A Phase 2 Study of Ex Vivo TCR αβ T Cell Depletion for Graft-Versus-Host Disease (GVHD) Prophylaxis in Mismatched Donor Peripheral Blood Stem Cell Transplantation for Hematologic Malignancies
Phase: PHASE2
Conditions: Hematologic Malignancy
Sponsor: Dana-Farber Cancer Institute

Page 1
NCI Protocol #:
N/A
DF/HCC Protocol #: 18-270
TITLE: A Phase 2 Study of ([9LYR7&5Įȕ T Cell Depletion for Graft-Versus-Host Disease 
(GVHD) Prophylaxis in Mismatched Donor Peripheral Blood Stem Cell Transplantation for 
Hematologic Malignancies
Coordinating Center:
Dana-Farber Cancer Institute
Principal Investigator (PI):
Vincent T. Ho, MD 
Dana-Farber Cancer Institute
Vincent_Ho@dfci.harvard.edu
Statistician:
Study Coordinator:
Haesook Kim, PhD 
Name: Evelyn Hipolito
Dana Farber Cancer Institute
Dana Farber Cancer Institute 
Haesook_Kim@DFCI.HARVARD.EDU
Responsible Research Nurse:
Responsible Data Manager:
Dana Breashears, RN/DFCI
Jennifer Brock, RN/DFCI
Susan Stephenson, RN/DFCI
Agent(s): Mobilized peripheral blood stem cells from 8/10 or 9/10 matched related or unrelated 
donors depleted of TCRDE T cells using the Miltenyi CliniMACS system
IDE #: 18107
IDE Sponsor: Vincent T. Ho, MD
Device Name: &OLQL0$&67&5Įȕ5HDJHQW.LW
Original / Protocol Version Date: June 8, 2017
Current version date: June 8, 2017

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SCHEMA 
This is a single-arm, two-VWDJHSKDVH,,VWXG\RIH[YLYRĮȕ7&57FHOOGHSOHWHG7&'
peripheral blood stem cell transplantation (PBSCT) as a GVHD prophylaxis for patients with 
hematologic malignancies undergoing allogeneic PBSCT. The primary objective is to evaluate 
the VDIHW\DQGHIILFDF\RIH[YLYRĮȕ7&57&'IRUSDWLHQWVUHFHLYLQJP\HORDEODWLYH3%6&7
IURPUHODWHGRUXQUHODWHGPLVPDWFKHGRUGRQRU7KHSUHPLVHLVWKDWH[YLYRĮȕ
TCR TCD will reduce the incidence of grade 3-4 acute GVHD and/or death. The target accrual 
goal is 25 evaluable patients over 3.5-4 year period. All surviving patients will be followed for at 
least 100 days. Patients who meet the eligibility criteria but deemed unevaluable per Section 3.2 
will be excluded from the study.

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TABLE OF CONTENTS
SCHEMA.........................................................................................................................................2 
1. 
OBJECTIVES......................................................................................................................7 
1.1 
Study Design............................................................................................................7 
1.2 
Primary Objectives...................................................................................................7 
1.3 
Secondary Objectives...............................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Study Disease: GVHD Prophylaxis.........................................................................8 
2.2 
IDE Agent ................................................................................................................9 
2.3 
Rationale ..................................................................................................................9 
3. 
PARTICIPANT SELECTION...........................................................................................11 
3.1 
Eligibility Criteria..................................................................................................10 
3.2 
Exclusion Criteria ..................................................................................................11 
3.3 
Inclusion of Women and Minorities ......................................................................12 
4. 
REGISTRATION PROCEDURES ...................................................................................13 
4.1 
General Guidelines for DF/HCC Institutions ........................................................13 
4.2 
Registration Process for DF/HCC Institutions.......................................................13 
4.3 
General Guidelines for Other Investigative Sites ..................................................13 
4.4 
Registration Process for Other Investigative Sites.................................................13 
5. 
TREATMENT PLAN........................................................................................................13 
5.1 
Preparative Regimens ............................................................................................13 
5.2 
Procurement of allogeneic PBSC...........................................................................14 
5.3 
T cell depletion of allogeneic PBSC using Miltenyi Clinimacs ............................15 
5.4 
CD34+ and alpha/beta T cell doses for graft composition ....................................15 
5.5 
Pharmacologic GVHD prophylaxis.......................................................................17 
5.6 
Growth Factor Support ..........................................................................................17 
5.7 
Supportive care .....................................................................................................18 
5.8 
Seizure Prophylaxis ...............................................................................................18
5.9 
Prophylaxis Against Infections..............................................................................18
5.10 
Intravenous Immune Globulin (IVIG)...................................................................19
5.11 
Hepatic Veno-occlusive Disease (VOD) Prophylaxis...........................................19
5.12 
Immune Monitoring...............................................................................................19
5.13 
Management of GVHD..........................................................................................19
5.14 
Post- transplant maintenance therapy ....................................................................19
5.15 
Criteria for Taking a Participant Off Protocol Therapy.........................................20
5.16 
Duration of Follow Up...........................................................................................20
5.17 
Criteria for Taking a Participant Off Study ...........................................................20

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6. 
ADVERSE EVENTS:LISTS AND REPORTING REQUIREMENTS ...........................21
6.1 
Expected Toxicity of Ablative Chemotherapy .....................................................21
6.2 
Expected toxicity of TBI........................................................................................21
6.3 
Expected Toxicity of TCR DE T depleted allogeneic PBSC transplantation
................................................................................................................................22
6.4 
Adverse Event Characteristics ..............................................................................22
6.5 
Adverse Event Reporting Guidelines ....................................................................24
6.6 
Adverse Event Reporting ......................................................................................24
6.7 
Reporting to the FDA.............................................................................................24
6.8 
Repoting to Hospital Risk Management ...............................................................25
6.9 
Routine Adverse Event Reporting ........................................................................25
6.10 
Expedited Adverse Event Reporting .....................................................................25
7. 
PHARMACEUTICAL ANDS/OR IMAGING AGENT INFORMATION......................25
7.1 
T-Cell Receptor (TCR) alphabeta T-Cell Depletion..............................................25
8. 
STUDY ENDPOINTS.......................................................................................................29 
8.1 
Engraftment............................................................................................................29 
8.2 
GVHD....................................................................................................................29 
8.3 
Disease Relapse .....................................................................................................29 
8.4 
Survival .................................................................................................................29
8.5 
Studies of Immune Reconstitution ........................................................................30
9. 
DATA REQUIREMENTS.................................................................................................30 
9.1 
Post-Transplant Evaluations ..................................................................................30
10. 
DATA REPORTING/ REGULATORY REQUIREMENTS............................................32 
10.1 
Data Reporting.......................................................................................................32 
11.
STATISTICAL CONSIDERATIONS...............................................................................33 
11.1 
Study Design/Endpoints.........................................................................................33 
11.2 
Endpoints ...............................................................................................................33 
11.3 
Accrual...................................................................................................................33 
11.4 
Randomization.......................................................................................................33 
11.5 
Sample Size and Power Calculation ......................................................................34 
11.6 
Monitoring Events .................................................................................................34 
11.7 
Analysis of Primary Endpoints..............................................................................35
11.8 
Reporting and Exclusions ......................................................................................35 
12. 
PUBLICATION PLAN .....................................................................................................36 
13.
REFERENCES ..................................................................................................................37 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................39 

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APPENDIX B
CLINIMACS TCR A/B REAGENT KIT INVESTIGATOR’S 
BROCHURE…..................................................................................................................40

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1. OBJECTIVES
1.1
Study Design
This is a single-arm, two-VWDJHSKDVH,,VWXG\RIH[YLYRĮȕ7&57FHOOGHSOHWHG7&'
peripheral blood stem cell transplantation (PBSCT) as a GVHD prophylaxis for patients with 
hematologic malignancies undergoing allogeneic PBSCT. The primary objective is to 
HYDOXDWHWKHVDIHW\DQGHIILFDF\RIH[YLYRĮȕ7&57&'IRUSDWLHQWVUHFHLYLQJ
myeloablative PBSCT from related or unrelated mismatched (8/10 or 9/10) donor.  The 
SUHPLVHLVWKDWH[YLYRĮȕ7&5 TCD will reduce the incidence of grade 3-4 acute GVHD 
and/or death. The target accrual goal is 25 evaluable patients over 3.5-4 year period. All 
surviving patients will be followed for at least 100 days. Patients who meet the eligibility 
criteria but deemed unevaluable per Section 3.2 will be excluded from the study.
1.2
Primary Objective:
To assess the day 100 severe acute GVHD-free survival rate. Events considered for 
the primary endpoint are grade 3-4 acute GVHD or death from any cause.
1.3
Secondary Objectives:
- Grades II-IV and III-IV acute GVHD
- Chronic GVHD and moderate/severe chronic GVHD
- Chronic GVHD-free survival
- Immune suppression-free survival
- Hematologic recovery (neutrophil and platelet engraftment)
- Immune reconstitution
- Disease relapse
- Transplant-related mortality
- Organ Toxicity (e.g. SOS/VOD and IPS)
- Rates of infections (CMV and EBV reactivation)
- Disease-free and overall survival
- Graft-versus-host disease and relapse free survival (GRFS).  GRFS will be defined 
as alive without having experienced grade 3-4 acute GVHD, moderate/severe chronic 
GvHD, or relapse of underlying malignancy.  
2. BACKGROUND
Unrelated donor hematopoietic stem cell transplantation (HSCT), especially in the HLA mismatched 
setting, is a risky procedure with high mortality compared to transplantation from HLA identical 
sibling donors.  The excess morbidity and mortality after URD HSCT are mainly attributable to 
increased incidence of infections and severe GVHD.  Unfortunately, only about 30% of patients in 
North America will have an HLA-identical sibling, and most patients in need of an allogeneic HSCT 
must rely upon unrelated donors.  With the development of an international network of registries 
worldwide, increasing numbers of unrelated HSCT are performed each year.  For patients who do 

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not have a fully matched unrelated donor, transplantation options are restricted to mismatched 
unrelated donor (8-9/10 or 7/8 match), haplo-identical related donor, or mismatched umbilical cord 
blood transplantation.  As of today, there have not been any published randomized trials to 
demonstrate superiority of any of these 3 options over each other, especially after myeloablative 
conditioning transplantation.
At the DFCI, we have continued to use 7/8 or 9/10 mismatched unrelated donor (or in some cases 1-
2 antigen mismatched related donors) for transplantation in cases where a 10/10 match donor is not 
available.  However, this approach is associated with a higher risk of acute and chronic GVHD, 
higher transplant related mortality and lower overall survival compared to full matched URD HSCT. 
[1] To overcome these hurdles, better techniques for GVHD prevention without exacerbating the 
risk of graft rejection and infections are needed.
2.1
Study Disease: GVHD Prophylaxis 
Since T lymphocytes are crucial mediators of the graft-versus-host reaction, they are the 
primary targets of most strategies aimed at reducing GVHD.  The current accepted 
standard regimen for GVHD prophylaxis involves the administration of methotrexate 
(MTX) and cyclosporine (CyA) or tacrolimus after transplantation.  These pharmacologic 
agents prevent GVHD by suppressing donor T cell function, but are in themselves 
associated with infectious risks and other undesirable side effects.  Over the past two 
decades, investigators have striven to alleviate our dependence from these pharmacologic 
agents by depleting donor T cells from the graft as GVHD prophylaxis.   Although many 
types of T cell depletion have been shown to reduce GVHD, none have been established 
to date that improve overall survival relative to conventional MTX/CyA or 
MTX/tacrolimus.   The few randomized trials comparing ex vivo TCD against standard 
pharmacologic prophylaxis have used broad specificity T cell depletion methods (counter 
flow centrifugal elutriation, T10B9 antibody) and have not demonstrated any 
improvement in long term overall survival after matched unrelated donor marrow 
transplantation, despite lower GVHD, primarily due to higher rates of infection and 
reciprocal increases in disease relapse, especially in patients with chronic phase CML.  
2.1.1 Pharmacologic agents as GVHD prophylaxis
Methotrexate (MTX) was the first efficacious drug used for prevention of GVHD. 
However, MTX at higher doses delayed hematopoietic engraftment and worsen 
mucositis.  With the advent of the calcineurin inhibitors, investigators subsequently found 
that in randomized trials, the combination of a short course of MTX (15 mg/m2 IV day 
+1, 10 mg/m2 IV days +3,6,11) with cyclosporine A (CyA) to be better tolerated and 
superior to using either agent alone.[2, 3]  In the 1990s, tacrolimus (FK506) plus MTX 
also emerged as an effective regimen for GVHD prophylaxis.  In a randomized trial 
involving unrelated donor BMT, patients receiving Tac/MTX had a significantly lower 
incidence of acute GVHD than those receiving CyA/MTX. [4] Based on these 
randomized studies, CyA/MTX or Tac/MTX have become the standard regimens for 
GVHD prophylaxis after allogeneic marrow or stem cell transplantation.  However, acute 

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and chronic GVHD rates are still substantial and remained significant contributors to 
morbidity and mortality.     
2.1.2 Donor T cell depletion (TCD) as GVHD prophylaxis
T cell depletion (TCD) of the donor graft represents an alternative, yet effective means of 
achieving GVHD prophylaxis.  This approach relies primarily upon the ex vivo removal 
of putative effector cells of GVHD from the donor graft prior to transplantation.  Many 
different methods of TCD have been used in human marrow transplantation.  These 
include monoclonal antibodies with [5-8] or without complement,[9] immunotoxins,[10, 
11] lectin agglutination, [12]and counter flow elutriation.[13]  Most of these trials 
demonstrated a decrease in the incidence of acute and chronic GVHD.  Unfortunately, the 
reduction in GVHD after TCD BMT has not resulted in improved overall survival due to 
unexpected increases in incidence of graft failure, post-transplant lymphoproliferative 
disorders (EBV-LPD) due to delayed immune reconstitution, and disease relapse from 
loss of GVL activity. 
Because of the increased genetic disparity and increased risk for GVHD, unrelated donor 
(URD) or mismatched BMT has been grounds for many studies of TCD over past two 
decades.  Cumulative data from the NMDP and IBMTR have indeed shown that TCD is 
associated with a lower incidence of GVHD after unrelated/mismatched donor BMT. [14, 
15]  However, it should be noted that many types of T cell depletion were included in 
these registry analyses, and that not all TCD methods are equivalent in terms of GVHD 
control and disease relapse.   For example, Champlin et al. have reported on the IBMTR 
experience from 870 patients who underwent T-depleted unrelated or mismatched donor 
BMT for leukemia.   They discovered that the leukemia free survival for patients whose 
grafts were T-depleted with “narrow specificity” antibodies (e.g. anti-CD5, CD6, CD8 
etc.) were significantly higher than those whose grafts had been T depleted with “broad 
specificity” antibodies (e.g. anti-CD2, ATG, CAMPATH-1, elutriation, or lectin/SRBC 
agglutination). [14]  These results suggest that in unrelated or mismatched BMT, TCD 
using “narrow specificity” antibodies is not associated with loss of GVL effect, but 
retains the advantage of decreased GVHD compared to conventional BMT.
2.2
IDE Agent 
2.2.1 T-Cell Receptor (TCR) DE T-Cell Depletion
Among the narrow specificity TCD methods, selective depletion of alpha/beta T cells has 
gained recent interest compared to CD34 selection methods since the selective depletion 
of  alpha/beta T cells preserves NK cells and gamma/delta T cells, which may be 
important for preserving innate immunity and the GVL effect. The majority of T cells 
express alpha/beta T cell receptors (TCR), whereas the gamma/delta TCR is expressed by 
only 2-10% of all T cells in human peripheral blood.  However, the gamma/delta T cells 
display a range of innate effector functions, including rapid secretion of chemokines and 

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cytokines, as well as target cell lysis.  Recent studies suggest that gamma/delta T 
lymphocytes are potential beneficial effector cells after allogeneic hematopoietic stem 
cell transplantation.[16]    These findings have spawned interest in the selective depletion 
of alpha/beta T lymphocytes in the graft for allogeneic transplantation.
Locatelli and colleagues have performed a clinical trial of T-cell depleted haplo-HSCT 
using the negative selection of TCRDE T cells (NCT01810120).[17] They have 
transplanted more than 80 children with malignant and non-malignant disorders with 
QHJDWLYHGHSOHWLRQRI7&5Įȕ7FHOOVDQd CD19 B cell using the Miltenyi CliniMACS 
device. The data collected to date clearly demonstrates that this method of graft 
manipulation is reliable and reproducible, leading to around a 4.1-log and 3.1-log 
GHSOHWLRQRIĮȕ7&57FHOOVDQG%FHOOVUHVSHFWively. The residual T-cell content was 
below the safe threshold (i.e. 1x105/Kg recipient body weight) for performing HLA-
haploidentical HSCT without any post-transplant immune suppression in all donor 
depletions performed.  The outcome of children with acuWHOHXNHPLDJLYHQ7&5Įȕ7-cell 
and B-cell depleted haplo-HSCT demonstrated a low transplant-related mortality (less 
than 10%) and an acceptable risk of disease recurrence (on the order of 20%). No patient 
has developed acute GVHD with either gastrointestinal or liver involvement, with skin-
only Grade I-II GVHD being recorded in around 30% of patients. No patient developed 
chronic GVHD.[17]
2.3
Rationale
Unrelated donor hematopoietic stem cell transplantation (HSCT), especially in the HLA 
mismatched setting, is a risky procedure with high mortality compared to transplantation from 
HLA identical sibling donors.  The excess morbidity and mortality after URD HSCT are mainly 
attributable to increased incidence of infections and severe GVHD.  Unfortunately, only about 
30% of patients in North America will have an HLA-identical sibling, and most patients in need 
of an allogeneic HSCT must rely upon unrelated donors.  With the development of an 
international network of registries worldwide, increasing numbers of unrelated HSCT are 
performed each year.  For patients who do not have a fully matched unrelated donor, 
transplantation options are restricted to mismatched unrelated donor (8-9/10 or 7/8 match), 
haplo-identical related donor, or mismatched umbilical cord blood transplantation.  As of today, 
there have not been any published randomized trials to demonstrate superiority of any of these 3 
options over each other, especially after myeloablative conditioning transplantation.
At the DFCI, we have continued to use 7/8 or 9/10 mismatched unrelated donor (or in some 
cases 1-2 antigen mismatched related donors) for transplantation in cases where a 10/10 match 
donor is not available.  However, this approach is associated with a higher risk of acute and 
chronic GVHD, higher transplant related mortality and lower overall survival compared to full 
matched URD HSCT. [1]  To overcome these hurdles, better techniques for GVHD prevention 
without exacerbating the risk of graft rejection and infections are needed.

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3. PARTICIPANT SELECTION
This study will enroll adults (age 18 or higher) with malignant hematological disorders who are 
deemed to be clinically eligible for a myeloablative allogeneic transplantation and who do NOT 
have 10/10 matched donor (related or unrelated) or whose disease status does not allow the 
extensive wait for a 10/10 matched unrelated donor to be identified.
3.1
Eligibility Criteria 
Participants must meet the following criteria on screening examination to be eligible 
to participate in the study:
3.1.1
Diagnoses and stage at time of transplant admission: 
x
Acute leukemia (AML or ALL or MPAL) in first or subsequent remission
x
Myelodysplastic syndromes (MDS) with <10% marrow blasts
x
Myeloproliferative neoplasm (MPN) with <10% marrow blasts
x
CMML with less than 10% marrow blast
x
CML accelerated phase or second or subsequent chronic phase 
x
Non-Hodgkin’s lymphoma in PR or CR2 or beyond
x
Hodgkin lymphoma in PR or CR2 or beyond
3.1.2
Age 18-65 years
3.1.3
Patient has a related or unrelated donor who is 8 or 9 out of 10 match at HLA    
A, B, C, DRB1 and DQB1, based on allele level typing.
3.1.4
Patient ECOG performance status 0-2 (Karnofsky VHH$SSHQGL[$)
3.1.5
Patient deemed to be appropriate candidate for myeloablative conditioning 
transplantation.
3.1.6
Ability to understand and the willingness to sign a written informed consent 
document.
3.2
Exclusion Criteria
Participants who exhibit any of the following conditions at screening will not be 
eligible for admission into the study.

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3.2.1
Patient with active HIV infection
3.2.2
Chronic active hepatitis B infection (HepB surface Ag+ or detectable Hep B 
viral load)
3.2.3
Prior allogeneic hematopoietic stem cell transplantation
3.2.4
Impaired cardiac function- ejection fraction < 40%
3.2.5
Impaired pulmonary function- pretransplant FEV1, DLCO < 50%
3.2.6
Impaired renal function, based on
Serum creatinine > 2.0 mg/dl
3.2.7
Impaired liver function unrelated to primary disease, based on
ALT or AST > 3x ULN, or
Total Bilirubin > 2.0mg/dl (with exception for known or suspected Gilbert’s 
disease)
3.2.8
Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would 
limit compliance with study requirements.
3.2.9
Women who are pregnant or breast feeding.  Women of child bearing 
potential must have a negative serum pregnancy test at study entry.
3.2.10 Participants who are receiving any other investigational agents are eligible but 
such agent must be discontinued before admission for HSCT, and if
resumption of investigation agent is planned after HSCT, this must be 
approved by the study PI.
3.2.11 Participants with known active CNS disease.  CNS disease that has been 
treated is eligible.
3.3
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.

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4. REGISTRATION PROCEDURES  
4.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management 
System (CTMS) OnCore. Registrations must occur prior to the initiation of protocol 
therapy. Any participant not registered to the protocol before protocol therapy begins 
will be considered ineligible and registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will 
complete the protocol-specific eligibility checklist.
Following registration, participants may begin protocol therapy. Issues that would 
cause treatment delays should be discussed with the Overall Principal Investigator 
(PI). If a participant does not receive protocol therapy following registration, the 
participant’s registration on the study must be canceled. Registration cancellations 
must be made in OnCore as soon as possible.
4.2
Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject 
Protocol Registration (SOP #: REGIST-101) must be followed.  
4.3
General Guidelines for Other Investigative Sites
N/A
4.4
Registration Process for Other Investigative Sites
N/A
5. TREATMENT PLAN
5.1
Preparative Regimens- Myeloablative conditioning regimen will consist of one of 2 
regimens, at the choice of the treating physician:  Bu/Flu/Mel or TBI/Flu/Thiotepa.
x
It is recommended that patients with myeloid malignancies receive Flu/Bu/Mel, and 
those with lymphoid malignancies receive Flu/TBI/Thiotepa. 
x
For patients who weigh less than 125% of their ideal body weight (IBW), dosing 
should be based on actual body weight. These dosing rules apply to all chemotherapy 
drugs used in this trial.

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x
)RU3DWLHQWV<HDUVRI$JH
Males IBW = 50 kg + 2.3 kg/inch over 5 feet (60 in)
Females IBW = 45.5 kg + 2.3 kg/inch over 5 feet (60 in)
For patients less than 5 feet, subtract 2.3 kg/inch
x
For patients who weigh greater than or equal to 125% of their IBW, dosing should be 
based on the adjusted ideal body weight (AIBW).
x
Adjusted Ideal Body Weight (AIBW) Formula:
AIBW = IBW + [(0.25) x (actual body weight – IBW)]
5.1.1
Busulfan, Melphalan, Fludarabine Regimen:
x
Days -9 to -7: Busulfan 0.8 mg/kg/dose Q6h IV x 12 doses (total 
9.6mg/kg)
x
Days -6 to -5: Melphalan 70 mg/m2/day x 2 (total 140mg/m2)
x
Days -6 to -2: Fludarabine 25mg/m2/day x 5 (total 125mg/m2)
Busulfan will be infused over 2 hours. Phamacokinetics are not required. 
Melphalan will be infused intravenously over approximately 30 minutes.
Fludarabine will be infused intravenously over approximately 30 minutes
5.1.2
TBI, Fludarabine, Thiotepa (Flu/TBI/Thio) regimen:
x
Days -10 to -7: fractionated TBI total 1375 cGy
x
Days -6 to -5: Thiotepa 5mg/kg/day x 2 days
x
Days -6 to -2: Fludarabine 25mg/m2/day x 5 days (total 125mg/m2) 
Fractionated TBI will be administered at a dose rate of < 20 cGy/minute.
Doses of 125 cGy/fraction are administered at a minimum interval
of 4 hours between fractions, three times/day for a total of 11 doses
(1375 cGy) over 4 days.
Thiotepa will be administered at a dose of 5mg/kg/day IV over 4 hours for two 
consecutive days (Day -6 and -5). 
Fludarabine will be administered at a dose of 25mg/m2/day IV over 30minutes for 5 
days (Day -6 to -2)
5.2
Procurement of allogeneic PBSC
PBSC will be mobilized from the donor in accordance with standard protocol at the 
DFCI (related donors) or at the unrelated donor’s collection center.   Ideally, 2.5 
blood volumes will be processed and a target of 6.0 x106 CD34+ cells/kg recipient 

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weight will be collected in one or two sessions.  The product will be delivered 
immediately by courier to the Dana-Farber Cancer Institute for processing.  The 
PBSC may not be cryopreserved before processing.
5.3
T cell depletion of allogeneic PBSC using Miltenyi Clinimacs
7KHPDQXIDFWXULQJSURFHVVRIWKH7&5Įȕ7-cell depleted cell grafts will be 
performed in the CMCF-GMP laboratory at the DFCI. The manufacturing process 
and quality control will be performed according to validated procedures and 
documented in accordance with full GMP requirements. 
7KHVWHPFHOODSKHUHVLVSURGXFWZLOOEHGHSOHWHGRI7&5Įȕ7FHOOVE\QHJDWLYH
selection using the automated CliniMACS® Plus device, the current version of the 
CliniMACS user manual and according to institutional Standard Operating
Procedures (SOPs) in place and validated at the manufacturing site. A detailed 
protocol for the preparation and use of this system is provided in the CliniMACS® 
7&5Įȕ5HDJHQW.LW,QYHVWLJDWRU¶V%URFKXUH$SSHQGL[B). Samples of the donor 
leukocyte preparation will be removed prior to processing and after completion.  
These samples will be used to determine cell viability and enumerate the total number 
of alpha/beta T cell, gamma/delta T cells, B cells, NK cells and CD34+ cells in the 
product before and after processing.
5.4
CD34+ and alpha/beta T cell target doses for graft composition
CD34+ stem cell counts will be obtained before and after processing with the 
Miltenyi ClinicMACs device.  
,IWKHLQLWLDO&'FRXQWRQWKH3%6&SULRUWR7&5ĮȕGHSOHWLRQLV[6 CD34+ 
cells/kg, then no T cell depletion will be performed and the patient will be started on 
standard pharmacologic GVHD prophylaxis. These patients are not evaluable for the 
primary endpoint and will be replaced on the study. 
After processing,  the volume of processed product infused will be adjusted to target a
TCRĮȕ T-FHOOVGRVH[5 cells/kg, while maintaining a minimal viable CD34+ 
cell dose  2.0 x106 cells/kg recipient weight 
The CD34+ cell dose may exceed 5.0 x 106 CD34+ cells/kg after selection so long as 
WKHILQDOVWHPFHOOSURGXFWFRQWDLQV[5 Įȕ + T cells/kg.  If the product after 
processing contains > 1.0 x 105 TCR Įȕ T cells/kg, then the volume of the product 
released for infusion should be adjusted to the cap T cell dose, as long as the CD34 
GRVHUHPDLQV[6 CD34+ cells/kg.   
If CD34 dose of 2.0 x 106 CD34+ cells/kg cannot be attained when the T cell dose is 
1.0 x 105 Įȕ+ T cells/kg, then the patient should receive the whole processed product 
(containing > 1.0 x 105 Įȕ+ T cells/kg and > 2.0 x 106 CD34+ cells/kg), and started 
on standard pharmacologic GVHD prophylaxis.  These patients will not be evaluable 

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for the primary endpoint, and will be replaced.  They will be included for the analysis 
of feasibility and intention to treat analysis since they received a processed product.
It is also possible that doses of CD34+ cells far exceeding 5 x 106/kg can be given 
without exceeding the maximum T-cell dose of 1.0 x 105 Įȕ+ T cells/kg.  High doses 
of CD34+ cells in extensively T-cell depleted transplants are postulated to hasten 
immune reconstitution, without altering the low risk of GVHD. Consequently, there is 
no upper limit for the dose of CD34+ cells/kg so long as the dose of Įȕ+ T cells does 
not exceed 1.0 x 105/kg. 
The mobilized T cell depleted PBSC product will be administered on Day 0, 
according to institutional guidelines. Stem cells are administered through an 
indwelling central venous catheter.   If infusion occurs over two days, Day 0 is the 
day the last infusion is completed.   For the purpose of cell infusion, the actual 
recipient body weight will be used to calculate cell dose.   
The flow chart for the processing and infusion of the stem cell product is outlined in 
the flow chart below:  

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G-CSF Mobilized PBSC 
product
[6
CD34/kg
< 4.0 x106
CD34/kg
TCRDE T [
105cells/kg
And
&'[6 
cells/kg
No,
Infuse entire 
processed 
product3 and add 
pharmacologic 
GvHD ppx
Yes,
Infuse adjusted 
volume2
Volume can be adjusted to:
TCRDE T = 1.0 x 105 
cells/kg AND
&'[6 cells/kg?
Infuse 
Product2
TCRDE T > 1.0 x 105 cells/kg
Off 
Study1
CliniMACS 
processing
No TCD processing
Add Pharm GvHD 
ppx
1. These patients will not be evaluable for the primary endpoint and will be replaced.
2. These patients will be evaluable for the primary endpoint.
3. These patients will not be evaluable for the primary endpoint, and will be replaced.  
They will be included for feasibility and intention to treat analysis since they received 
a processed product.

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$WDUJHWGRVH[6 &'FHOOVNJDIWHUVHOHFWLRQFRQWDLQLQJ[5
alpha/beta T cells/kg is desired.  The CD34+ cell dose can exceed 5.0 x 106 CD34+ 
cells/kg after selection so long as the final stem cell SURGXFWFRQWDLQV[5 Įȕ +
T cells/kg.  If the product after processing contains > 1.0 x 105 TCR Įȕ T cells/kg, 
then the volume of the product released for infusion should be adjusted to the cap T 
FHOOGRVHDVORQJDVWKH&'GRVHUHPDLQV[6 CD34+ cells/kg.   
If CD34 dose of 2.0 x 106 CD34+ cells/kg cannot be attained when the T cell dose is 
1.0 x 105 Įȕ+ T cells/kg, then the patient should receive the whole processed product 
(containing > 1.0 x 105 Įȕ+ T cells/kg and > 2.0 x 106 CD34+ cells/kg), and started 
on standard pharmacologic GVHD prophylaxis.  These patients will not be evaluable 
for the primary endpoint, and will be replaced.  They will be included for the analysis 
of feasibility and intention to treat analysis since they received a processed product.
It is also possible that doses of CD34+ cells far exceeding 5 x 106/kg can be given 
without exceeding the maximum T-cell dose of 1.0 x 105 Įȕ+ T cells/kg.  High doses 
of CD34+ cells in extensively T-cell depleted transplants are postulated to hasten 
immune reconstitution, without altering the low risk of GVHD. Consequently, there is 
no upper limit for the dose of CD34+ cells/kg so long as the dose of Įȕ+ T cells does 
not exceed 1.0 x 105/kg. 
5.5
Pharmacologic GVHD prophylaxis
,IWKHLQIXVHGWDUJHWRI[5 TCR Įȕ T cells/kg is achieved in the infused 
product, then patients will not receive any additional pharmacologic GVHD 
prophylaxis after transplantation.  
If the final infused product contains > 1.0 x 105 Įȕ+T cells/kg, or if no TCD is 
performed due to low starting CD34 dose in the donor product, then patients should 
receive tacrolimus and methotrexate as GVHD prophylaxis, in accordance with 
standard institutional practice. These patients will be unevaluable for the primary 
endpoint.
5.6
Growth Factor Support
Patients may receive growth factor support starting on day +5 using TBO-filgrastim 
(or filgrastim) at 5 mcg/kg/day IV/SC until ANC exceeds 1.0 x 106 neutrophils/ml for 
2 consecutive days.

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5.7
Supportive care
All patients will be maintained on HEPA-filtered units to decrease the risk of 
exposure to pathogenic organisms.  All patients will receive prophylactic oral or IV 
antibiotics until they are placed on parenteral antibiotics.  Total parenteral nutrition 
will be employed when deemed clinically appropriate. Blood product support will 
include red cell, platelet and granulocyte transfusions if necessary.  All blood 
products will be irradiated.
5.8
Seizure Prophylaxis
Keppra (Levetiracetam) will be administered for the prevention of busulfan-
associated seizures to all participants receiving busulfan, starting prior to starting 
busulfan, and stopping 1 days after the last dose of busulfan. Dosing of Levetiracetam 
will be administered as per the BMT guidelines. In case of allergic 
reactions/intolerance to levetiracetam, alternative anti-seizure medications will be 
used as clinically indicated.
5.9
Prophylaxis Against Infections
Patients will receive infection prophylaxis in accordance with institutional guidelines. 
Infection prophylaxis should include, but is not limited to, agents or strategies (e.g., 
PCR screening and preemptive therapy) to reduce the risk of bacterial, herpes 
simplex, CMV, EBV, Pneumocystis jiroveci, toxoplasmosis, and fungal infections:
5.9.1 Antifungal therapy: Prophylaxis with fluconazole or other antifungal 
agents can be given as per institutional guidelines, with appropriate dose 
adjustment in tacrolimus dosing if an azole is started on a patient who is 
receiving tacrolimus. 
5.9.2 Cytomegalovirus (CMV): CMV viral load monitoring by PCR will 
be done weekly starting around day +20 to Day 90-100 and then at each 
clinical assessment until Day 180 post-transplant. Pre-emptive treatment is 
the preferred strategy for patients with CMV reactivation. Use of 
letemavir as CMV prophylaxis is allowed.
5.9.3 Epstein-Barr Virus (EBV): EBV monitoring through quantitative 
PCR should be done weekly starting around day +20 through Day 90- 100
and then at each clinical assessment until Day 180 post-transplant.  EBV 
reactivation with rising levels above 1000 copies or evidence of PTLD 
should be treated with Rituximab, as per institutional standards
5.9.4 Pneumocystis jiroveci: Prophylaxis with agents against 
Pneumocystis jiroveci should be given as per institutional guidelines, until 
at least 1 year after HSCT.

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5.9.5 Herpes virus (HSV or VZV): Patients should receive acyclovir or 
valacyclovir for at least 2 years after transplant as prophylaxis against 
HSV and VZV per institutional Guidelines.
5.9.6 Toxoplasmosis: In patients at risk (seropositive patient or donor) for 
toxoplasmosis. Prophylaxis against toxoplasmosis with Bactrim 
(trimethroprim/sulfamethoxzalole) should be given starting after transplant 
admission. If patient cannot take Bactrim, toxoplasmosis monitoring 
by PCR every 1-2 weeks is recommended during the first 100 days 
after transplant.
5.10
Intravenous Immune Globulin (IVIG)
IVIG administration for post HSCT hypogammaglobulinemia is recommended and 
should follow institutional standard practice.  
5.11
Hepatic Veno-occlusive Disease (VOD) Prophylaxis
Prophylaxis against SOS/VOD with ursodiol is recommended per institutional 
practice, and should be started 1-2 weeks before start of conditioning.  Ursodiol may 
be discontinued about 2-3 months post HSCT, at the discretion of the treating 
physician.
5.12
Immune Monitoring
Peripheral blood samples will be obtained to perform immunological tests
for assessment of TCR repertoire and immune reconstitution. Both phenotypic and 
functional studies of peripheral blood lymphocytes will be performed. Blood samples 
will be banked periodically at around day +30, +60, day+100, and at about 6, 12, 18 
and 24 months after transplantation.[18]
5.13
Management of GVHD
Acute and chronic GVHD will be managed per standard practice at the discretion of 
the treating transplant physician.  It is recommended that for patients who develop 
overall grade 2-4 acute GVHD, that tacrolimus and corticosteroids be started together 
as initial therapy since patients on this trial do not routinely receive tacrolimus as 
GVHD prophylaxis.
5.14
Post-transplant maintenance therapy
For patients who have CML, Ph+ ALL, or FLT-3 mutation positive AML, 
maintenance therapy with TKIs or FLT-3 inhibitor agents for the prevention of 
relapse is permitted.  It is recommended that maintenance therapy be started after day 
42, after stable engraftment of WBC and Platelets, and only after a restaging marrow 
biopsy has been performed to rule out early relapse or minimal residual disease.

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5.15
Criteria for Taking a Participant Off Protocol Therapy
Patients will be removed from this study prior to infusion of stem cells if for any reason, 
fresh or sufficient numbers of mobilized peripheral blood stem cells could not be 
obtained from the donor to allow for the T cell depletion processing.  If this occurs, the 
patient will receive a standard transplant with unmanipulated bone marrow or PBSC, 
using tacrolimus and standard dose methotrexate (recommended), or other standard 
pharmacologic GVHD prophylaxis regimen at the discretion of the transplant physician. 
Patients are free to discontinue participation or withdraw consent from the study at 
any time, for any reason, and without prejudice to further treatment.
Patients who discontinue/withdraw from the study will receive treatment as deemed 
appropriate by their treating physician
An ODQ Treatment Ended/Off Study Form will be filled out when a participant is 
removed from protocol therapy. This form can be found on the DF/HCC website at 
http://www.dfhcc.harvard.edu/research/clinical-research-support/document-library-
forms-sops-etc/.
In the event of unusual or life-threatening complications, treating investigators must 
immediately notify the Overall PI, Vincent Ho, MD at 617-632-5938
5.16
Duration of Follow up
Participants will be followed for overall survival at Day 100 and after 1 year and 2 
years after removal from protocol therapy or until death, whichever occurs first.  
Participants removed from protocol therapy for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event.
5.17
Criteria for Taking a Participant Off Study
Participation in the study also may be discontinued at any time at the discretion of the 
investigator. The following may be justifiable reasons for the Investigator to remove 
a subject from the study:
x
The subject was erroneously included in the study
x
The subject developed an exclusion criterion after having been considered   
eligible for the trial but before the start of the preparative regimen
x
Disease progression

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x
Intercurrent illness that prevents further administration of treatment
x
Unacceptable adverse event(s)
x
Participant demonstrates an inability or unwillingness to comply with the 
oral medication regimen and/or documentation requirements
x
Participant decides to withdraw from the protocol therapy
x
General or specific changes in the participant's condition render the 
participant unacceptable for further treatment in the judgment of the 
treating investigator
Participants will be removed from the protocol therapy when any of these criteria 
apply.  The reason for removal from protocol therapy, and the date the participant was 
removed, must be documented in the case report form (CRF). In addition, the study 
team will ensure Off Treatment/Off Study information is updated in OnCore in 
accordance with DF/HCC policy REGIST-101. Alternative care options will be 
discussed with the participant.
6. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
6.1
Expected Toxicity of ablative chemotherapy
High dose chemotherapy will cause severe marrow aplasia with subsequent 
immunoablation and myeloablation, leading to pancytopenia and increased risk for 
bleeding and infections. Additional expected toxicities associated with 
chemotherapies used in the conditioning regimens of this study include:
x
General toxicity: 
Alopecia, anorexia, dysgeusia 
x
GI toxicity: 
Nausea, vomiting, mucositis and esophagitis, abdominal pain, typhlitis, 
diarrhea 
x
Pulmonary toxicity: 
Pulmonary fibrosis, Interstitial pneumonitis
x
Hepatic toxicity:
Hepatic transaminase elevations, Hepatic veno-occlusive disease

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x
Neurologic toxicity: 
Seizure, peripheral neuropathy
x
Dermatologic toxicity:
Skin rash/irritation, darkening of skin
6.2
Expected toxicity of TBI 
TBI will cause permanent ablation of normal bone marrow and profound immune 
suppression.  Additional acute toxicities may include nausea, vomiting, diarrhea, 
parotitis, and skin erythema.  Patients who receive TBI are likely to have permanent 
sterility.  Delayed toxicity which occurs in some patients includes interstitial 
pneumonitis, hepatic veno-occlusive disease, radiation nephritis, and cataracts.
6.3
Expected toxicity of TCR DE T depleted allogeneic PBSC transplantation
T cell depletion may increase the risk of graft failure or graft rejection.  However, this 
risk may be mitigated with the increased intensity of the conditioning regimens used, 
and the assurance that sufficient CD34+ cells are infused with the graft.  This study is 
designed such that it will be halted if the graft failure rate is significantly higher than 
expected.  
Acute and chronic GVHD are major complications of transplantation. The major 
target organs of acute GVHD are the skin, alimentary tract, and liver.  Treatment 
usually consists of corticosteroids and other immune suppressive medications. 
Depletion of TCR Įȕ T cells from donor graft may reduce the incidence of GVHD 
but it does not eliminate that risk. 
Engraftment with T cell depleted grafts may impair reconstitution of the donor 
immune system and render the transplant recipient more susceptible to infections, and 
the development of lymphoma/post-transplant lymphoproliferative disease (PTLD).  
T cell depletion and may also impair graft-versus-tumor activity and subject patients 
to higher risk for relapse of their malignancy.
6.4
Adverse Event Characteristics
CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0.  A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
6.4.1
Definitions of AE and SAE

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Adverse Event- An AE is any unfavorable and unintended sign, symptom, or 
disease temporally associated with the use of an investigational medicinal 
product (IMP) or other protocol-imposed intervention, regardless of 
attribution. This includes the following:
1. AEs not previously observed in the subject that emerge during the 
protocol-specified AE reporting period, including signs or symptoms 
that were not present prior to the AE reporting period.
2. Pre-existing medical conditions judged by the investigator to have 
worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period.
Serious Adverse Event- An SAE is any AE that is any of the following:
1. Fatal (i.e., the AE actually causes or leads to death)
2. Life threatening (i.e. The AE, in the view of the investigator, places 
the subject at immediate risk of death)
3. Requires or prolongs inpatient hospitalization
4. Results in persistent or significant disability/incapacity (i.e., the AE 
results in substantial disruption of the subject’s ability to conduct 
normal life functions)
5. A congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the investigational product(s)
6. Considered a significant medical event by the investigator (e.g., may 
jeopardize the subject or may require medical/surgical intervention to 
prevent one of the outcomes listed above)
All AEs that do not meet any of the criteria for serious should be regarded as 
non-serious AEs. The terms “severe” and “serious” are not synonymous. 
Severity refers to the intensity of an AE (as in mild, moderate, or severe pain); 
the event itself may be of relatively minor medical significance (such as severe 
headache). “Serious” is a regulatory definition and is based on subject or event 
outcome or action criteria usually associated with events that pose a threat to a 
subject’s life or vital functions. Seriousness (not severity) serves as the guide 
for defining regulatory reporting obligations. Severity and seriousness should 
be independently assessed when recording AEs and SAEs.
6.5
Adverse Event Reporting Guidelines  

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Since patients undergoing myeloablative conditioning stem cell transplantation are 
expected to experience many, and often severe, side effects from the procedure, we 
will restrict the reporting of AEs to those events which are serious (CTC grade 3 or 
higher) AND unexpected with regards to myeloablative stem cell transplantation.  
AEs that are listed in section 6.0, and/or are expected after myeloablative 
conditioning stem cell transplantation, are to be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information.
Grade 3 or higher AEs that are expected and do not meet the above criteria for 
reporting will be recorded in the transplant database as per standard post HSCT data 
collection. Safety assessments will consist of monitoring and recording protocol-
defined AEs and SAEs;
AEs will be reported directly to the DFCI Office for Human Research Studies 
(OHRS) per the DFCI IRB reporting policy. Events and time line for reporting are 
defined below:
Attribution of AE is defined below:
Definite – The AE is clearly related to the study treatment.
Probable – The AE is likely related to the study treatment.
Possible – The AE may be related to the study treatment.
Unlikely – The AE is doubtfully related to the study treatment.
Unrelated – The AE is clearly NOT related to the study treatment
6.6
Adverse Event Reporting 
6.6.1
In the event of an unanticipated problem or life-threatening complications 
treating investigators must immediately notify the Overall PI.
6.6.2
Investigators must report to the Overall PI any adverse event (AE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of 
the last dose of treatment on the local institutional SAE form.
6.7
Reporting to the Food and Drug Administration (FDA)
The Overall PI, as study sponsor, will be responsible for all communications with the 
FDA. The Overall PI will report to the FDA, regardless of the site of occurrence, any 
serious adverse event that meets the FDA’s criteria for expedited reporting following 
the reporting requirements and timelines set by the FDA.
6.8
Reporting to Hospital Risk Management

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Participating investigators will report to their local Risk Management office any 
participant safety reports, sentinel events or unanticipated problems that require 
reporting per institutional policy.
6.9
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall 
PI on the toxicity case report forms.  AEs reported through expedited processes 
(e.g., reported to the IRB, FDA, etc.) must also be reported in routine study data 
submissions.
6.10
Expedited Adverse Event Reporting 
Investigators must report to the Overall PI any serious adverse event (SAE) that 
occurs after the initial dose of study treatment, during treatment, or within 30 days of 
the last dose of treatment on the local institutional SAE form.
7. PHARMACEUTICAL AND/OR IMAGING AGENT INFORMATION
7.1
T-Cell Receptor (TCR) DE T-Cell Depletion
7.1.1
Description
TCR alpha/beta reagent system:  Description of the TCR a/b reagent system based on the user 
manual is appended below.

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7.1.2
Storage and Stability

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The Cell Manipulation Core Facility (CMCF) of the Dana-Farber Cancer 
Institute is an FDA approved facility with laboratories equipped with state of 
the art equipment for generating cells and cellular products for clinical use. 
Dr. Jerome Ritz is director of the facility and Dr. Hélène Nègre is the Novel 
Cell Therapy Director.
The CMCF is accredited by The Joint Commission (JC) and FACT and is 
CLIA certified (ID #22D1010753). The CMCF laboratory was last surveyed 
by JC in January 2017. The laboratory was inspected by FACT in February 
2016 and received a three-year accreditation as the cell processing laboratory 
for both the adult and pediatric transplant programs at DFCI. The laboratory is 
also FDA registered to package, process, store, label, and distribute 351 and 
361 cell therapy products such as; peripheral blood stem cells, Cord Blood, 
somatic cellular products. The FDA registration number the CMCF is FEI 
3003934255.
7.1.3
Handling
Qualified personnel, familiar with procedures that minimize undue exposure 
to themselves and the environment, should undertake the preparation, 
handling, and safe disposal of the chemotherapeutic agent in a self-contained 
and protective environment.
7.1.4
Availability
Materials are all commercially available and will be bought with internal grant 
funding from Miltenyi. 
7.1.5
Preparation
Cell Manufacture: The blood stem cell product will be mobilized with G-
CSF from the donor in accordance with standard protocol at the DFCI (related 
donors) or at the unrelated donor’s collection center.   Ideally, 2.5 blood volumes will 
be processed and a target of 6.0 x106 CD34+ cells/kg recipient weight will be 
collected in one or two sessions.  The product will be delivered immediately by 
courier to the Dana-Farber Cancer Institute for processing.  The PBSC product will 
not be cryopreserved before processing.  
The manufacturing SURFHVVRIWKH7&5Įȕ7-cell depleted cell grafts will be 
performed in the CMCF-GMP laboratory at the DFCI. The manufacturing process 
and quality control will be performed according to validated procedures and 
documented in accordance with full GMP requirements.  
7KHVWHPFHOODSKHUHVLVSURGXFWZLOOEHGHSOHWHGRI7&5Įȕ7FHOOVE\QHJDWLYH
selection using the automated CliniMACS® Plus device, the current version of the 
CliniMACS user manual and according to institutional Standard Operating 

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Procedures (SOPs) in place and validated at our manufacturing site. A detailed 
protocol for the preparation and use of this system is provided in the CliniMACS® 
7&5Įȕ5HDJHQW.LW,QYHVWLJDWRU¶V%URFKXUH6DPSOHVRIWKHGRQRUOHXNRF\WH
preparation will be removed prior to processing and after completion.  These samples 
will be used to determine cell viability and enumerate the total number of alpha/beta 
T cell, gamma/delta T cells, B cells, NK cells and CD34+ cells in the product before 
and after processing.  After processiQJWKH7&5Įȕ7FHOOGHSOHWHGSURGXFWZLOOEH
delivered immediately in a cooler at room temperature to the bedside for intravenous 
infusion to the designated transplant recipient.
7.1.6
Administration
Please reference Section 5, Treatment Plan.
7.1.7
Ordering
Product Tracking: When a patient’s product is received in the Cell 
Manipulation Core Facility (CMCF), the product is assigned a unique number, 
if it does not have one from the collection facility. The product is inspected 
and signed in noting the products condition, study subject’s name and 
identifiers (medical records). This information is recorded into the “CMCF 
Product Receipt Log” directly from the unit’s label and the accompanying 
paper work. This information is compared with the identifiers on the order to
process the cells for a patient. The products unique identifier, subject’s name, 
MR #, and other required information are maintained on all intermediated 
labels during manufacturing and on the final product label along with the 
products name and “Caution: New Drug—Limited by Federal (or United 
States) law to investigational use.” Additional information is recorded as part 
of the batch record during each manufacturing step.
7.1.8
Accountability
Experience with the Miltenyi ClinicMACs device: The CMCF has extensive 
experience with the Miltenyi CliniMacs device.  We were a high accrual 
center for the national CTN phase II study that tested CD34 selection using 
CliniMACs in related donor transplantation, and we have conducted our own 
clinical trial of CD25 T reg selection using CliniMACs for infusion as a 
treatment for cGVHD.  We also have a standard treatment plan for performing 
CD34 selection of allogeneic PBSC products for use in stem cell rescues or 
stem cell boosts for patients who experience graft failure after HSCT.  

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8. STUDY ENDPOINTS
8.1
Engraftment
Engraftment of neutrophils will be defined as the first of 3 consecutive days in which 
the absolute neutrophil count exceeds 500 x 106 neutrophils/ml.  Patients will be 
considered to have graft failure if neutrophil engraftment is not achieved within 30 
days of PBSC infusion.  Engraftment of platelets will be defined as the first day of a 
seven-day span in which they maintain a platelet count over 20,000 x 106 platelets/ml 
without transfusion.
Primary graft faLOXUHLVGHILQHGDVWKHIDLOXUHWRDFKLHYHDQ$1&!FHOOVȝ/E\'D\
+28. Secondary graft failure is defined as initial neutrophil engraftment followed by 
VXEVHTXHQWGHFOLQHLQQHXWURSKLOFRXQWVFHOOVȝ/XQUHVSRQVLYHWRJURZWKIDFWRU
therapy. 
8.2
GVHD
Acute GVHD will be graded according to the modified Glucksberg criteria.[19]
Beyond day +100, development of chronic GVHD will be assessed as per the NIH 
2014 consensus criteria for cGVHD.[20]
8.3
Disease Relapse 
Relapse of disease post-HSCT will be assessed by standard criteria, including 
physical exam, laboratory tests, radiographs, CT scans or MRI, and tissue (bone 
marrow, lymph node, etc.) biopsy deemed as appropriate for the patient’s diagnosis.  
Disease assessment is required at approximately day +100, and at12 and 24 months 
after transplant, and whenever clinically appropriate at the discretion of the treating 
physician.
8.4
Survival
8.4.1 Overall survival (OS) is defined as time from transplantation to death or last 
follow-up and will be assessed at Day 100 and after 1 year and 2 years. 
8.4.2 Disease-free survival (DFS) is defined as time from transplantation to relapse/ 
recurrence or death from any cause, whichever occurs first.  Patients who are alive 
and disease free at the time of data analysis will be censored. 
8.4.3 GVHD-Relapse-free-Survival (GRFS) is defined as time from transplantation 
to grade 3-4 acute GVHD, moderate-severe chronic GVHD, relapse or death of any 
cause, whichever occurs first. Patients who are alive and free of any of these events 
will be censored.

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8.4.4 Chronic GVHD-free Survival (CRFS) is defined as time from transplantation 
to moderate-severe chronic GVHD or death of any cause, whichever occurs first. 
Patients who are alive and free of any of these events will be censored.
8.4.5 Immune suppression-free survival (IFS) is defined as time from 
transplantation to the first date of requiring immunosuppressant or death of any cause,
whichever occurs first. Patients who are alive and free of any of these events will be 
censored.
8.5
Studies of immune reconstitution
Blood specimens will be obtained from patients weekly after day 0 during the 
transplant admission, then monthly up to about day 100, and then at about 6, 12, 18, 
and 24 months after transplantation.  Immune reconstitution will be monitored using 
flow cytometry to examine recovery of CD4Treg, CD4Tcon, CD8 T cells, NK cells 
and B cells in peripheral blood samples. Recovery of T cells expressing DE and JG T
cell receptors will also be monitored.
9. DATA REQUIREMENTS
9.1
Post-Transplant Evaluations
The following observations should be performed according to Table I:
x
History and physical exam weekly through Day 100 post-transplant, then at 
around monthly intervals until 1 year, at 1.5 year and 2 years from transplant.
x
GVHD assessments
¾ GVHD should be assessed weekly from approximately Day 7 until Day 
90-100 post-transplant, then at all routine clinical follow visits after 100 
days as per standard care practice.
¾ Acute and chronic GVHD should be monitored in accordance with 
institutional guidelines and whenever possible, recorded in the GVHD 
flowsheet in the Epic EMR system.  Acute GVHD will be scored 
according to the standard Keystone criteria [19]and cGVHD will be 
assessed according to the 2014 NIH consensus criteria for cGVHD 
grading [20].
x
CMV Monitoring: CMV monitoring through PCR viral load testing will be done 
weekly until about Day 90.

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x
EBV Monitoring: EBV monitoring through quantitative PCR viral load testing 
will be done weekly until about Day 90.
x
Disease evaluation: Restaging studies with radiology imaging or bone marrow 
aspirate/biopsy as appropriate for the underlying disease should be performed at 
about day 180, 1 year, and 2 years post-transplant.
Table I. Required Data
Pre-
Studyc
Weekly to 
day +90d
Day 
+30d
Day 
+60d
Day 
+100e
6
monthse
12
monthse
18
monthsf
24
monthsf
Informed consent
X
Standard pre-HSCT 
FACT testing
X
Medical history
X
HCT-CI
X
B-HCGa
X
Donor and Recipient 
HLA and ABO typing
X
HIV/HepB testing
X
Physical exam
X
X
X
X
X
X
X
X
X
Performance status
(ECOG)
X
X
X
X
X
X
X
X
ECHO
X
PFT
X
CBC w/diff
X
X
X
X
X
X
X
X
X
Serum Chemistryb
X
X
X
X
X
X
X
X
X
Primary Disease 
Stagingg
X
Staging studies (marrow biopsy and/or radiology) appropriate for the patient’s cancer 
type should be performed at about day 180, 12 months, and 24 months after HSCT.
GVHD Assessment
X
X
X
X
X
X
Toxicity Assessment
X
X
X
X
X
X
Chimerism studies: 
PB, Gran, CD3 Chim
X
X
X
X
X
X
X
Viral Monitoring: CMV 
and EBV Quant PCR
X
X
Immune reconstitution 
blood
X
Weekly 
during 
inpatient 
admission
X
X
X
X
X
X
X
a:
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b:
BMP panel including LFTs (AST, ALT, Alk Phos, BILT).
c.
Baseline tests to be performed within 42 days of transplant day 0.
d:     +/- 3 days.
e.     +/- 7 days
f:      +/- 2 weeks
g:    For patients who have CML, Ph+ ALL, or FLT-3 mutation positive AML, maintenance therapy with TKIs or FLT-3
inhibitor agents for the prevention of relapse is permitted.  It is recommended that maintenance therapy be started 
after day 42, after stable engraftment of WBC and Platelets, and only after a restaging marrow biopsy has been 
performed to rule out early relapse or minimal residual disease.
10.
DATA REPORTING / REGULATORY REQUIREMENTS
10.1
Data Reporting
10.1.1      Method
The Office of Data Quality (ODQ) will collect, manage, and perform 
quality checks on the data for this study.
10.1.2      Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for 
submitting data and/or data forms to the Office of Data Quality (ODQ) in 
accordance with DF/HCC policies.
10.1.3
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will 
review and monitor toxicity and accrual data from this study. The 
committee is composed of medical oncologists, research nurses, 
pharmacists and biostatisticians with direct experience in cancer clinical 
research.  Information that raises any questions about participant safety 
will be addressed with the Overall PI and study team.
The DSMC will review each protocol up to four times a year with the 
frequency determined by the outcome of previous reviews. Information to 
be provided to the committee may include: up-to-date participant accrual; 
current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths 
occurring within 30 days of intervention for Phase I or II protocols; for 
gene therapy protocols, summary of all deaths while being treated and 
during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, 
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11. STATISTICAL CONSIDERATIONS
11.1
Study Design/Endpoints
This is a single-arm, two-VWDJHSKDVH,,VWXG\RIH[YLYRĮȕ7&57FHOOGHSOHWHG
(TCD) peripheral blood stem cell transplantation (PBSCT) as a GVHD prophylaxis 
for patients with hematologic malignancies undergoing allogeneic PBSCT. The 
SULPDU\REMHFWLYHLVWRHYDOXDWHWKHVDIHW\DQGHIILFDF\RIH[YLYRĮȕ7&57&'IRU
patients receiving myeloablative PBSCT from related or unrelated mismatched (8/10 
RUGRQRU7KHSUHPLVHLVWKDWH[YLYRĮȕ7&57&'ZLOOUHGXFHWKHLQFLGHQFH
of grade 3-4 acute GVHD and/or death. The target accrual goal is 25 evaluable 
patients over 3.5- 4 year period. All surviving patients will be followed for at least 
100 days. Patients who meet the eligibility criteria but deemed unevaluable per 
Section 5.4 will be excluded from the study. 
11.2
Endpoints
11.2.1 Primary Endpoint: The primary endpoint of this study is day 100 severe 
acute GVHD-free survival rate. Events considered for the primary endpoint 
are grade 3-4 acute GVHD or death from any cause.
11.2.2 Secondary Endpoints
x
Grades II-IV acute GVHD
x
Chronic GVHD
x
GRFS
x
Immunosuppression-free survival 
x
Hematologic recovery (neutrophil and platelet engraftment)
x
Immune reconstitution
x
Disease relapse
x
Transplant-related mortality
x
Organ Toxicity (e.g. SOS/VOD and IPS) 
x
Rates of infections (CMV and EBV reactivation)
x
Relapse-free and overall survival
11.3
Accrual 
Based on the accrual of the DFCI transplant group between 2010 and 2015 who meet 
the eligibility criteria, the projected accrual rate will be 7-8 patients per year.  
Conservatively extrapolating this projection, it is anticipated that the accrual will 
complete in 3.5-4 years to enroll the targeted sample size of 25 patients.

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11.4
Randomization 
N/A
11.5
Sample Size and Power Calculation
A retrospective analysis of patients who underwent myeloablative PBSCT between 
2010 and 2015 at DFCI who meet the eligibility criteria shows that the estimated day 
100 severe acute GVHD-free survival rate is 67%. Basing this information as the null 
hypothesis, we hypothesize that with the ex vivRĮȕ7&57&'WKHGD\VHYHUH
acute GVHD-free survival rate will be increased by 20% from 67% to 87%. With 
the sample size of 25, there will be 82% power to detect a 20% difference in severe 
acute GVHD-free survival rate.
The study is a two-stage design with early stopping rules if the proposed therapy 
shows no efficacy after the first stage or excessive rate of graft failure. In the first 
stage, 10 patients will be accrued. If 7 or fewer patients are alive and severe acute 
GVHD-free by day 100 of transplantation, the study will be terminated early for lack 
of efficacy. If, however, 8 or more patients are alive without severe acute GVHD by 
day 100, then additional 15 patients will be accrued. After the second stage, if the 
total number of patients who are alive without sever acute GVHD is 20 or more, then 
proposed prophylaxis will be considered efficacious for preventing acute GVHD.
Conversely, if 19 or fewer patients are alive and severe acute GVHD-free, then this 
regimen will be considered inefficacious. If 20 patients are alive and severe acute 
GVHD free after the second stage, the 95% confidence interval for this rate is (61%, 
94%). This confidence interval is calculated based on the Atkinson and Brown 
method (Biometrics, 1985).  
With this design, the probability of concluding the proposed prophylaxis efficacious 
is 0.82 if the true but unknown day 100 severe acute GVHD-free survival rate is 87% 
and 0.09 if the true rate is 67%. The probability of early stopping is 0.69 if the rate is 
67% and 0.13 if the rate is 87%. Table 1 below presents the operating characteristics 
of this design.
Table 1. Operating Characteristics
True but Unknown severe acute GVHF-free survival 
Rate 
67%
72%
77%
82%
87%
Probability of stopping early (<=7 in 10)
0.69
0.56
0.41
0.26
0.13
Overall Probability of accepting the treatment 
0.09
0.21
0.39
0.61
0.82
11.6
Monitoring Events 
The occurrence of graft failure will be monitored closely and continuously throughout 
the study period.  In particular, if 3 or more of the first 10 patients enrolled experience 

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graft failure, defined as lack of neutrophil engraftment by day+30, then the study will 
be halted for further review.  With this design, the probability of early termination is 
0.07 if the true but unknown unknown graft failure rate at day +30 is 10% but 0.62 if 
the true rate is 30%. This decision rule is calculated using an exact binomial 
distribution. Table 2 shows probabilities of stopping early under various scenarios.
Table 2.
True but Unknown Graft Failure Rate 
10%
15%
20%
25%
30%
Prob JUDIWIDLOXUHLQWKH
first 10 patients)
0.07
0.18
0.32
0.47
0.62
11.7
Analysis of Primary Endpoints
When data are ready for analysis, the primary endpoint will be reported descriptively, 
reporting the proportion and confidence interval.  Time to event endpoints such as 
chronic GVHD-free survival, GRFS, immunosuppression-free survival (IFS), disease-
free survival (DFS) and overall survival will be estimated using the Kaplan-Meier 
method. Cumulative incidence of acute/chronic GVHD, relapse, and transplant-
related mortality (TRM) will be estimated in the competing risks framework 
considering relapse or death without developing GVHD, TRM, and relapse as a 
competing event, respectively. Cumulative incidence of engraftment and CMV/EBV 
reactivation will also be estimated in the competing risks framework considering 
death without engraftment and CMV/EBV as a competing event, respectively. Other 
endpoints such as organ toxicity, immune reconstitution and quality of life will be 
analyzed descriptively.
11.8
Reporting and Exclusions
Precisely define the analysis population for the various endpoints and subset analyses. 
Participants who never start protocol therapy are usually excluded (“inevaluable”) 
from most analyses in Phase I and Phase II studies.
11.7.1
Evaluation of Toxicity
Define “evaluable.” For example: All participants will be evaluable for toxicity from 
the time of their first treatment.
11.7.2
Evaluation of the Primary Efficacy Endpoint
Analyses should be intent-to-treat unless justification can be provided for not doing 
so. Specifically, all eligible participants included in the study must be assessed for 
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Subanalyses may then be performed on the basis of a subset of participants, excluding 
those for whom major protocol deviations have been identified (e.g., early death due 
to other reasons, early discontinuation of treatment, major protocol violations, etc.).  
However, these subanalyses may not serve as the basis for drawing conclusions 
concerning treatment efficacy, and the reasons for excluding participants from the 
analysis should be clearly reported.  If applicable to the endpoint, the 95% confidence 
intervals should also be provided.
12. PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.

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13. REFERENCES
1.
Lee, S.J., et al., High-resolution donor-recipient HLA matching contributes to the 
success of unrelated donor marrow transplantation. Blood, 2007. 110(13): p. 4576-83.
2.
Storb, R., et al., Marrow transplantation for severe aplastic anemia: methotrexate 
alone compared with a combination of methotrexate and cyclosporine for prevention of acute 
graft-versus-host disease. Blood, 1986. 68(1): p. 119-25.
3.
Storb, R., et al., Methotrexate and cyclosporine versus cyclosporine alone for 
prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for 
leukemia: long-term follow-up of a controlled trial. Blood, 1989. 73(6): p. 1729-34.
4.
Nash, R.A., et al., Phase 3 study comparing methotrexate and tacrolimus with 
methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow 
transplantation from unrelated donors. Blood, 2000. 96(6): p. 2062-8.
5.
Reinherz, E.L., et al., Reconstitution after transplantation with T-lymphocyte-
depleted HLA haplotype-mismatched bone marrow for severe combined immunodeficiency. 
Proc Natl Acad Sci U S A, 1982. 79(19): p. 6047-51.
6.
Soiffer, R.J., et al., Prevention of graft-versus-host disease by selective depletion of 
CD6-positive T lymphocytes from donor bone marrow. J Clin Oncol, 1992. 10(7): p. 1191-200.
7.
Drobyski, W.R., et al., Effect of T-cell depletion as graft-versus-host disease 
prophylaxis on engraftment, relapse, and disease-free survival in unrelated marrow 
transplantation for chronic myelogenous leukemia. Blood, 1994. 83(7): p. 1980-7.
8.
Champlin, R., et al., Selective depletion of CD8+ T lymphocytes for prevention of 
graft-versus-host disease after allogeneic bone marrow transplantation. Blood, 1990. 76(2): p. 
418-23.
9.
Hale, G., S. Cobbold, and H. Waldmann, T cell depletion with CAMPATH-1 in 
allogeneic bone marrow transplantation. Transplantation, 1988. 45(4): p. 753-9.
10.
Antin, J.H., et al., Selective depletion of bone marrow T lymphocytes with anti-CD5 
monoclonal antibodies: effective prophylaxis for graft-versus-host disease in patients with 
hematologic malignancies. Blood, 1991. 78(8): p. 2139-49.
11.
Filipovich, A.H., et al., T cell depletion with anti-CD5 immunotoxin in 
histocompatible bone marrow transplantation. The correlation between residual CD5 negative T 
cells and subsequent graft-versus-host disease. Transplantation, 1990. 50(3): p. 410-5.
12.
Reisner, Y., et al., Transplantation for severe combined immunodeficiency with 
HLA-A,B,D,DR incompatible parental marrow cells fractionated by soybean agglutinin and 
sheep red blood cells. Blood, 1983. 61(2): p. 341-8.
13.
Wagner, J.E., et al., Lymphocyte depletion of donor bone marrow by counterflow 
centrifugal elutriation: results of a phase I clinical trial. Blood, 1988. 72(4): p. 1168-76.
14.
Champlin, R.E., et al., T-cell depletion of bone marrow transplants for leukemia from 
donors other than HLA-identical siblings: advantage of T-cell antibodies with narrow 
specificities. Blood, 2000. 95(12): p. 3996-4003.
15.
Kernan, N.A., et al., Analysis of 462 transplantations from unrelated donors 
facilitated by the National Marrow Donor Program. N Engl J Med, 1993. 328(9): p. 593-602.
16.
Daniele, N., et al., Transplantation in the onco-hematology field: focus on the 
manipulation of alphabeta and gammadelta T cells. Pathol Res Pract, 2012. 208(2): p. 67-73.

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17.
Bertaina, A., et al., HLA-haploidentical stem cell transplantation after removal of 
alphabeta+ T and B cells in children with nonmalignant disorders. Blood, 2014. 124(5): p. 822-6.
18.
Alho, A.C., et al., Unbalanced recovery of regulatory and effector T cells after 
allogeneic stem cell transplantation contributes to chronic GVHD. Blood, 2016. 127(5): p. 646-
57.
19.
Przepiorka, D., et al., 1994 Consensus Conference on Acute GVHD Grading. Bone 
Marrow Transplant, 1995. 15(6): p. 825-8.
20.
Jagasia, M.H., et al., National Institutes of Health Consensus Development Project on 
Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and 
Staging Working Group report. Biol Blood Marrow Transplant, 2015. 21(3): p. 389-401 e1.
14. APPENDIX 
A. Performance Status Criteria 
B. &OLQL0$&67&5Įȕ5HDJHQW.LW,QYHVWLJDWRU¶V%URFKXUH

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APPENDIX A
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 B     CLINIMAC67&5ǹǺ5($*(17.,T  INVESTIGATOR’S BROCHURE

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