approved as a 
Humanitarian Use Device (HUD) by the U.S. FDA. The approved label indication is 
“The CliniMACS® CD34 Reagent System is indicated for processing hematopoietic 
progenitor cells collected by apheresis (HPC, Apheresis) from an allogeneic, HLA-
identical, sibling donor to obtain a CD34+ cell-enriched population for hematopoietic 
reconstitution following a myeloablative preparative regimen without the need for 
additional graft versus host disease (GVHD) prophylaxis in patients with acute 
myeloid leukemia (AML) in first morphologic complete remission.” In this clinical 
protocol, the CliniMACS® CD34 Reagent System will be used for processing 
hematopoietic progenitor cells collected by apheresis (HPC, Apheresis) from an 
allogeneic, HLA-haploidentical, related donor to obtain a CD34+ cell-enriched 
population for hematopoietic reconstitution following a preparative regimen in 
patients with hematologic disorders who require transplant. The procedure used to 
enrich the CD34+ cells will be identical to the procedure used under the HUD.   
While sufficient clinical data exists to warrant the use haploidentical CD34+ 
selected cells combined with single unit umbilical cord blood as a standard of care 
stem cell transplant strategy, the strategy requires T-cell depletion and enrichment 
for CD34+ cells using the Miltenyi CliniMACS® CD34 Reagent System1-12. Miltenyi 
CliniMACS® CD34 Reagent System is used for haploidentical CD34+ selected cells 
combined with single unit umbilical cord blood transplant at numerous centers, but 
the device is not FDA approved for this specific indication.  This protocol supports 

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the use of this device under the proposed IDE. We therefore propose this clinical 
protocol of umbilical cord blood and haploidentical CD34+ cells transplant following 
standard conditioning regimen as treatment for subjects with hematologic disorders.   
 
5. STUDY DESIGN 
This is an investigator initiated clinical study to evaluate the safety and efficacy 
of Miltenyi CliniMACS® CD34 Reagent System to promote engraftment.  
The haploidentical donor will be mobilized by G-CSF and undergo apheresis to 
collect CD34+ selected stem cell product after Miltenyi CD34+ selection. The 
products will be cryopreserved until the time of transplantation.  
Recipients will receive a standard conditioning regimen (Please refer to section 
8 for dosing and schedule). After the conditioning regimen, the subjects will receive 
an allograft on day 0 containing donor CD34+ cells that have been positively 
selected and T-cell depleted following G-CSF mobilization (goal CD34+ cell dose of 
3 x 106 CD34+ cells /kg recipient) combined with a single UCB unit (serologically 
matched at ≥ 4/6 HLA loci).  UCB unit will not be manipulated, and will be prepared 
and infused separately following standard of care procedure. 
 
Figure 1. Study Schema 
 
 Transplant 
recipient 
 Umbilical 
cord blood 
 Haploidentical 
family donor 
 Standard 
Follow up 
visits 
Standard conditioning 
regimen 
G-CSF 
 5 day 
Stem cell 
apheresis 
Day 0 
Standard GVHD prophylaxis 
 
Daily assessment  
until engraftment  
and discharge 
CD34 selection using 
Miltenyi CliniMACS  

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6. ELIGIBILITY ASSESSMENT 
6.1. Inclusion Criteria - Recipient  
• Ages 18-80 years inclusive 
• Diagnosed with high risk hematologic disorders warranting stem cell transplant 
per institutional standard of care 
• Lack HLA-identical related donor  
• Availability of at least one HLA- haploidentical (i.e. ≥ 5/10 and  ≤ 8/10 HLA 
match) related donor (HLA-A, B, C, DR, and DQ loci) who is available to donate 
CD34+ cells. 
• Availability of at least one 4/6 HLA-matched (HLA-A, B, and DR loci) cord blood 
unit from the National Marrow Donor Program (NMDP). The cord blood unit 
must contain a minimum TNC (prior to thawing) of at least 2x107 cells per 
kilogram of recipient body weight  
• Ability to comprehend the nature of the treatment  
6.2. Exclusion Criteria – Recipient (any of the following) 
• HLA identical (6/6) related donor available and readily accessible at time of 
transplantation evaluation 
• Any patient not meeting institutional standard guidelines for transplant eligibility 
6.3. Donor Eligibility 
• Follow standard of care donor eligibility procedure, outlined in the standard 
operation procedure (SOP). 
• Deferral of donors that:    
1) Have traveled to active Zika virus zones (if donor happed to travel to 
Zika zone, patient will discuss with treating physician and sign medical 
necessity form). 
2) Are at potential risk of transmissible spongiform encephalopathy (TSE), 
including Creutzfeldt–Jakob disease (CJD), based on family and travel 
history 
 

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7. CLINICAL EVALUATION OF THE TRANSPLANT RECIPIENT 
All clinical care will be provided according to institutional standard practice for stem 
cell transplants. 
8. TREATMENT PLAN 
Patients will be treated according to the standard of care treatment plan outlined 
below. 
8.1. Preparative Regimens 
8.1.1. Preparative Regimen for patients with hematologic malignancies 
• Fludarabine (Flu): 30 mg/m2/dose IV infusion administered once daily for 
5 doses on Days -6, -5, -4, -3, -2 (total dose of 150 mg/m2).  
• Cyclophosphamide (Cy): 50 mg/kg/dose IV infusion administered once 
daily for 1 dose on Days -6 (total dose of 50 mg/kg).  
• Thiotepa: 5mg/kg/dose IV infusion administered once daily for 2 doses on 
Days -5, -4 (total dose of 10 mg/kg). 
• Total body irradiation (TBI):  Timing and dose:  4 Gy of total body 
irradiation (TBI) will be administered in 2 fractions over 2 days on days -2 
to -1. 
8.1.2. Medium intensity preparative regimen for patients with hematologic 
malignancies 
• Fludarabine (Flu): 30 mg/m2/dose IV infusion administered once daily for 
5 doses on Days -6, -5, -4, -3, -2 (total dose of 150 mg/m2).  
• Cyclophosphamide (Cy): 50 mg/kg/dose IV infusion administered once 
daily for 1 dose on Days -6 (total dose of 50 mg/kg).  
• Thiotepa: 5mg/kg/dose IV infusion administered once on day -5 (total dose 
of 5mg/kg). 
• Total body irradiation (TBI):  Timing and dose:  4Gy of total body 
irradiation (TBI) will be administered in 2 fractions over 2 days on days -2 
to -1. 

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8.1.3. Reduced intensity conditioning (RIC) preparative regimen for patients 
with hematologic malignancies who cannot tolerate high intensity 
regimen 
• Fludarabine (Flu): 40 mg/m2/dose IV infusion administered once daily for 
5 doses on Days -6, -5, -4, -3, -2 (total dose of 200 mg/m2).  
• Cyclophosphamide (Cy): 50 mg/kg/dose IV infusion administered once 
daily for 1 dose on Days -6 (total dose of 50 mg/kg).  
• Total body irradiation (TBI):  Timing and dose:  3 Gy of total body 
irradiation (TBI) will be administered on day -1. 
8.1.4. Preparative Regimen with high dose total body irradiation (TBI) for 
patients with hematologic malignancies 
• Fludarabine (Flu): 25 mg/m2/dose IV infusion administered once daily for 
3 doses on Days -7, -6, -5 (total dose of 75 mg/m2).  
• Cyclophosphamide (Cy): 60 mg/kg/dose IV infusion administered for 2 
doses on Days -6, -5 (total dose of 120 mg/kg).  
• Total body irradiation (TBI):  Timing and dose:  12Gy of total body 
irradiation (TBI) will be administered twice a day over 3 days on days -3 to 
-1. 
8.1.5. Preparative Regimen for patients with aplastic anemia 
• Cyclophosphamide (Cy): 60 mg/kg/dose IV infusion administered once 
daily for 2 dose on Days -7, -6 (total dose of 120 mg/kg).  
• Fludarabine (Flu): 25 mg/m2/dose IV infusion administered once daily for 
5 doses on Days  -5, -4, -3, -2, -1 (total dose of 125 mg/m2).  
• Atgam 40mg/kg/dose for 4 doses on Days -5, -4 , -3,  -2 (total dose of 160 
mg/kg). 
• Total body irradiation (TBI):  Timing and dose:  4 Gy of total body 
irradiation (TBI) will be administered over 1 day on Day  -1. 

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8.2. Stem Cell Transplantation (Day 0) 
 
8.2.1. Cord blood: 
Unit will be selected and prepared following institutional standard 
guidelines:  Minimum total nucleated cells (TNC) (prior to thawing) of 2 x 
107 per kilogram of recipient body weight. Confirmatory typing reveals a 
minimum antigen level match in 4/6 HLA loci. Shipment of the cord blood 
unit will not be requested until the G-CSF mobilized T-cell depleted graft 
collected from the haploidentical donor contains a suitable number of 
CD34+ cells (≥2 x 106/kg) and CD3+ T-cells (<1 x 104 CD3+ cells/ kg). 
8.2.2. Haploidentical donor:  
The target, minimum and maximum cell doses (given in terms of recipient 
body weight) are: 
CD34+ cells 
Target dose: 3 x 106/kg 
Minimum for transplant 
2 x 106/kg 
Maximum 
5 x 106/kg 
CD3+ cells 
Target dose: ≤ 5 x 103/kg 
Maximum 
1 x 104/kg 
Minimum 
None 
 
8.3. GVHD Prophylaxis:   
Cyclosporine:  Cyclosporine will be initiated at a dose of 2.5 mg/kg IV BID 
starting on day -3. The cyclosporine dose will be adjusted to obtain goal 
therapeutic drug levels of 200-400 ng/mL.  When the recipient is able to take 
oral medications, cyclosporine will be give PO in two divided doses every 12 
hours, and will be continued for at least 6 months.     
 
Mycophenolate mofetil (MMF):  1 gram administered orally or intravenously 
three daily starting day 0. When the recipient is able to take oral medications, 
MMF will be given PO in two divided doses every 12 hours, and will be 
continued until around day 30 and tapered off.   
 

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9. BIOSTATISTICAL CONSIDERATIONS 
Primary Endpoint: To determine the rate of successful engraftment of patients 
who received haploidentical CD34+ selected cells combined with single unit 
umbilical cord blood transplant.  Failure defined as failure of Miltenyi CliniMACS® 
CD34 Reagent System to select CD34+ cells, and/or failure to engraft by day 42.  
9.1. Methods of Statistical Analysis  
  There will be 200 individuals who may be included in this study of safety analysis.  
The primary outcome of this study is the proportion of individuals who have had a 
successful engraftment by the end of the 42 day period. Assuming a sample size 
of 200, if there is an engraftment success rate of 75% (or a failure rate of 25%), 
there would be a resulting 95% confidence interval of 63% to 87% (that is a width 
of 12% on either side of 75% successful engraftments). 
 
9.2. Sample Size 
A maximum of 200 subjects will be evaluated for safety analysis.  
 
9.3. Stopping Rules for Safety 
 Safety will be monitored continuously with a stopping rule for toxicity based on 
the treatment-related serious adverse event rate (TRSAE). Safety monitoring will 
continue until engraftment. 
 Stopping rule for TRSAE is defined as failure of Miltenyi CliniMACS® CD34 
Reagent System to select CD34+ cells, and/or failure to engraft. The number of 
TRSAE which will end the study are based on an acceptable rate of 10% of 
patients with hematologic malignancies and 20% of patients with severe aplastic 
anemia having adverse events. 
 
 
 
 
 
 

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Table 1: Stopping rules for patients with hematologic malignancies.  
Number of 
subjects in the 
experiment 
Stop if the number of subjects who 
develop any TRSAE reaches 
≤5 
3 
≤10 
4 
≤15 
5 
≤20 
6 
≤26 
7 
≤32 
8 
≤39 
9 
≤46 
10 
 
The termination conditions which yield a probability of termination of 5% 
 when the rate of adverse events is at 10%. 
 
 
Table 2: Stopping rules for patients with severe aplastic anemia. 
Number of 
subjects in the 
experiment 
Stop if the number of subjects who 
develop any TRSAE reaches 
≤3 
3 
≤4 
4 
≤8 
5 
≤11 
6 
≤14 
7 
≤17 
8 
≤20 
9 
≤23 
10 
≤27 
11 
≤30 
12 
≤34 
13 
≤38 
14 
≤41 
15 
≤45 
16 
≤49 
19 
 
The termination conditions which yield a probability of termination of 5% 
when the rate of adverse events is at 20%. 

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10. 
DATA AND SAFETY MONITORING 
10.1. Safety Monitoring and Oversight 
The sponsor investigator will be responsible for monitoring the trial per the 
trial monitoring plan, in addition to overseeing the safety and efficacy of the trial 
including any specimens collected, executing the data and safety monitoring 
(DSM) plan, and complying with all reporting requirements to local and federal 
authorities. This oversight will be accomplished through additional oversight 
from the Data and Safety Monitoring Committee (DSMC) at the University of 
Colorado Cancer Center (CU Cancer Center). The DSMC is responsible for 
ensuring data quality and study participant safety for all clinical studies at the 
CU Cancer Center, which is the coordinating institution of this trial. A summary 
of the DSMC’s activities is as follows:  
• Conduct of internal audits  
• Ongoing review of all unanticipated adverse device effects, serious adverse 
events (SAEs) and unanticipated problems (UAPs)  
• May submit recommendations for corrective actions to the CU Cancer 
Center’s Executive Committee  
Per the CU Cancer Center Institutional DSM Plan, SAEs and UAPs are 
reported to the DSMC, IRB and the sponsor investigator per protocol. All SAEs 
and UAPs including unanticipated adverse device effects are to be reported to 
the DSMC within 7 (for fatal or life-threatening events) or 15 (non-life-
threatening events) calendar days of the sponsor investigator receiving 
notification of the occurrence. 
Each subject’s treatment outcomes will be discussed by the site PI and 
appropriate staff at weekly meetings. Data regarding number of subjects, 
adverse device effects, treatment modifications and treatment responses will 
be discussed and documented in the meeting’s minutes.  
The sponsor investigator will provide a DSM progress report to the CU 
Cancer Center DSMC on a recurring basis (either every six or twelve months 
based on DSMC vote). The DSM report will include a protocol summary, 
current enrollment numbers, summary of adverse device effects to include 

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specific unanticipated adverse device effects, SAEs, UAPs and AEs, any 
treatment modifications, all protocol deviations, and protocol amendments. The 
DSM report submitted to the DSMC will also include, if applicable, the results 
of any efficacy data analysis conducted. Results and recommendations from 
the review of this progress report by the DSMC will then be provided to the 
sponsor investigator in a DSMC review letter. The sponsor investigator is then 
responsible for ensuring this letter is submitted to the site’s IRB of record at the 
time of IRB continuing review.  
 
Site monitoring visits will be performed by the sponsor investigator’s 
authorized representative on a regular basis, pursuant to the Monitoring Plan. 
During these visits, information recorded on the CRFs will be verified against 
source documents. Additional computer programs that identify selected 
protocol deviations, out-of-range data, and other data errors within the 
electronic data entry may also be used to help monitor the study. As necessary, 
requests for data clarification or correction will be sent to the appropriate site 
PI. Independent auditors from the sponsor investigator’s authorized 
representative will be allowed by the site’s PI to audit. In addition, audits may 
be conducted at any time by appropriate regulatory authorities and/or the IRB. 
 
Miltenyi Biotec, Inc.: An annual progress report, any amendments to the 
protocol, and any change in the status of the protocol will be forwarded to 
Miltenyi Biotec, Inc to:  
 
 
 
 
General Manager, US Clinical Operations 
Miltenyi Biotec, Inc. 
85 Hamilton Street  
Cambridge, MA 02139- 4524 
 
FDA: An annual progress report, any amendments to the protocol, and any 
change in the status of the protocol will be forwarded to FDA to:   
U.S. Food and Drug Administration 
Center for Biologics Evaluation and Research 
Document Control Center 

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10903 New Hampshire Avenue 
WO71, G112 
Silver Spring, MD 20993-0002 
 
In compliance with 21 CFR 812.150(a), the principal investigator will submit the 
following reports: unanticipated adverse device effects, withdrawal of IRB 
approval, progress report, deviations from the investigational plan, if the 
investigator uses a device without obtaining informed consent, and a final 
report. 21 CFR 812.150(a) specifies time frames for these reports. 
11. 
REPORTING 
11.1. Treatment Related Serious Adverse Events 
TRSAE is defined as failure of Miltenyi CliniMACS® CD34 Reagent System to 
select CD34+ cells, and/or failure to engraft.  
Reports to the IRB:  The PI must report TRSAE as soon as possible 
but not more than 5 days after the PI first learns of the event. 
For device, the PI must report to the IRB any deviation from the 
investigational plan to protect the life or physical well-being of a subject 
in an emergency as soon as possible, but no later than 5 working days. 
11.2. Reports at the time of continuing IRB review 
At continuing review, the PI will provide to the IRB a summary of:  All TRSAE 
11.3. Reporting to Miltenyi Biotec, Inc. 
Reports of any TRSAE observed during the clinical trial and for which there is 
a relationship with the use of the Miltenyi CliniMACS CD34 Selection System 
and/or its components will also be forwarded as soon as possible to Miltenyi 
Biotec. 
 
 
 
General Manager US Clinical Operations 
 
 
 
Miltenyi Biotec, Inc. 
 
 
 
85 Hamilton Street  
 
 
 
Cambridge, MA 02139- 4524 
11.4. Reporting to the FDA 
IDE Unanticipated Adverse Device Effects Report (Refer to 21 CFR 
812.50): The IDE sponsor, Jonathan Gutman, MD, will report suspected 

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unexpected serious adverse reaction (SUSARs), and any unanticipated 
adverse device effect observed during the clinical trial for which there is a 
relationship with the use of the Miltenyi CliniMACS CD34 Selection System 
and/or its components on the conduct of the study to the FDA as soon as 
possible, but in no event later than 10 working days after the sponsor learns of 
the effect. Thereafter, the sponsor shall submit such additional reports 
concerning the effects as FDA requests. 
 
Any positive sterility test result will be reported to FDA within 30 calendar 
days after initial receipt of the positive culture test results.   
 
FDA Annual Reports (Refer to 21 CFR 812.150):  The study sponsor will 
submit progress reports at regular intervals and at least annually to the FDA. 
All communications to the FDA will be submitted to: 
U.S. Food and Drug Administration 
Center for Biologics Evaluation and Research  
Document Control Center 
10903 New Hampshire Avenue 
WO71, G112 
Silver Spring, MD 20993-0002 
11.4.1. 
Expectant Outcomes 
The following are expected events or outcomes for the any type of 
transplant recipient and will be documented in the subject’s medical record.  
However, only TRSAE as defined in Section 11.1 will be reported for the 
purpose of this study. 
• Renal insufficiency 
• Hepatic insufficiency 
• Transient cardiac arrhythmias 
• Transient cardiac insufficiency 
• Pulmonary insufficiency 
• Neutropenia and its complications 
• Thrombocytopenia and its complications 
• Anemia and its complications 
• Transfusion reactions 

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• Treatable infections from bacteria, viruses, protozoa and fungi 
• Late effects of transplant regimens including: chronic fatigue, 
cataracts, infertility, growth impairment, hypothyroidism, bone 
complications, and dental caries 
• Headache, insomnia, psychosis, mood changes, disorientation, 
seizures from metabolic imbalance 
• Nausea, vomiting, diarrhea, mucositis, weight loss, dry mouth, 
hiccoughs, constipation 
• Well-characterized drug reactions - allergic manifestations, "red 
man" syndrome, steroid effects 
• Well-characterized drug side effects from drugs used routinely in 
transplant recipients (e.g.; preparative regimen chemotherapy, 
immunosuppressive drugs, antimicrobials)  
• Common side effects of antiemetics, analgesics, anti-inflammatory 
agent and known complications of steroid therapy 
• Complications from intravenous catheters, thrombotic occlusion, 
infection, local reactions, cardiac arrhythmia 
 
Should any of the above events result in death while a subject is being 
followed for engraftment, it will be documented in the electronic Case 
Report Form (eCRF) and study record as the subject not completing the 
study or reaching engraftment, if applicable.  The diagnosis at death will 
also be captured in the study record and eCRF. 
 
11.5. Data Management 
The PI will be responsible for overseeing entry of data into an in-house 
password protected electronic system and ensuring data accuracy, 
consistency and timeliness. Laboratory values from referring home physicians 
will be entered into the system. The principal investigator, associate 
investigators/research nurses and/or a contracted data manager will assist with 
the data management efforts to ensure that data is verifiable and evaluable. 
   

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Neither individual personal identifiers nor the key linking coded data to 
individuals will be released to Miltenyi Biotec, Inc. without prior IRB approval 
and an executed MTA or CTA. 
 
End of study procedures:  Data will be stored in restricted access area and in 
a password protected database until it is no longer of scientific value. Identifiable 
data will not be sent outside University of Colorado without prior IRB approval or 
appropriate conditions for disclosure outlined in the executed MTA or CTA. 
Loss or destruction of data:  Should we become aware that a major breech in 
our plan to protect patient confidentiality and trial data has occurred, the IRB will 
be notified. 
 
CIBMTR: For the purposes of quality assurance (i.e. accreditation of the 
Transplant program), data will be released to the Center for International Blood 
and Marrow Transplant Research (CIBMTR) in accordance with federally 
mandated policies and procedures. 
 
11.6. Protocol Monitoring - Quality Control and Quality Assurance  
Site monitoring visits will be performed by the sponsor investigator’s 
authorized representative on a regular basis, pursuant to the Monitoring Plan. 
During these visits, information recorded on the CRFs will be verified against 
source documents.  Additional computer programs that identify selected 
protocol deviations, out-of-range data, and other data errors within the 
electronic data entry may also be used to help monitor the study.  As necessary, 
requests for data clarification or correction will be sent to the appropriate site 
PI.  
Independent 
auditors 
from 
the 
sponsor 
investigator’s 
authorized 
representative will be allowed by the site’s PI to audit.  In addition, audits may 
be conducted at any time by appropriate regulatory authorities and/or the IRB. 

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12. 
HUMAN SUBJECT PROTECTIONS 
Patients will be treated according to the standard of care treatment plan.  
The investigators will protect the rights and welfare of human research 
subjects set forth in 45 C.F.R. Part 46 and 21 C.F.R Part 50, Protection of 
Human Subjects. 
12.1. Rationale for Subject Selection 
This protocol is open to males and females from all ethnic and racial groups.  
12.2. Recruitment 
The study will be listed on clinicaltrials.gov, clinical center research studies. 
12.3. Participation of Children  
Patients less than 18 years of age will not be eligible in this study. 
12.4. Hazards and Discomforts 
Related to the CliniMACS CD34 Reagent Systems:  
Theoretical risks to the patient could include system failure, operator error, or 
patient reaction to selected product components (i.e. residual amounts of 
unbound CliniMACS CD 34 Reagent, Iron dextran, or human anti-mouse 
antibodies). Specifically, theoretical risks are 1) failure of Miltenyi CliniMACS® 
CD34 Reagent System to select CD34+ cells, and/or 2) failure to engraft. For full 
text see Investigator’s brochure for Miltenyi CliniMACS CD34+ system, Version 
7, dated 6/13/2011, section 6, Summary and Guidance for the Investigator). 
 
Transplant procedure will be carried out as a standard of care per 
institution guidelines. 
12.5. Informed Consent Processes and Procedures 
Miltenyi CliniMACS® CD34 Reagent System will be explained to the patient. 
The research objectives of this trial, the procedure and its attendant risks and 
discomforts will be carefully explained to the subject and a signed informed 
consent document will be obtained prior to entry onto this study.  The PI and 
delegated personnel will lead this discussion. 
 

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13. 
CliniMACS® CD34 Reagent System (see current Investigator’s Brochure) 
13.1. Investigational Product 
Miltenyi Biotec’s CliniMACS® CD34 Reagent System was approved as a 
Humanitarian Use Device (HUD) by the U.S. FDA. The approved label 
indication is “The CliniMACS® CD34 Reagent System is indicated for 
processing hematopoietic progenitor cells collected by apheresis (HPC, 
Apheresis) from an allogeneic, HLA-identical, sibling donor to obtain a CD34+ 
cell-enriched population for hematopoietic reconstitution following a 
myeloablative preparative regimen without the need for additional graft versus 
host disease (GVHD) prophylaxis in patients with acute myeloid leukemia 
(AML) in first morphologic complete remission. 
In this clinical protocol, the CliniMACS® CD34 Reagent System will be used 
for processing hematopoietic progenitor cells collected by apheresis (HPC, 
Apheresis) from an allogeneic, HLA-haploidentical, sibling donor to obtain a 
CD34+ cell-enriched population for hematopoietic reconstitution following a 
preparative regimen in patients with severe hematologic disorders who require 
transplant. The procedure used to collect the cells will be identical to the 
procedure used under the HUD. 
 
The CliniMACS® CD34 Reagent System is a medical device that is used 
in vitro to select and enrich specific cell populations. When using the 
CD34 Reagent, the system selects CD34+ cells from heterogeneous 
hematological cell populations for transplantation in cases where this is 
clinically indicated. The CliniMACS CD34 Reagent System is comprised 
of four primary components: 
• CliniMACS CD34 Reagent: a sterile monoclonal antibody reagent 
specific for CD34+ cells  
• CliniMACS plus Instrument: a software controlled instrument that 
processes the blood sample (cell product)  
• CliniMACS Tubing Sets: single-use, sterile, disposable tubing sets with 
two proprietary cell selection columns (CliniMACS Tubing Set and 

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CliniMACS Tubing Set LS)  
• CliniMACS PBS/EDTA Buffer: a sterile, isotonic phosphate-buffered, 
1 mM EDTA, saline solution, used as external wash and transport fluid 
for the in vitro preparation of blood cells. 
 
 
13.2. Physical, Chemical and Toxicological Information 
• CD34 Reagent Description:  the CliniMACS CD34 Reagent is a dark amber, 
nonviscous, colloidal solution containing the antibody conjugate in buffer. 
The conjugate consists of a monoclonal antibody towards the class II 
epitope of the human CD34 antigen. The murine monoclonal IgG1 antibody 
is covalently linked to dextran beads that have an iron oxide/hydroxide core 
and are superparamagnetic. 
• Safety testing of the CD34 Monoclonal Antibody:  cell banking, cell culture, 
as well as subsequent purification of the antibody, follow the applicable 
current international guidelines as described in Section 4 of the 
Investigator’s brochure for Miltenyi CliniMACS CD34+ system, Version 7, 
dated 6/13/2011. The testing of the CD34 Master Cell Bank, the End of 
Production Cells, the CD34 mAb pooled cell culture harvest (unprocessed 
bulk) and the purified CD34 monoclonal antibody (mAb) have been 
completed and the purified CD34 mAb has been released for manufacturing 
of the CD34 Reagent. Additionally, the viral inactivation/removal steps used 
in the purification of the CD34 monoclonal antibody have been validated. 
• Safety testing of the CD34 Reagent: detailed toxicity studies have been 
undertaken to assess the safety of the CD34 Reagent when delivered in 
dosages significantly greater than the projected maximum dosage 
anticipated in clinical use. The testing was performed in accordance with 21 
CFR §58, Good Laboratory Practices for Nonclinical Laboratory Studies. A 
summary of this testing is provided in Table 3. 
 
 

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Table 3: Toxicity studies to assess the safety of the CD34 Reagent 
Summary of Toxicology of the CliniMACS CD34 Reagent 
Test  
Results  
Human Cryosection Cross 
Reactivity Study  
CD34 Reagent specifically reacted with cell types known to 
possess the CD34 antigen. Not considered toxicologically 
significant.  
Interspecies Cross 
Reactivity Study  
CD34 antibody does not cross react with non–human primate 
hematopoietic cells expressing the CD34 antigen. These species 
could be used for safety testing.  
Subchronic Toxicity  
No Toxicity  
Cardiovascular Safety 
Study in Rhesus Monkeys  
No drug-related effects on mean arterial pressure, mean right 
ventricle pressure, cardiac output, ECGs, respiration rate, heart 
rate or cage side observations were noted when escalating doses 
of CD34 Reagent  
Irritation  
No Irritation  
Hemocompatibility 
Compatible with human blood  
Sterility assay of final 
container  
Reproducibly sterile product  
 
13.3. Safety Testing of CliniMACS® System Components 
Instrument, Tubing Sets and PBS/EDTA Buffer - Biocompatibility testing of 
the CliniMACS System components (Tubing Sets and PBS/EDTA Buffer) was 
performed according to ISO 10993. The requirements of ISO 10993 were 
fulfilled for the CliniMACS CD34 Reagent System.   The CliniMACS plus 
Instrument has been tested for electrical safety and the potential for fire, shock, 
explosion, or mechanical damage.  Potential safety issues have been reduced 
by using a design to meet European standards EN 60601-1. It is UL and CSA 
listed and approved. 
 
13.4. Overall Safety of the CliniMACS® CD34 Reagent System 
The results summarized in this Investigator’s Brochure support that 
CliniMACS CD34 Reagent System is sufficiently safe for clinical use with 

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human subjects. The potential application of the CliniMACS CD34 Reagent is 
broad. Infusion of purified CD34+ cells is indicated in a number of clinical 
applications after myeloablative or lymphoablative therapy including reduction 
of tumor cells in the transplant and depletion of T cells for autologous 
(autoimmune diseases) and allogeneic transplantations. 
 
Individual risk analysis on the therapeutically used target cells isolated in 
conjunction with CliniMACS CD34 Reagent System should be addressed by 
each site using these cells. A European safety study, ACS 950101, for the 
CliniMACS System was published in Bone Marrow Transplantation 25; 243-49, 
February 2001. The study was designed to meet European Essential 
Requirements 3 and 14 (MDD 93/42/EEC) and was conducted per EN540 to 
support the CE Marking of the device (received December 1997).  
 
The initial clinical study with the CliniMACS System was conducted in 
subjects undergoing high-dose chemotherapy for breast cancer. The purpose 
of the European Safety Study was to show:  
• 
Suitability of the CD34 Reagent and other CliniMACS components 
for selection of CD34+ cells with high, yield, purity viability and 
safety  
• 
CD34+ cells can safely be administered to subjects after 
myeloablative chemotherapy  
• 
Selected CD34+ cells are effective in reconstituting the 
hematopoietic system after myeloablative chemotherapy  
• 
Rate of device failures  
 
Cells were isolated from leukapheresis products from sixty-five subjects 
enrolled in the study. Fifty-four subjects received selected CD34+ cells and 
fifty-two were evaluable for engraftment as summarized in the table below (one 
patient died 5 days post-transplant and prior to engraftment and one patient did 
not recover platelet counts even after back-up cells were infused). All subjects 
receiving selected cells completed 60 and 100-day follow-up after infusion, 

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during which time their hematological and immune status were monitored, as 
was HAMA production. A summary of the results of the European Clinical Trial 
is provided below.  
Table 4: European Clinical Trial results 
Time to Hematological Engraftment After Infusion of CliniMACS Selected CD34+ Cells 
Time to Engraftment (Days)  
Platelets (≥ 20 x 109/L)  
Neutrophils (≥ 500/uL)  
Median (Kaplan Meier)  
SD  
Quartile range (Kaplan Meier)  
Range  
Number  
11.6  
6.05  
10.0-12.0  
8-29  
52  
9.1  
5.81  
8.0-10.0  
8-11  
52  
 
The following conclusions were made regarding this clinical study:  
• The CliniMACS CD34 Reagent System selects CD34+ cells from 
heterogeneous hematological cell populations. The resulting CD34+ 
product is of high purity (median of 96.1 %, range 27.4 – 99.4 %); the 
median recovery of CD34+ cells was 52.3 % (range 15.2 – 146.3%). 
The reported performance results are similar to those seen in pre-
clinical studies.  
• Infusion of selected, autologous CD34+ cells after high dose 
chemotherapy resulted in rapid engraftment (see Table 4). These 
data are comparable to previously reported results, using bone 
marrow or peripheral blood cells as stem cell source. Following 
cyclophosphamide, thiotepa and carboplatin (CTCb), Weaver et al. 
reported median times to platelet and neutrophil engraftment of 9 
days (range 0-53 days) and 9 days (range 5-26 days), respectively. 
Also after CTCb, Elias et al., reported median times to platelet and 
neutrophil recovery of 12 days (range 8-134 days) and 14 days 
(range 10-57 days), respectively19,20.  
• The selection process has no discernable effect on cell viability or 

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sterility.  
• There were no adverse events or device malfunctions reported as 
related to the infusion of the cells or use of the CliniMACS CD34 
Reagent System. None of the subjects were reactive for HAMA post 
infusion. There were no reports of late engraftment failure or 
evidence of delayed immune reconstitution.  
 
 
 
 
 
 

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