Use of T-allo10 Cell Infusions Combined With Mismatched Related or Mismatched Unrelated Hematopoietic Stem Cell Transplantation (HSCT) for Hematologic Malignancies
Phase: PHASE1
Conditions: AML - Acute Myeloid Leukemia, MDS (Myelodysplastic Syndrome), Mixed Phenotype Acute Leukemia, NHL - Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, ALL
Sponsor: Roncarolo, Maria Grazia, MD

Use of T-allo10 Cell Infusions Combined with Mismatched Related or 
Mismatched Unrelated Hematopoietic Stem Cell Transplantation (HSCT) 
for Hematologic Malignancies 
Study Protocol and Statistical Analysis Plan 
NCT03198234 
January 19, 2022 

Protocol No: T-allo10, Version 5 
 
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USE OF T-allo10 CELL INFUSIONS COMBINED WITH MISMATCHED RELATED OR 
MISMATCHED UNRELATED HEMATOPOIETIC STEM CELL TRANSPLANTATION 
(HSCT) FOR HEMATOLOGIC MALIGNANCIES 
 
 
DEPARTMENT OF PEDIATRICS 
DIVISION OF STEM CELL TRANSPLANTATION AND REGENERATIVE MEDICINE 
725 Welch Road 
Palo Alto, CA 94304 
 
 
Sponsor Investigator: 
Maria-Grazia Roncarolo, MD 
Study Drug: 
T-allo10 
Protocol Version: 
5 
Release Date: 
January 19, 2022 
 
 
Confidentiality Statement 
This document contains confidential information of Stanford University School of Medicine.   
Do not copy or distribute without written permission of the sponsor. 
 
 
 

 
 
  
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SPONSOR SIGNATURE PAGE 
Maria-Grazia Roncarolo, MD  
 
George D. Smith Professor of Pediatrics and Medicine 
Division Chief, Pediatric Stem Cell Transplantation and Regenerative Medicine 
Co-Director, Institute for Stem Cell Biology and Regenerative Medicine 
Co-Director, Bass Center for Childhood Cancer and Blood Diseases 
 
 
 
Signature 
 
Date 
 
 
 
 

 
 
  
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SPONSOR DETAILS 
Name of Sponsor:   
Maria-Grazia Roncarolo, MD 
Address: 
265 Campus Drive West 
Room G3021A 
Stanford, California, 94305 
Telephone Number: 
 
Fax Number: 
 
Stanford Principal 
Investigator 
Rajni Agarwal, MD 
Stanford Sub-
Investigators 
Alice Bertaina, MD PhD 
Rosa Bacchetta, MD 
 
Matthew Porteus, MD PhD 
 
Parveen Shiraz, MD  
 
 
Bio-Statistician 
Philip Lavori, PhD 
Research Staff 
Natalie Pukesh, RN 
 
Nivedita Kunte, BHMS, Research Coordinator 
 
 
External Collaborators: 
Fabio Ciceri, MD, Ospedale San Raffaele, Milano Italy 
Silvia Gregori, PhD, San Raffaele Telethon Institute for Gene 
Therapy, Milan Italy 
 
 
 
 
 
 
 
 

 
 
  
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SYNOPSIS 
 
Protocol Number 
IRB 38734/ BMT 297 
Protocol Title 
Use of T-allo10 cell infusion combined with mismatched related or mismatched unrelated 
donor hematopoietic stem cell transplantation (HSCT) for hematologic malignancies. 
Sponsor 
Maria Grazia Roncarolo, MD 
Protocol Director 
Rajni Agarwal, MD 
Name of Investigational 
Product 
T-allo10  
Clinical Phase  
Phase 1 
Background and 
Rationale 
Hematologic malignancies are the most common childhood cancer. Although there are 
chemotherapy protocols to treat these patients, we have reached the zenith of tolerable dose 
intensity for chemotherapy, and a significant number of patients need HSCT for cure, often 
due to drug resistance, relapse, or other unfavorable features. Since less than 50% of these 
patients have a fully matched family or unrelated donor, the remaining patients will require 
an HSCT from a mismatched related or mismatched unrelated donor. A major complication 
of mismatched related or mismatched unrelated donor HSCT is Graft-versus-Host Disease 
(GvHD), which results in significant morbidity and increased non-relapse mortality. 
The objective of this clinical program is to develop a cell therapy to prevent GvHD and 
induce graft tolerance in patients receiving mismatched related or mismatched unrelated 
unmanipulated donor HSCT. The cell therapy consists of a cell preparation (T-allo10) 
containing T regulatory type 1 (Tr1) cells, which have been shown to suppress allogenic 
responses (1, 2). 
We plan to infuse the donor T-allo10 product one day before HSCT so that the Tr1 cells 
contained within the T-allo10 product will be able to prevent anti-host alloreactivity of the 
T cells present within the unmanipulated HSC graft. Indeed, Tr1 cells need to be present 
at the time of effector T cell activation to exert their most potent suppressive activity (3); 
therefore, we expect that the early infusion of T-allo10 cells will optimally modulate host 
alloreactivity of the donor T cells and prevent GvHD. 
Objectives  
Primary Objective:  
• 
To assess the tolerability and safety of escalating doses of T-allo10 cell infusions 
that can be feasibly manufactured to meet release specifications in mismatched 
related or mismatched unrelated unmanipulated HSCT in patients with 
hematologic malignancies. 
Secondary Objective: 
• 
To assess the incidence of grade III and IV acute GvHD. 
Exploratory Objectives: 
• 
To assess the incidence and severity of chronic GvHD. 
• 
To assess the time to immune reconstitution. 
• 
To assess Disease Free Survival. 

 
 
  
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Primary Endpoint(s) 
The primary endpoints for this study are: 
-Tolerability of T-allo10 cells as evidenced by the incidence and severity of treatment-
emergent adverse events (TEAE), laboratory abnormalities, changes in vital signs, and 
changes in physical examination following infusion of T-allo10 cells, recorded and 
graded according to the Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0 (see link). 
-Safety of T-allo10 cells as evidenced by the time to stem cell engraftment after HSCT. 
Stem cell engraftment is defined as:  
• 
An Absolute Neutrophil Count (ANC) above 500/mm3 for three consecutive days 
by Day +42. 
• 
Presence of hematopoiesis at bone marrow examination, with cellularity >5 % and 
donor chimerism >90% by short tandem repeat (STR) analysis for the presence of 
donor cells by Day +42. 
• 
Absence of disease relapse as evidenced by minimal residual disease (MRD) assay 
< 0.1% by Day +42. 
- Feasibility defined by the rate of successful manufacture of the T-allo10 product to 
satisfy the targeted dose level and meet the required release specifications. 
Secondary and 
Exploratory Endpoints 
The secondary endpoint for this study is: 
-The incidence of grade III and IV acute GvHD at Day +100 following infusion of T-
allo10 cells, assessed using the Modified Keystone scale administered by an 
independent evaluator on study visits through Day +100 according to schedule of 
events (Section 9.6). 
The exploratory endpoints for this study are: 
- The incidence and severity of chronic GvHD after Day +100 through Day +365, 
assessed by the National Institutes of Health (NIH) consensus guidelines administered 
by an independent evaluator on study visits from Day +100 through Day +365 
according to schedule of events (Section 9.6). 
- The time to immune reconstitution, assessed by the time to reach >200/microliter CD3+ 
T cells. 
- Disease Free Survival at Day +365, assessed by bone marrow aspirate examination, 
morphology, MRD assay and donor chimerism by STR analysis. 
Study Centers 
This is a Stanford University, sponsor-investigator initiated protocol conducted at Lucile 
Packard Children’s Hospital Stanford (LPCHS) and Stanford Health Care (SHC) only. 
Sample Size  
Up to 27 eligible patients will be given investigational cell product (T-allo10) sequentially 
at 3 escalating dose cohorts to determine the maximum tolerated dose (or the highest dose 
tested if no maximum tolerated dose is reached). Each cohort will begin by evaluating 3 
patients. There will be a 28 day safety evaluation between the first and second subject in 
cohort one.  The second subject in cohort one will be treated no sooner than 29 days after 
the first subject’s infusion of T-allo10 (after safety assessment). Subsequent subjects in 
cohort one may be treated with T-allo10 at least 28 days after the preceding subject is 
treated with T-allo10 in the cohort.  After infusion of T-allo10 in the last subject of each 
cohort, there will be a 28 day safety evaluation period. If the cohort meets safety and 
tolerability criteria, subsequent subjects may be enrolled in the cohort of the next higher 
cell dose. In cohorts two and three subjects may be treated with T-allo10 at least 28 days 
after the preceding subject is treated with T-allo10 in the cohort. If one out of 3 patients in 
a cohort has a DLT, 3 additional patients will be evaluated at the same dose level. If one 

 
 
  
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out of 6 patients experiences a DLT, dose escalation will occur. If 2 out of ≤ 6 patients 
experience a DLT, dose escalation will cease and that dose will be designated the 
maximally administered dose. Up to three (3) additional patients will be entered at the next 
lowest dose level if only 3 patients were treated previously at that dose.  
The maximally tolerated dose (MTD) is: 
a) the highest dose level that can be feasibly generated to meet established release 
criteria at which no more than 1 out of 6 patients experience a DLT from the 
infusion of T-allo10 cells,  
or  
b) the dose below that at which at least 2 (of ≤6) patients have a DLT as a result of 
the infusion of T-allo10 cells. 
In addition to evaluating up to 6 patients at a given dose level with respect to toxicity, the 
number of patients for whom the targeted dose can successfully be manufactured to meet 
release criteria will be determined.  Dose escalation will proceed as long as adequate 
numbers of T-allo10 cells are manufactured that meet release criteria for a targeted dose 
level for at least 3 patients out of ≤6 patients in a dose cohort.  If cells generated for any 
patient do not meet the minimal T-allo10 dose for the specified cohort, the patient will 
receive the total number of manufactured T-allo10 cells, as the efficacious dose level is 
not known; that patient will be evaluable for toxicity, but will be considered a 
manufacturing failure in the targeted dose cohort (as outlined in Section 10).  A maximum 
of 3 additional patients may be added to a dose cohort due to inability to achieve the 
target dose (Section 10). 
If any patient is withdrawn from study for any reason (withdrawal of consent, relapse 
before start of chemotherapy, etc.) before receiving the T-allo10 cells, the patient will not 
be counted in total evaluable patients and will be replaced. Up to a maximum of 3 
inevaluable patients may be replaced. The maximum number of patients that may be 
enrolled will be 30 (18 in the dose escalation + 9 to replace 3 per dose cohort that fail to 
meet manufacturing specifications + 3 who withdraw from study for any reason). 
Overall Duration of the 
Study 
The recruitment period for this study is expected to be 2 years and 6 months. Subjects will 
be followed for 1-year post treatment. The total duration of this study is expected to be 3 
years and 6 months. 
Duration of Study per 
Subject 
Subject’s active participation in this study is expected to be 1 year. 
Subject Population 
Subjects recruited for this study will be patients from ≥3 years of age to ≤45 years of age.  
Subjects 1 and 2 (in Cohort 1) will be ≥ 12 years old. Pediatric and young adult patients 
with a hematologic malignancy undergoing an allogeneic mismatched related or unrelated 
unmanipulated HSCT are eligible to be enrolled in this study.  
Eligibility criteria 
Patient Inclusion Criteria:  
1) Eligible diseases include: 
A. Acute Lymphoblastic Leukemia (B- or T-ALL) 
a. 
CR-1-ultra high risk features 
• Unfavorable cytogenetics 
• 
Hypodiploidy 
• 
Induction failure 

 
 
  
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• 
MRD positive after consolidation 
b. CR-2  
• 
Any of the high risk features listed in CR1 
• 
B-ALL: any relapse considered eligible for transplant  
• 
T- ALL 
c. 
CR-3-any 
d. Any feature that is considered high risk by the treating 
physician  
B. Acute Myeloid Leukemia 
a. 
CR1 -ultra high-risk features (eligible for stem cell 
transplantation) 
• 
Unfavorable cytogenetics 
• 
Persistent disease after induction 1 or 2 
b. AML in 2nd or subsequent CR 
c. 
Therapy related or Secondary AML 
d. RAEB2 
e. 
Any feature that is considered high risk by the treating 
physician  
f. 
Patients with active disease, who in the opinion of the 
treating physician would benefit from an allogeneic stem cell 
transplant  
C. Myelodysplastic syndrome 
D. Mixed Phenotype Acute Leukemia MRD>1% after consolidation 
E. Non-Hodgkin’s lymphoma (NHL) or Hodgkin’s lymphoma (HL) 
beyond first remission  
F. Chronic Myeloid Leukemia 
a. 
Chronic phase with incomplete response to TKI 
b. Accelerated or Blast crisis 
2) Age ≥3 to ≤50 years old. Subjects 1 and 2 (in Cohort 1) will be ≥ 12 years old 
3) Available mismatched related donor (mMRD) or mismatched unrelated donor 
(mMUD), HLA matched 8/10 or 9/10 
4) Lansky (age <16) or Karnofsky (age ≥16) performance status ≥60% 
5) Able and willing to provide written, signed informed consent (assent as 
appropriate) 
6) Have adequate organ function defined as the following: 
• 
Serum Creatinine <1.5 X upper limit of normal (ULN) or 24-hour 
creatinine clearance >50 ml/min 
• 
Serum bilirubin ≤ 2 x ULN 
• 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
≤10 x ULN 

 
 
  
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• 
DLCO >60% predicted (in children, O2 saturation >92% on room air) 
• 
Left ventricular ejection fraction >45% (in children, shortening fraction 
>26%) 
7) Male and female subjects of child bearing potential must agree to use an 
effective method of birth control to avoid pregnancy throughout the transplant 
procedure, while on immunosuppression, and if the subject experiences any 
chronic GvHD. 
Patient Exclusion Criteria: 
1. Prior bone marrow or peripheral blood HSCT within the last 6 (six) months 
2. HLA-matched related or unrelated donor available 
3. Any active, uncontrolled infection at the time of enrollment 
4. Pregnant or lactating females 
5. Any severe concurrent disease which, in the judgement of the investigator, 
would place the patient at increased risk during participation in the study  
6. Any subject with a history of significant renal, hepatic, pulmonary, or cardiac 
dysfunction or on treatment to support cardiac dysfunction 
7. HIV positive 
8. Non-cooperative behavior or non-compliance of the patient and/or of his/her 
family 
9. Received another investigational agent within 30 days of enrollment 
10. Patients with Down’s syndrome 
Investigational Product, 
Dose, and Mode of 
Administration 
T-allo10 cells will be infused intravenously on Day -1 (day before transplant) in a 3+3 
dose escalation fashion. The first cohort of 3 patients will receive 1x106 cells/kg (+/- 
10%). The subsequent two cohorts will receive 3x106 cells/kg (+/- 10%), and 9x106 
cells/kg (+/- 10%), respectively. 
Study Design and 
Methodology 
This is a single center, non-randomized, non-controlled open-label Phase I trial to evaluate 
the feasibility of manufacturing T-allo10 drug product and the tolerability and safety of 
infusion of T-allo10 cells in children and young adults undergoing mismatched related or 
mismatched unrelated donor HSCT for hematologic malignancies (study schema). 
Before enrollment of a patient in the study, the physician must ensure the patient meets all 
eligibility criteria to be enrolled on the protocol. Eligibility criteria will be reviewed and 
confirmed by the Principal Investigator (PI)/Sub-Investigator (SubI) prior to subject being 
enrolled into the study. 
Patient is considered enrolled into the study on the day of apheresis and will be assigned a 
unique study number. Each study number will be assigned consecutively in increasing 
order starting with “297-01-01”. 
The donor selection is made via a team meeting with attending physicians and an HLA 
expert. The mismatched donors in the patient’s family or NMDP will be eligible for 
donation upon meeting all other criteria for bone marrow or peripheral blood stem cells 
(PBSC) donation. 
Unrelated donors selected from the NMDP must be ≥ 18 as per NMDP guidelines. 

 
 
  
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Related donors will be selected from the patient’s family members and relatives. 
Preference will be given to related donors over the age of 18 whenever possible. 
Related donors under the age of 18 must meet the requirements for apheresis in order to 
be eligible to participate in this study. Detailed apheresis criteria for pediatric patients is 
outlined in Section 6.1. 
Donors will be selected and informed about stem cell donation according to standard 
practice. This will be the responsibility of the transplantation center/NMDP. The donor 
informed consent will be collected (assent as appropriate). A detailed work up will be 
undertaken for the donors as per standard guidelines and institutional SOPs to establish 
eligibility for donation. Detailed inclusion criteria can be found in Section 6. 
The donors will undergo two procedures: 
1. Apheresis for collection of unstimulated mononuclear cells for generation of T- 
allo10 to occur between D– 108 to D- 21.  
2. Bone Marrow Harvest (≥1x108 TNC/kg minimum) or Apheresis for collection of 
mobilized PBSC (≥3x108 TNC/kg minimum) for the infusion of hematopoietic stem 
cells for transplant. 
The PI, according to applicable regulatory requirements, or a person designated by the PI, 
will fully inform the patient of all pertinent aspects of the clinical trial. Prior to a patient’s 
participation in the clinical trial, the Informed Consent Form will be signed and dated by 
the patient, or the patient’s legally authorized representative, and by the person who 
conducted the Informed Consent discussion. 
The Informed Consent Form used by the PI will be reviewed and approved by the IRB prior 
to study initiation.  
The patient will undergo a detailed pre-transplant work up as per institutional guidelines 
including:  
1. Clinical history (previous and concomitant diseases and previous medications). 
2. Physical examination: all organ systems (including a basic neurological 
examination).  
3. Performance status (Lansky or Karnofsky) index.  
4. Complete Blood count + differential. 
5. Comprehensive metabolic panel. 
6. Pregnancy test (if applicable): beta-HCG. 
7. Organ functions- Pulmonary function test, EKG, echocardiography, creatinine 
clearance, nuclear renal scan, liver function test. 
8. Markers of infectious disease. 
If a patient withdraws or fails to meet the screening guidelines, the patient will not be 
enrolled on the clinical trial. 
Apheresis will be performed according to institutional standards to collect unstimulated 
mononuclear cells to generate DC-10 cells between D-109 to D- 27.  Pure red blood cell 
priming of the apheresis machine will be performed when the system extracorporeal blood 
volume exceeds 10-15% of the patient’s blood volume. Institutional guidelines will be 
followed for catheter placement and apheresis procedures. 
 

 
 
  
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Patient Treatment: 
Patient treatment will be divided into 4 phases 
• 
Conditioning 
• 
T-allo10 Cell infusion 
• 
Stem Cell Infusion (Bone Marrow 
Infusion/Peripheral Blood Stem Cells) 
• 
Follow-up 
Conditioning chemotherapy will be administered to prepare the recipient for transplant as 
per the schedule below: 
Day 
Agent 
Dose 
GvHD 
Prophylaxis 
-8 
FTBI 
120cGy X3 
doses 
 
-7 
FTBI 
120cGy X3 
doses 
 
-6 
FTBI 
120cGy X3 
doses 
 
-5 
FTBI 
120cGy X2 
doses 
 
-4 
Cyclophosphamide 
60 mg/kg 
 
-3 
Cyclophosphamide 
60 mg/kg 
Start Sirolimus 
-2 
Rest 
 
 
-1 
T-allo10 cell infusion 
 
 
0 
Stem Cell Infusion 
(TNC/kg) 
BM: ≥1x108 
PBSC: ≥3x108 
 
+1 
 
 
Start 
Mycophenolate 
Mofetil 
 
The last dose of conditioning with cyclophosphamide will be administered on Day -3, 
allowing sufficient time (half-life of cyclophosphamide is 3 to 12 hours) for the clearance 
of the drug before the T-allo10 cell infusion. 
On Day -1 (day before HSCT infusion), T-allo10 will be brought to the stem cell unit and 
thawed at the patient’s bedside. Patients will receive premedication with acetaminophen 15 
mg/kg not to exceed 650 mg and diphenhydramine 1 mg/kg not to exceed 50 mg as per 
institutional standards. The cells will be infused within 30 minutes (or as appropriate for 

 
 
  
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patient weight), and patients will be observed for infusion related reactions for the next 24 
hours. All infusion related toxicities will be recorded, and treatment emergent adverse 
events (TEAE) and treatment emergent serious adverse events (TESAE) will be reported 
according to Section 17.  
On Day 0, the bone marrow will be collected from the donors under general anesthesia; the 
target for collection is ≥1x108 TNC/kg. The bone marrow will be processed in the Bone 
Marrow Transplant Cellular Therapy Facility (BMT-CTF) for red cell or plasma depletion 
as indicated by the blood group incompatibility. The marrow will be transported to the stem 
cell unit by a courier. Patients will receive premedication with acetaminophen and 
diphenhydramine. The bone marrow will be released by the BMT-CTF after release criteria 
are met.  The cells will be infused at least 24 hours after the T-allo10 cell infusion. If the 
patient will receive HSCT from PBSC, granulocyte-colony-stimulating factor (G-CSF) (10 
microgram/kg/day) will be administered to the donor for 5 days prior to undergoing the 
apheresis for collection of PBSC, according to the institutional guidelines. The target for 
PBSC collection is ≥3x108 TNC/kg. Collected cells will be transported to the BMT-CTF 
and released for infusion. Patients will be observed for infusion related reactions to the 
HSCT graft for 24 hours following infusion. All HSC infusion related toxicities will be 
recorded, and adverse events (AE) and serious adverse events (SAE) will be reported 
according to Section 17. 
Patients will be started on Sirolimus on Day -3 at a loading dose of 3 mg/m2, followed by 
1 mg/m2 daily. Sirolimus levels will be monitored at least twice a week to keep the levels 
between 8-12 ng/ml. Mycophenolate Mofetil (MMF) will be started on Day +1 after 
transplant at a dose of 15 mg/kg every 8 hours. Grading of GvHD and all treatments will 
be recorded in the Case Report Form (CRF). 
For the follow-up phase, patients will be evaluated weekly with blood count, blood 
chemistry, microbiological evaluation, clinical evaluation, and GvHD evaluation up to Day 
+60 after HSCT; these same parameters will be then evaluated monthly until Day +365. On 
Days +28, +42, +90, and +180, engraftment will be evaluated (absolute neutrophil count, 
bone marrow cellularity and STR) on peripheral blood and bone marrow. 
Immune reconstitution will be evaluated per Section 7.4. 
Time points outlined in schedules should be closely followed up to Day +60 (+/- 3 days), 
but a tolerance of +/- 10 days is allowed in the later phase (after Day 60). 
Concomitant and prophylactic antimicrobial therapies will be administered according to 
institutional clinical standards. 
Leukocyte-depleted, irradiated red cells and platelet preparations from individual donors or 
pool will be transfused as needed according to clinical standards. 
Statistical Methodology 
The primary analytic focus for this study is to determine and describe the tolerability and 
safety profile of the investigational cellular product at 3 escalating dose levels that can be 
feasibly generated to meet established release criteria. Descriptive statistics for tolerability 
and safety endpoints will be presented for each dose cohort. Examination of any potential 
dose-response relationship with respect to tolerability and safety outcomes will also be 
assessed. Since the study is not designed to provide adequate power for hypothesis testing 
related to clinical activity, the analytic focus for both the primary and secondary endpoints 
will be descriptive. Although hypothesis testing will be conducted for clinical activity, the 
interpretation will be considered exploratory. 
 

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TABLE OF CONTENTS
SPONSOR SIGNATURE PAGE ......................................................................................................2
SPONSOR DETAILS.........................................................................................................................3
PROTOCOL SCHEMA...................................................................................................................18
Recipient, Donor, and Manufacturing Timeline .......................................................................... 19
Transplant Timeline........................................................................................................................ 20
LIST OF ABBREVATIONS ...........................................................................................................21
1
INTRODUCTION.................................................................................................................28
1.1
Hematopoietic Stem Cell Transplantation in Hematologic Malignancies................... 28
1.2
T-allo10 Cells..................................................................................................................... 28
1.3
Adoptive Immunotherapy with T-allo10 Cells in Allogeneic HSCT............................ 29
2
OBJECTIVES........................................................................................................................32
2.1
Primary Objectives........................................................................................................... 32
2.2
Secondary Objective......................................................................................................... 32
2.3
Exploratory Objective...................................................................................................... 32
3
INVESTIGATIONAL PLAN...............................................................................................33
3.1
Study Description.............................................................................................................. 33
3.2
Study Stopping Rules ....................................................................................................... 33
3.3
Number of Patients........................................................................................................... 34
3.4
Number of Sites................................................................................................................. 34
3.5
Investigational material.................................................................................................... 34
T-allo10 cells................................................................................................................... 34
T-allo10 cell dose............................................................................................................ 34
4
STUDY POPULATION........................................................................................................35
4.1
Patient Inclusion Criteria................................................................................................. 35
4.2
Patient Exclusion Criteria................................................................................................ 36
4.3
Donor Selection................................................................................................................. 36
4.4
Study Timeline .................................................................................................................. 37
Primary Completion........................................................................................................ 37
Study Completion ........................................................................................................... 37

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5
PATIENT SCREENING ASSESSMENTS.........................................................................37
5.1
General considerations for Patient and Donor Screening ............................................ 37
5.2
Informed Consent ............................................................................................................. 37
Pediatric Assent............................................................................................................... 37
5.3
Patient Medical History ................................................................................................... 37
5.4
Patient Physical exam....................................................................................................... 38
5.5
Patient Transplant workup.............................................................................................. 38
6
DONOR STUDY PROCEDURES AND DONOR GRAFT PROCESSING ...................38
6.1
Donor Inclusion Criteria.................................................................................................. 38
6.2
Donor Exclusion Criteria................................................................................................. 38
6.3
Donor Screening................................................................................................................ 38
Related Donor Additional Screening .............................................................................. 39
6.4
Donor Consent .................................................................................................................. 39
Unrelated Donor Consent................................................................................................ 39
Related Donor Consent/Assent ....................................................................................... 40
6.5
Donor Apheresis for Generation of T-allo10 Cells ........................................................ 40
6.6
Donor Stem Cell Collection for HSCT............................................................................ 40
Unrelated Donor Apheresis............................................................................................. 40
Unrelated Donor Bone Marrow Collection..................................................................... 40
Related Donor Apheresis ................................................................................................ 40
Related Donor Bone Marrow Collection ........................................................................ 40
6.7
Donor Timeline ................................................................................................................. 41
7
PATIENT STUDY PROCEDURES ....................................................................................42
7.1
Patient Enrollment: Day of recipient apheresis............................................................. 42
7.2
Description of Study Procedures..................................................................................... 42
Medical History............................................................................................................... 42
Physical Exams ............................................................................................................... 42
Vital Signs....................................................................................................................... 42
7.3
Standard Laboratory Assessments ................................................................................. 43
7.4
Immune Function Tests.................................................................................................... 44
Table 7.4.1Immune function test table describing minimum required values to initiate specific tests
44

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Table 7.4.2Immune function test frequency table............................................................................. 44
7.5
Research sample collection and handling....................................................................... 45
7.6
Bone Marrow Aspirate..................................................................................................... 45
7.7
Recipient Apheresis .......................................................................................................... 45
7.8
Screening and Baseline Assessments............................................................................... 45
7.9
Randomization Procedures.............................................................................................. 45
7.10
Unblinding Procedure ...................................................................................................... 45
7.11
Graft-versus-Host Disease Assessments ......................................................................... 45
Independent Evaluator .................................................................................................... 45
Physician Evaluations ..................................................................................................... 45
8
INVESTIGATIONAL PRODUCT ADMINISTRATION.................................................46
8.1
Dose Calculation ............................................................................................................... 46
8.2
Administration.................................................................................................................. 46
8.3
Safety Monitoring ............................................................................................................. 46
9
PATIENT TREATMENT PLAN.........................................................................................47
9.1
Conditioning...................................................................................................................... 47
Cranial Spinal Boost (CSB) ............................................................................................ 47
9.2
GvHD Prophylaxis............................................................................................................ 48
9.3
T-allo10 Cell Infusion....................................................................................................... 48
9.4
Bone Marrow or PBSC Infusion ..................................................................................... 49
9.5
Follow up Phase ................................................................................................................ 49
9.6
Schedule of Events (Recipient) ........................................................................................ 50
10
COHORT MANAGEMENT PLAN ....................................................................................52
10.1
Safety and tolerability: ..................................................................................................... 53
11
DOSE LIMITING TOXICITIES.........................................................................................55
11.1
Definitions.......................................................................................................................... 55
11.2
DLT Exceptions ................................................................................................................ 55
11.3
DLT Assessment Window ................................................................................................ 55
11.4
DLT Reporting Procedures ............................................................................................. 55
Sponsor-Investigator- DLTs will be reported to the sponsor within 24 hours................ 56
Data Safety Monitoring Committee (DSMC)................................................................. 56
12
PATIENT STUDY EVALUATIONS AND PROCEDURES ............................................57

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12.1
Screening Evaluations and Procedures .......................................................................... 57
12.2
Baseline Evaluations and Procedures ............................................................................. 57
12.3
Treatment Evaluations and Procedures ......................................................................... 58
Conditioning:  Day -8 to Day -2 ..................................................................................... 58
T-allo10 Cell Infusion:  Day -1....................................................................................... 58
HSC Infusion:  Day 0...................................................................................................... 58
Post-Transplant follow up phase:.................................................................................... 59
12.4
Early Termination ............................................................................................................ 59
12.5
Screen Failures.................................................................................................................. 60
13
CONCOMMITANT MEDICATIONS................................................................................61
13.1
Medications used to treat AE, SAE, TEAE, and TESAE ............................................. 61
13.2
Immunosuppressive Medications.................................................................................... 61
13.3
Supportive Medications.................................................................................................... 61
Viral Prophylaxis ............................................................................................................ 61
Fever Prophylaxis ........................................................................................................... 61
Fungal Prophylaxis ......................................................................................................... 61
VOD Prophylaxis............................................................................................................ 61
13.4
Medications for GvHD ..................................................................................................... 62
Sirolimus ......................................................................................................................... 62
Mycophenolate Mofetil (MMF)...................................................................................... 62
13.5
Prohibited Medications .................................................................................................... 63
14
CRITERIA FOR SUBJECT REMOVAL FROM STUDY AND COMPLETION ........64
14.1
Dose Limiting Toxicity (DLT) ......................................................................................... 64
14.2
Withdrawal of Consent .................................................................................................... 64
14.3
Completion of Study Visits and Procedures................................................................... 64
14.4
Disease Relapse ................................................................................................................. 64
14.5
Unable to receive T-allo10 cells ....................................................................................... 64
15
CORRELATIVE STUDIES .................................................................................................65
15.1
Laboratory Correlative Studies....................................................................................... 65
16
STUDY ENDPOINTS ...........................................................................................................66
16.1
Primary Endpoint............................................................................................................. 66
16.2
Secondary Endpoint ......................................................................................................... 66

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16.3
Exploratory Endpoint ...................................................................................................... 66
16.4
Analysis of Safety.............................................................................................................. 66
17
SAFETY REPORTING/DATA AND SAFETY MONITORING PLAN.........................67
17.1
Definitions.......................................................................................................................... 67
Adverse Event (AE)........................................................................................................ 67
Treatment-Emergent Adverse Events (TEAE) ............................................................... 67
Serious Adverse Event (SAE)......................................................................................... 68
Suspected Adverse Reaction........................................................................................... 68
Unexpected adverse reaction .......................................................................................... 69
Pregnancies ..................................................................................................................... 69
Protocol Deviations......................................................................................................... 69
17.2
Adverse Event Characteristics ........................................................................................ 69
Severity ........................................................................................................................... 69
Relationship to Investigational Product .......................................................................... 69
17.3
Adverse Event and Serious Adverse Event Reporting.................................................. 70
Type and Duration of Follow-Up of Adverse Events..................................................... 70
Post-Study Adverse Event .............................................................................................. 71
Investigator Reporting Requirements ............................................................................. 71
Fatal/Life-Threatening SAE Related to Investigational Product .................................... 72
17.4
Sponsor-Investigator Reporting to FDA and DSMC .................................................... 72
Suspected Unexpected Serious Adverse Reactions (SUSARs) ...................................... 72
Serious Adverse Event Reporting on Cell Therapy Products to the FDA...................... 73
Reporting to the DSMC .................................................................................................. 73
17.5
Data Safety Monitoring Committee (DSMC)................................................................. 74
DSMC review for grade III-IV acute GvHD .................................................................. 74
17.6
Graft versus Host Disease (GvHD) Evaluator ............................................................... 74
18
INVESTIGATIONAL PRODUCT MANAGEMENT.......................................................75
18.1
T-allo10.............................................................................................................................. 75
18.2
Cyclophosphamide............................................................................................................ 75
Administration ................................................................................................................ 75
Dose adjustments ............................................................................................................ 75
Patient Monitoring .......................................................................................................... 75

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18.3
Mesna................................................................................................................................. 75
Administration ................................................................................................................ 75
18.4
Total Body Irradiation (TBI)........................................................................................... 75
Cranial Spinal Boost (CSB) ............................................................................................ 75
19
GENERAL CONSIDERATIONS........................................................................................75
19.1
Basic Principles ................................................................................................................. 75
19.2
Institutional Review Board (IRB) ................................................................................... 76
19.3
Informed Consent ............................................................................................................. 76
Pediatric Assent Process ................................................................................................. 77
19.4
Study Termination............................................................................................................ 77
19.5
Regulatory Documentation.............................................................................................. 77
19.6
Study Documentation....................................................................................................... 78
19.7
Data Handling and Record Keeping............................................................................... 78
19.8
Use of Information and Publication................................................................................ 79
20
STATISTICAL ANALYSIS METHODOLOGY...............................................................80
20.1
Tolerability and safety endpoints.................................................................................... 80
20.2
Feasibility endpoint .......................................................................................................... 81
20.3
Efficacy endpoints............................................................................................................. 81
20.4
Analysis Datasets .............................................................................................................. 81
20.5
Disposition and Study Population Characteristics........................................................ 82
21
REFERENCES ......................................................................................................................83
22
APPENDICES .......................................................................................................................85
22.1
Lansky Performance Score.............................................................................................. 85
22.2
Karnofsky Performance Score ........................................................................................ 86

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PROTOCOL SCHEMA
Patient
Age [3y-45y] Hematologic Malignancy
Donor
8/10 or 9/10 mMRD, mMUD
Transplant
Workup
Patient Enrollment /
Un-stimulated Apheresis
Donor NMDP/IRB Consent
Patient Consent
Patient Cells
Donor Cells
T-allo10 cell 
Manufacturing
Day (-8 to -3)
Conditioning: TBI-Cy
HSC Donation (BM/PB)
   Day (-3) Sirolimus
T-allo10 cell 
infusion (Day-1)
Observation
Days {-1 to +365}
•
Tolerability
•
Safety
Pre-HSCT
Evaluations,
Cell preparation
HSC infusion
(Un-manipulated) 
(Day 0)
Patient Pre-
Screening
Patient Study 
Screening
Donor Pre-
Screening
Donor Un-stimulated 
Apheresis
Donor Study 
Screening

 
 
  
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Recipient, Donor, and Manufacturing Timeline  
Ideal 
Day 
Window Recipient 
Procedure 
Donor Procedure Manufacturing Procedure 
D-27 
D-109 to 
D-27 
Recipient 
Apheresis 
(Enrollment) 
 
D-26 
D-108 to 
D-26 
 
7 day culture of recipient CD14+ cells 
in the presence of GM-CSF + IL-4 
D-24 
D-108 to 
D-21 
Donor Apheresis 
(LPCHS or NMDP) 
D-19 
D-101 to 
D-19 
 
DC-10 & CD4+ cells co-cultured for 10 
days 
D-9 
D-91 to 
D-9 
Finish co-culture for T-allo10; Cells 
frozen at the end of co-culture;  Testing 
of T-allo10 to meet release criteria 
D-2 
D-84 to 
D-2 
 
  
CoA/Product Release (Ready for 
Infusion) 
D -1 
T-allo10 cell 
infusion 
D 0 
Stem Cell 
Infusion 
  
 
 

 
 
  
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Transplant Timeline 
Day 
Agent 
Dose 
GvHD 
Prophylaxis 
-8 
FTBI 
120cGYx3 doses 
-7 
FTBI 
120cGYx3 doses 
-6 
FTBI 
120cGYx3 doses 
-5 
FTBI 
120cGYx2 doses 
 
-4 
Cyclophosphamide 
60mg/kg 
-3 
Cyclophosphamide 
60mg/kg 
Start sirolimus 
-2 
Rest 
-1 
T-allo10 cell infusion 
0 
Stem Cell Infusion 
(TNC/kg) 
BM: ≥1 x 108 
PBSC: ≥3 x 108 
+1 
Start MMF 
 
 

 
 
  
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LIST OF ABBREVATIONS 
ABO 
Blood grouping 
Abs 
Absolute 
AE 
Adverse event 
AdV 
Adenovirus 
ADR 
Adverse Drug Reaction 
Ag 
Antigen 
aGvHD 
Acute Graft-versus-Host Disease 
ALL 
Acute Lymphoblastic Leukemia 
Allo 
Allogeneic 
ALT 
Alanine transaminase 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute Neutrophil Count 
APC 
Antigen presenting cell 
AST 
Aspartate transaminase 
Auto 
Autologous 
BM 
Bone marrow 
BM bx 
Bone marrow biopsy 
BMI 
Body mass index 
BMT 
Bone Marrow Transplant 
BP 
Blood pressure 
BSA 
Body surface area 
BUN 
Blood Urea Nitrogen 
CBC 
Complete blood count 
CCTO 
Cancer Clinical Trials Office 

 
 
  
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CD 
Crohn’s Disease 
cGvHD 
Chronic Graft-versus-Host Disease 
CI 
Confidence interval 
CMAX 
Maximum concentration of drug 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
Co-PI(s) 
Co-Investigator(s) 
COA 
Certificate of Analysis 
CRF 
Case report/record form 
CR 
Complete response 
CSB 
Cranial Spinal Boost 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTF 
Cellular Therapy Facility 
CXR 
Chest X-ray 
CY 
Cyclophosphamide (Cytoxan) 
DLI 
Donor Leukocyte Infusion 
DLT 
Dose Limiting Toxicity 
DSMC 
Data Safety Monitoring Committee 
EBV 
Epstein Barr Virus 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
Echo/ECO 
Echocardiogram  
EFS 
Event-free survival  
F 
Fahrenheit 

 
 
  
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FA 
Fanconi Anemia 
FACT 
Foundation for the Accreditation of Cellular Therapy 
FAB 
French-American-British 
FDA 
Food and Drug Administration 
FLT 
FMS-like tyrosine Kinase 
FTBI 
Fractionated total body irradiation 
GCP 
Good clinical practice 
G-CSF 
Human granulocyte-colony stimulating factor  
GI 
Gastrointestinal 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyltransferase 
GvHD 
Graft-versus-Host Disease 
GVL 
Graft-versus-Leukemia 
IB 
Investigator brochure 
IBW 
Ideal body weight 
ICF 
Informed consent form 
IND 
Investigational new drug application 
IP 
Investigational product 
IS 
Immunosuppression 
ITD 
Internal tandem duplication 
IV 
Intravenous 
HBV 
Hepatitis B Virus 
HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C Virus 
Hgb 
Hemoglobin 

 
 
  
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HIV 
Human Immunodeficiency Virus 
HHV 
Human Herpes Virus 
HLA 
Human leukocyte antigen  
HR 
Heart rate 
HRS. 
Hours 
HSC 
Hematopoietic Stem Cell 
HSCT 
Hematopoietic Stem Cell Transplantation 
HSV 
Herpes Simplex Virus 
HTLV 
Human T Cell Lymphotropic Virus 
HTN 
Hypertension 
IRB 
Institutional Review Board 
IV 
Intravenous 
LAR 
Legal authorized representative 
LDH 
Lactate dehydrogenase 
LLN 
Lower limit of normal 
LPCHS 
Lucile Packard Children’s Hospital at Stanford 
M2 
Meter squared 
MAD 
Maximally Administered Dose 
MD 
Medical Doctor 
MDS 
Myelodysplastic Syndrome 
MFD 
Maximum Feasible Dose 
MMF 
Mycophenolate Mofetil 
mMRD 
Mismatched related donor 
mMUD 
Mismatched unrelated donor 

 
 
  
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MRD 
Minimal Residual Disease 
MTD 
Maximum Tolerable Dose 
MUGA 
Multi Gated Acquisition Scan 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NIH 
National Institute of Health 
NMDP 
National Marrow Donor Program 
NTE 
Not to exceed 
OS 
Overall survival 
PB 
Peripheral blood 
PBSC 
Peripheral blood stem cells 
PCR 
Polymerase chain reaction 
PCR-SSOP 
Polymerase chain reaction –sequence specific oligonucleotide probe 
PD 
Progressive diseased 
Peds 
Pediatric patients 
PFS 
Progression free survival 
PFT 
Pulmonary function test 
PD 
Protocol Director 
pHA 
Polyhydroxyalknoates 
PHA SI 
Phytohaemaglutinin Stimulation Index 
PHI 
Protected Health Information 
PI 
Principal investigator 
PLT 
Platelet 
PMRD 
Partially matched donor 
PO 
‘per Os’ –daily 

 
 
  
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PR 
Partial response 
Q 
Every 
QD 
Once daily 
QIg 
Qualitative Immunoglobulin 
QOD 
Every other day 
r-ATG 
Polyclonal rabbit anti-thymocyte globulin  
RAEB 
Refractory anemia with excess blasts 
RN 
Registered Nurse 
RNA 
Ribonucleic acid 
RR 
Response rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCCI 
Stanford Center for Clinical Informatics 
SCID 
Severe Combined Immune Deficiency 
SCT 
Stem cell transplantation 
SD 
Stable disease 
SCT&RM 
Stem Cell Transplantation and Regenerative Medicine 
SDV 
Source document verification 
SHC 
Stanford Health Care 
Siro 
Sirolimus 
SOP 
Standard Operating Procedure  
STR 
Short tandem repeat 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TBI 
Total body irradiation 
Td 
Tetanus, (reduced) Diphtheria 

 
 
  
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TCR 
T cell Receptor 
TEAE 
Treatment-emergent adverse events 
TGFβ 
Transforming Growth Factor beta 
TH 
Thursday 
TNC 
Total Nucleated Cells 
TRM 
Transplant-related mortality 
Treg 
T regulatory cells 
tTreg 
Thymic derived T regulatory cells 
TTP 
Time to progression 
UCB 
Umbilical Cord Blood 
ULN 
Upper limit of normal 
UNK 
Unknown 
URD 
Unrelated donor 
VNTR 
Variable number tandem repeat 
VZV 
Varicella Zoster Virus 
WB 
Whole blood 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 
 

 
 
  
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1 INTRODUCTION 
1.1 
Hematopoietic Stem Cell Transplantation in Hematologic Malignancies 
Hematologic malignancies comprise 34% of all childhood cancers. Approximately one third of these 
patients will have an urgent need for Hematopoietic Stem Cell Transplantation (HSCT) to achieve 
better long-term outcomes. Allogeneic HSCT is the curative option for several hematologic 
malignancies; however, its broad application is limited by the frequent occurrence of GvHD, a life-
threatening complication mediated by alloreactive donor T cells recognizing host healthy tissues (4). 
The incidence and severity of GvHD directly correlates with the degree of HLA histo-incompatibility 
between the donor and the host, posing a significant limitation to the clinical applicability of 
allogeneic HSCT. Less than 50% of the patients have a HLA matched sibling or unrelated donor 
suitable for transplant. The rest of the patients need either to find a HLA mismatched related donor 
or a HLA mismatched unrelated donor for the source of HSC. Patients who receive HSCT from 
mismatched related or mismatched unrelated donors are at high risk for developing severe GvHD. 
Importantly, the benefit of the transplant resides not only in the possibility of reconstituting new blood 
tissue but also in providing allogeneic T cells which can kill the leukemic cells (GvL effect).  
We analyzed the incidence of acute and chronic GvHD in patients (ages 3 to 30 years) undergoing 
mismatched related or mismatched unrelated HSCT at Lucile Packard Children’s Hospital Stanford 
(LPCHS) and Stanford Hospital and Clinics (SHC). In this analysis, the incidence of acute GvHD 
was 57%, and of these patients, 26% developed grade III-IV GvHD leading to significant morbidity 
and mortality. In addition, 30% of patients developed chronic GvHD. The presence of acute and 
chronic GvHD requires treatment with systemic pharmacological immunosuppression, which is 
associated with serious side effects including delayed immune reconstitution, increased incidence 
of infections and organ damage. These results confirm the need for novel strategies to reduce GvHD 
and improve long-term tolerance between mismatched donor-host pairs, with the ultimate goal of 
extending the application and improving the outcomes of HSCT from allogeneic donors with partial 
HLA histocompatibility. 
1.2 
T-allo10 Cells 
T-allo10 cells consist of CD4+ cells of donor origin that have been exposed to host alloantigens in 
vitro in the presence of IL-10. During this primary stimulation, the CD4+ cells acquire a 
hyporesponsive state (anergy) to subsequent stimulation with the same alloantigens (2, 5, 6). In 
addition, they become able to suppress primary responses of autologous CD4+ and CD8+ T cells 
towards the same alloantigens (7). This property is mainly due to the induction of a specific population 
of T regulatory cells called T regulatory type 1 (Tr1) cells during the in vitro culture in the presence 
of IL-10. IL-10 is an immunomodulatory cytokine that plays a central role in controlling inflammation, 
down-regulating immune responses, and inducing immunological tolerance (8, 9). IL-10 inhibits 
proliferation and cytokine production by T cells via down-regulating production of inflammatory 
cytokines as well as expression of costimulatory molecules on antigen presenting cells (APC). 
Importantly, IL-10 induces long lasting antigen specific T cell anergy and differentiation of Tr1 cells 
in both mice and humans (6, 10). Tr1 cells have been described in several preclinical and clinical 
models in association with induction and maintenance of immunological tolerance (1, 10, 11).  
Tr1 cells are characterized by a unique cytokine production profile since they produce high levels of 
IL-10, TGF-β and IL-5, low levels of IFN-γ and IL-2, and no IL-4 and IL-17 (12, 13, 14). Tr1 cells 

 
 
  
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are anergic in vitro and actively suppress immune responses by T effector cells mainly via IL-10 and 
TGF-β. Until recently, Tr1 cells could be identified only based on their cytokine production profile. 
We have recently demonstrated that CD49b+LAG-3+ cells are good markers to define Tr1 cells (12).  
The vast majority of memory CD4+CD49b+LAG-3+ T cells secrete large amounts of IL-10 but not 
significant levels of IL-4 and IL-17, do not constitutively express FOXP3, and display regulatory 
activity both in vitro and in vivo (12). Both CD49b and LAG-3 are stably expressed on functional 
human Tr1 cell clones. CD49b is expressed on Tr1 cells irrespectively of their activation state, whereas 
LAG-3 is expressed on Tr1 cells upon activation when the cells produce IL-10 and display suppressor 
activity. CD49b and LAG-3 have been used to identify Tr1 cells in the peripheral blood of healthy 
donors and, at higher frequency, of tolerant patients (12). Furthermore, CD49b and LAG-3 can track 
Tr1 cells in cell products generated in vitro (12). 
Tr1 cells were first identified and characterized in Severe Combined Immune Deficient (SCID) 
patients who were immune reconstituted after HSCT from HLA mismatched donors (15, 16). These 
patients developed spontaneous split chimerism, with T and natural killer (NK) cells of donor origin 
and B and professional APC of host origin in the absence of GvHD. Cultures of the PBMC of these 
chimeras led to the isolation of donor derived CD4+ and CD8+ T cell clones that were specific for the 
HLA of the host. These data indicated that alloreactive T cells were not deleted from the T cell 
repertoire of the patients. However, a high proportion of these T cell clones had the Tr1 cytokine 
production profile as described above and IL-10 dependent low proliferation when activated with the 
host alloantigens in vitro (16). These findings correlated with the absence of GvHD and a state of 
active tolerance between host and donor cells. Similar data were also obtained from β thalassemic 
patients when these patients developed persistent mixed chimerism following HSCT (7). The presence 
of Tr1 cells in vivo was confirmed by detection of CD49b+ and LAG-3+ T cells at higher frequency 
in the peripheral blood mononuclear cells (PBMC) of these tolerant patients as compared to normal 
donors’ PBMC (12). This provides a strong rationale for the clinical application of these cells to favor 
immunological tolerance.   
Several protocols have been developed to generate Tr1 cells in vitro that are suitable for in vivo use, 
and it is clear that, although IL-10 is indispensable for Tr1 cell induction, efficient in vitro production 
of Tr1 cells also requires APC.  
Tr1 cell induction in vitro is optimal when DC-10 are used as APC. DC-10 are monocyte-derived 
dendritic cells generated in vitro in the presence of exogenous IL-10 in addition to GM-CSF and IL-
4, commonly required for mature myeloid derived DC generation in vitro (17). Stimulation of CD4+ 
cells with allogeneic DC-10 and IL-10 is more efficient in generating a Tr1 cell product that can 
suppress primary antigen-specific proliferative responses of autologous naïve CD4+ cells (12, 18).  
The T-allo10 cell culture we are planning to use in the present trial is optimized to maximize the 
induction of Tr1 cells, detectable as IL-10 producing CD4+CD49b+LAG-3+ T cells, starting from 
purified CD4+ cells cultured with DC-10 as APC in the presence of IL-10. This cell product is suitable 
for controlling host alloantigen specific immune responses by donor T cells in the transplant. 
 
1.3 
Adoptive Immunotherapy with T-allo10 Cells in Allogeneic HSCT 
The clinical use of different types of T regulatory cells has been explored by several groups to 
improve the outcome of allogeneic HSCT by boosting the natural mechanisms of tolerance mediated 

 
 
  
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by the T regulatory cells. In particular, adoptive transfer of CD4+CD25+ Treg containing a high 
proportion of FOXP3+ T cells has been performed by several groups, and has been shown to be safe 
(19, 20, 21).  
The main advantage of adoptive immunotherapy with Tr1 cells compared to Treg cells is the host 
alloantigen specificity that is established in the donor Tr1 cells during in vitro culture in the presence 
of IL-10 and host alloantigens (T-allo10 cells or IL-10 anergized T cells). The Tr1 cells present in 
the resulting T-allo10 cell product can exert their function without purification. Indeed, the presence 
of additional CD4+ cells can also mediate transfer of immune competence. 
We first performed a cell therapy trial (ALT TEN trial) using IL-10 anergized T cells prepared in 
vitro and administered to adult patients transplanted with purified CD34+ HSC from haploidentical 
donors with the objective to favor immune reconstitution without severe GvHD, in the absence of 
any immunosuppression (22). These donor-derived, host alloantigen specific, IL-10 anergized T cells 
were infused in a total of 12 patients approximately one month after transplant and after the patients 
showed myeloid engraftment. Overall, feasibility and safety of infusion of the IL-10 anergized T cells 
was demonstrated. Four out of eight evaluable patients fully immune reconstituted, remained disease 
free and had evidence of a tolerance signature on long-term follow-up (22). Although assessed in a 
limited number of patients, this outcome suggests efficacy of the IL-10 anergized T cell therapy when 
compared to the outcomes obtained from haploidentical transplants with purified CD34+ HSC alone 
in which infections and disease-relapse occurred in the majority of the patients (23, 24).  The safety 
data from the ALT TEN trial supports the decision to administer the T-allo10 cells in children and 
young adults (≥3 to ≤30) who have no other effective treatment options.  For an abundance of caution, 
we will evaluate the safety of the T-allo10 cell product for up to 28 days in patients who are ≥ 12 
years of age in the first dose cohort prior to treating children < 12 years of age.   We are planning to 
initiate our proposed Phase I dose escalation study with a dose of 106 T-allo10 cells/kg. This cell dose 
is similar to that used in other adoptive transfer trials with Treg cells (21) although it is higher than 
that previously used in the ALT TEN trial. The rationale for choosing a higher initial cell dose in the 
proposed trial is related to the following considerations:   
i. 
T-allo10 cells are infused with 8/10 or 9/10 HLA mismatched related and mismatched 
unrelated unmanipulated HSCT. The ALT TEN trial patients received IL-10 anergized T cells 
after purified CD34+ HSCT from haploidentical donors with minimal T cell content (≤ 
2.6x104 CD3+ T cells/kg). In the present trial the presence of a higher number of T cells (≥ 
107 CD3+ T cells /kg and ≥ 108 CD3+ T cells /kg in BMT and PBSC transplants, respectively) 
(25) within the HSCT will require an incremental increase in the number of Tr1 cells in order 
to suppress the alloreactive donor T cells, which are responsible for the GvHD incidence.  The 
T-allo10 cells will contain a higher frequency of Tr1 cells as compared to the IL-10 anergized 
T cells used in the ALT TEN trial. Nevertheless, because of the presence of higher number of 
T cells within the graft, the infused T-allo10 cells may be less able to undergo homeostatic 
expansion, as compared to the ALT TEN trial patients who were severely lymphopenic (26).    
ii. 
T-allo10 cells are infused in the presence of immunosuppression, which is the standard of care 
for the study population receiving the mismatched related and mismatched unrelated 
unmanipulated HSCT. The ALT TEN trial patients were not treated with immunosuppressive 
drugs for GvHD prophylaxis at the time of the HSC graft and at the time of IL-10 anergized 
T cell infusion.  

 
 
  
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In the trial described herein, we propose to administer T-allo10 cells, one day before the infusion of 
hematopoietic stem cells for the transplant in the setting of mismatched related or mismatched 
unrelated unmanipulated HSCT, as opposed to the timing of cell administration in the ALT TEN trial 
where Tr1 cells were infused after 4 weeks of stem cell transplantation. We expect that early T-allo10 
cell infusion will modulate the host alloreactivity of the donor T cells present in the unmanipulated 
mismatched HSCT. At the same time, the donor T-allo10 cells specific for the host alloantigen will 
not interfere with the ability of the other donor T cells to mount immune responses against pathogens.  
We will start immunosuppression with sirolimus and mycophenolate mofetil (MMF), as described in 
Section 9.2.  As compared to calcineurin inhibitors, sirolimus is permissive and favorable to the in 
vivo expansion of Tr1 cells (27) and MMF does not appear to interfere with T regulatory cell function 
(21).  
 
 

 
 
  
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2 OBJECTIVES 
2.1 
Primary Objectives 
To assess the tolerability and safety of escalating doses of T-allo10 cell infusions that can be feasibly 
manufactured to meet release specifications in mismatched related or mismatched unrelated 
unmanipulated HSCT in patients with hematologic malignancies.  
 
2.2 
Secondary Objective 
• To assess the incidence of grade III and IV acute GvHD. 
 
2.3 
Exploratory Objective 
• To assess the incidence and severity of chronic GvHD. 
• To assess the time to immune reconstitution. 
• To assess Disease Free Survival. 
 
 
 

 
 
  
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3 INVESTIGATIONAL PLAN 
3.1 
Study Description 
This is a single center, non-randomized, non-controlled open-label Phase I trial to evaluate the 
feasibility of generating T-allo10 cells that meet the established release criteria, and the tolerability 
and safety of administration of escalating doses of T-allo10 cell infusions in mismatched related or 
unrelated donor HSCT for hematologic malignancies.  
The study design is outlined in the protocol schema. Up to 27 eligible patients will be evaluated 
sequentially in 3 escalating dose cohorts of T-allo10 cells. Each cohort will begin by evaluating 3 
patients. There will be a 28 day safety evaluation between the first and second subject in cohort one.  
The second subject in cohort one will be treated no sooner than 29 days after the first subject’s 
infusion of T-allo10 (after safety assessment). Subsequent subjects in cohort one may be treated with 
T-allo10 at least 28 days after the preceding subject is treated with T-allo10 in the cohort. After 
infusion of T-allo10 in the last subject of each cohort, there will be a 28 day safety evaluation period. 
If the cohort meets safety and tolerability criteria, subsequent subjects may be enrolled in the cohort 
of the next higher cell dose. In cohorts two and three subjects may be treated with T-allo10 at least 
28 days after the preceding subject is treated with T-allo10 in the cohort. If 1 out of 3 patients in a 
cohort has a DLT, 3 additional patients will be evaluated at the same dose level. If 1 out of 6 patients 
experience a DLT, dose escalation will occur. If 2 out of ≤ 6 patients experience DLT, dose escalation 
will cease and that dose will become maximally administered dose. Up to three (3) additional patients 
will be evaluated at the next lowest dose level if only 3 patients were treated previously at that dose. 
The maximum tolerated dose (MTD) is the highest dose level that can be feasibly generated to meet 
established release criteria at which no more than 1 out of 6 patients experience a DLT from the 
infusion of T-allo10 cells, or the dose below that at which at least 2 (of ≤ 6) patients have a DLT as 
a result of the infusion of T-allo10 cells. 
In addition to evaluating up to 6 patients at a given dose level with respect to toxicity, the number of 
patients for whom the targeted cell dose number can be successfully manufactured will be 
determined.  Dose escalation will proceed as long as an adequate cell dose can be manufactured for 
at least 3 of the first ≤ 6 patients in a dose level for evaluation.  If cells generated for any patient do 
not meet the minimal T-allo10 cell dose for the specified cohort, the patient will receive the total 
number of manufactured T-allo10 cells, as the efficacious dose level is not known; that patient will 
be evaluable for toxicity, but will be considered a manufacturing failure in the targeted dose cohort 
(as outlined in Section 10).  A maximum of 3 additional patients may be added to a dose cohort due 
to inability to achieve target doses. 
3.2 
Study Stopping Rules 
The stopping rules for this study will be as follows: 
• Any Treatment Related Mortality (TRM) for any subject at any dose within 100 days of 
HSCT. 
• TRM – Treatment Related Mortality is defined as death possibly related to the T-
allo10 cell infusion as per Section 17.2.2. 
• Failure to engraft in 2 out of 3 or 3 out of 6 patients. 

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•
If 4 out of 6 patients develop grade III and above acute GvHD.
If any of the above stopping rules are met, enrollment to the study will be suspended pending 
discussions with the FDA and DSMC.
3.3
Number of Patients
Each dose cohort is expected to evaluate a minimum of 3 patients and a maximum of 6 patients to 
determine MTD. In addition, the study will allow for up to 3 additional patients to be evaluated in 
each of the dose cohorts (total of 9 additional patients) due to inability to achieve target doses. If any 
patient is withdrawn from study for any reason (withdrawal of consent, relapse before start of 
chemotherapy) before receiving the T-allo10 cells, the patient will not be counted in total evaluable 
patients and will be replaced. Up to a maximum of 3 inevaluable patients may be replaced. The 
maximum number of patients that may be enrolled will be 30 (18 in the dose escalation + 9 to replace 
3 per dose cohort that fail to meet manufacturing specifications + 3 who withdraw from study for any 
reason).
3.4
Number of Sites
This trial will be conducted at Lucile Packard Children’s Hospital Stanford (LPCHS) and Stanford 
Health Care (SHC).
3.5
Investigational material
T-allo10 cells
T-allo10 cells are donor derived CD4+ cells that have been exposed in vitro to the host (patient) 
antigen presenting cells (APC) in the presence of IL-10.  These CD4+ cells are hyporesponsive 
(anergic) to the host alloantigens and contain host alloantigen-specific Tr1 cells.
T-allo10 cell dose
T-allo10 cells will be administered in suspension as a single intravenous infusion at doses of 106/kg
(+/- 10%) or 3 x106/kg (+/- 10%) or 9x106/kg (+/- 10%). If any patient does not meet the minimal T-
allo10 cell dose for their specified cohort, they will receive the total manufactured T-allo10 cells. If 
de-escalation is needed the de-escalation dose will be defined as per Section 10.  All dosing for the 
T-allo10 cells will be based on actual body weight.

 
 
  
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4 STUDY POPULATION 
4.1 
Patient Inclusion Criteria 
1. Eligible diseases include: 
A. Acute Lymphoblastic Leukemia (B- or T-ALL) 
a. CR-1-ultra high risk features 
• Unfavorable cytogenetics 
• Hypodiploidy 
• Induction failure 
• MRD positive after consolidation 
b. CR-2  
• 
Any of the high risk features listed in CR1 
• 
B-ALL: any relapse considered eligible for transplant  
• 
T- ALL 
c. CR-3-any 
d. Any feature that is considered high risk by the treating physician  
B. Acute Myeloid Leukemia 
a. CR1 -ultra high-risk features (eligible for stem cell transplantation) 
• Unfavorable cytogenetics 
• Persistent disease after induction 1 or 2 
b. AML in 2nd or subsequent CR 
c. Therapy related or Secondary AML 
d. RAEB2 
e. Any feature that is considered high risk by the treating physician  
f. Patients with active disease, who in the opinion of the treating physician 
would benefit from an allogeneic stem cell transplant  
C. Myelodysplastic syndrome 
D. Mixed Phenotype Acute Leukemia MRD>1% after consolidation 
E. Non-Hodgkin’s lymphoma (NHL) or Hodgkin’s lymphoma (HL) beyond first 
remission  
F. Chronic Myeloid Leukemia 
a. Chronic phase with incomplete response to TKI 
b. Accelerated or Blast crisis 

 
 
  
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2. Age ≥3 to ≤50 years old. Subjects 1 and 2 (in Cohort 1) will be ≥ 12 years old 
3. Available mismatched related (mMRD) or mismatched unrelated (mMUD) donor, HLA 
matched 8/10 or 9/10  
4. Performance status Lansky (age < 16) or Karnofsky score (age ≥ 16) ≥ 60%. 
5. Able and willing to provide written, signed informed consent (assent as appropriate) 
6. Have adequate organ function defined as the following: 
• Serum creatinine < 1.5 × ULN or 24-hour creatinine clearance > 50 ml/min 
• Serum bilirubin ≤ 2 × ULN  
• ALT and AST ≤ 10 × ULN 
• DLCO > 60% predicted (in children, O2 saturation > 92% on room air) 
• Left ventricular ejection fraction >45% (in children, shortening fraction >26%) 
7. Male and female subjects of childbearing potential must agree to use an effective means 
of birth control to avoid pregnancy throughout the transplant procedure, while on 
immunosuppression, and if the subject experiences any chronic GvHD 
4.2 
Patient Exclusion Criteria 
1. 
Prior bone marrow or peripheral blood stem cell transplantation within the last 6 (six) 
months 
2. 
HLA-matched related or unrelated donor available 
3. 
Any active, uncontrolled infection at the time of enrollment 
4. 
Pregnant or lactating females 
5. 
Any severe concurrent disease which, in the judgment of the investigator, would place 
the patient at increased risk during participation in the study 
6. 
Any subject with a history of significant renal, hepatic, pulmonary dysfunction, or 
cardiac dysfunction or on treatment to support cardiac dysfunction 
7. 
HIV-positive 
8. 
Non-cooperative behavior or non-compliance of the patient and/or of his/her family 
9. 
Received another investigational agent within 30 days of enrollment 
10. Patients with Down’s syndrome 
4.3 
Donor Selection 
The donor selection is made via a team meeting with attending physicians and an HLA expert. The 
mismatched donors in the patient’s family or NMDP (National Marrow Donor Program) will be 
eligible for donation upon meeting all other criteria for bone marrow or peripheral blood stem cells 
(PBSC) donation. 
Unrelated donors selected from the NMDP must be ≥ 18 as per NMDP guidelines. 

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Related donors will be selected from the patient’s family members and relatives. Preference will be 
given to related donors over the age of 18 whenever possible. Detailed apheresis criteria for pediatric 
patients is outlined in Section 6.1.
Donors will be selected and informed about stem cell donation according to standard practice. This 
will be the responsibility of the transplantation center/NMDP. Donors screening and workup will be 
performed according to 21CFR1271 (see link) requirements and institutional guidelines. NMDP 
patients will be screened according to NMDP institutional requirements. Confirmatory testing will 
be performed at LPCHS or SHC as required by law. The donor informed consent will be collected. 
A detailed work up will be undertaken for the donors as per standard guidelines and institutional 
SOPs to establish the eligibility for donation. 
4.4
Study Timeline
Primary Completion
Recruitment period for this study is expected to be 2 years and 6 months.  Subjects will be followed 
for 1 year after treatment. 
Study Completion
Total duration of this study is expected to be 3 years and 6 months.
5
PATIENT SCREENING ASSESSMENTS
5.1
General considerations for Patient and Donor Screening
Patients who are considered to be appropriate for the study will be initially pre-screened based upon 
review of the medical record, their oncologic history, and performance status.  In order to confirm 
patient eligibility for the study, patients must first undergo an informed consent process to permit 
review of qualifying laboratories and to perform additional tests. All patients will undergo the 
screening procedures according to Section 12.1.
Donors will undergo a separate screening and qualification evaluation in accordance to Section 6.
5.2
Informed Consent
All participants will be provided a consent form describing the study with sufficient information for 
participants to make an informed decision regarding their participation in this study.  Details of the 
consent process are outlined in Section 19.3. IRB approval will be obtained prior to initiating the 
consenting process.  
Pediatric Assent
All participants between the ages of 7 and 17 years old will be provided with an assent describing all 
procedures to be performed throughout this study. See Section 19.3.1 for details regarding the assent 
process.
5.3
Patient Medical History
The patient’s complete history through review of medical records and by interview will be collected 
and recorded.  Concurrent medical signs and symptoms must be documented to establish baseline 

 
 
  
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severities.  A disease history, including the date of initial diagnosis and list of all prior treatment, 
responses, and duration of response to the prior treatment also will be recorded. 
5.4 
Patient Physical exam 
A complete physical examination will be performed.  The exam will include general appearance of 
the patient, height (at baseline only) and weight, examination of the skin, eyes and ears, nose, throat, 
lungs, heart, abdomen, musculoskeletal system, and nervous system.  Performance status will be 
scored on all subjects. Subjects under the age of 16 will be scored according to the Lansky Scale. 
Subjects who are ≥16 will be scored according to the Karnofsky Performance Status.  
5.5 
Patient Transplant workup 
The patient will undergo an extensive pre-transplant work up. Work-up procedures must be 
completed prior to the start of conditioning. Infectious disease markers (IDMs) may be repeated to 
comply with Federal guidelines concerning transplantation. Recipient work up will follow the 
institutional guidelines. 
 
6 DONOR STUDY PROCEDURES AND DONOR GRAFT PROCESSING 
6.1 
Donor Inclusion Criteria 
Donors will be evaluated for participation in this study according to the following inclusion criteria: 
1. Donors must meet all criteria for donation as per 21 CFR1271 Subpart C. 
2. Unrelated donors must be ≥ 18 as per NMDP guidelines. 
3. Related donors will be selected from the patient’s family members and relatives. Preference will 
be given to related donors over the age of 18 whenever possible.  If minor donors are to be enrolled, 
they will be a minimum of 12 years old.  Detailed apheresis criteria for pediatric patients is outlined 
in section 6.3 of the protocol. 
4. Related donors must meet all requirements to donate as per LPCH SOP for donors. 
5. Able and willing to provide written, signed informed consent (assent as appropriate). 
 
6.2 
Donor Exclusion Criteria 
Donors will be excluded from participating in this study according to the following exclusion criteria: 
1. Donors who do not meet 21 CFR 1271 Subpart C requirements per the FDA to donate. 
2. Donors who are unwilling or unable to sign informed consent (assent when appropriate). 
3. Pregnant females will not be eligible to donate as per NMDP and LPCH guidelines. 
 
6.3 
Donor Screening 
All donors will undergo HLA-typing.  If original typing was not done with PCR-based typing, it must 
be repeated. 

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Donors will be evaluated with a full history and physical examination at SHC (Stanford Health Care) 
or through national or international bone marrow registries (i.e., National Marrow Donor Program), 
all under FACT guidelines. 
Donors screening laboratories will include complete blood count with differential, serum chemistries 
including electrolytes, creatinine, liver function tests including bilirubin and alkaline phosphatase.  
Donor infectious disease screening laboratories will include: HIV1 and HIV2 (by antibody) and HIV 
PCR, Hepatitis B surface antigen and core antibody, Hepatitis C by PCR and antibody, Treponema 
pallidum (syphilis), HTLV1/2 and CMV by total antibody according to required testing set forth in 
21 CFR Part 1271 Subpart C.  In addition, donors will be screened for West Nile Virus, Zika Virus,
and Trypanosoma cruzi.  Viral and other infectious disease studies will be performed as per standard 
donor work-up guidelines. Donors will be screened for Creutzfeldt Jacob Disease through a 
questionnaire, which asks about previous exposure and travel/residence history. 
The donor selection is made via a team meeting with attending physicians and an HLA expert. The 
mismatched donors in the patient’s family or NMDP will be eligible for donation upon meeting all 
other criteria for bone marrow or peripheral blood stem cells (PBSC) donation.
Unrelated donors selected from the NMDP must be ≥ 18 as per NMDP guidelines.
Related donors will be selected from the patient’s family members and relatives. Preference will be 
given to related donors over the age of 18 whenever possible.
Related donors under the age of 18 must meet all requirements for apheresis. Enrollment of related 
donors will be limited to those who can undergo unstimulated apheresis with minimal risk criteria as 
follows:
•
Apheresis can be performed with peripheral venous access obtained without sedation and not 
with a central line
•
The apheresis does not need a blood prime before the procedure(as per institutional apheresis 
SOP 
•
Related donors must meet all apheresis requirements as outlined in the Apheresis SOP for 
pediatric donors
Related Donor Additional Screening
All related donors will undergo an independent evaluation and examination by a licensed health care 
professional other than the intended recipient’s primary transplant team. All related donors will be 
evaluated according to the institutional SOP for Donor Evaluation and Workup.
6.4
Donor Consent
Donors must be consented prior to any study related procedures. 
Unrelated Donor Consent
All unrelated donors will be consented as per NMDP guidelines for unrelated donor consent.

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Related Donor Consent/Assent
Related donors will be consented as per institutional guidelines. All donors between the ages of 7 and 
17 years old will be provided with an assent describing all procedures to be performed throughout 
this study. See Section 19.31 for details regarding the assent process.
6.5
Donor Apheresis for Generation of T-allo10 Cells
All donors will undergo an apheresis procedure for collection of mononuclear cells for generation of 
T-allo10 cells. This collection will occur prior the scheduled recipient HSCT based on the T-allo10 
manufacturing timeline.
Institutional guidelines will be followed for peripheral venous access and apheresis procedures. The 
cells collected will then undergo CD4 selection using CliniMACS®.
6.6
Donor Stem Cell Collection for HSCT
Donors will undergo either bone marrow collection or apheresis for collection of stimulated 
mononuclear cell for the purpose of HSCT. Absolute number of CD34+ stem cells and CD3+ T cells 
in the graft will be calculated.
Unrelated Donor Apheresis
Unrelated donor apheresis will be performed by the NMDP authorized transplant center. The HSCT 
cell dose for PBSC will be a minimum of ≥3x108 TNC/kg. 
Unrelated Donor Bone Marrow Collection
Unrelated donor bone marrow collection will be coordinated by the NMDP and will follow the 
NMDP guidelines for donor bone marrow collection. Cell dose for BM will be a minimum of ≥1x108
TNC/kg.
Related Donor Apheresis
Related donors will undergo apheresis as per institutional guidelines stated above. Cell dose for PBSC 
will be a minimum of ≥3x108 TNC/kg.
Related Donor Bone Marrow Collection
Related donor bone marrow collection will be performed according to institutional bone marrow 
collection guidelines. Cell dose for BM will be a minimum of 1x108 TNC/kg.

 
 
  
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6.7 
Donor Timeline 
 
 
 
 
 
 
 
Donor Study Evaluations 
Screening 
4 weeks before 
Recipient HSCT  (D-
108 to D-21) 
Day -2 to D 0e of 
Recipient HSCT 
Consent a 
X 
 
 
Donor Workup b 
X 
 
 
Donor Apheresis c 
 
X 
 
Bone Marrow/ PBSC 
collection d 
 
 
X 
Infectious Disease 
Confirmation 
X 
X 
 
 
 
 
 
a 
Consent to be completed per institutional and NMDP Guidelines  prior to 
any study related procedures  
b 
Workup to be completed per institutional and NMDP Guidelines 
c 
Non-mobilized apheresis of single unit collection 
d 
Bone marrow/ PBSC collection as per institutional and NMDP guidelines. 
e 
Donors may be collected up to 2 days prior to D0 depending on HSCT 
source and institutional guidelines.  

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7
PATIENT STUDY PROCEDURES
7.1
Patient Enrollment: Day of recipient apheresis
Before enrollment of a patient into the study, the physician must ensure the patient meets all eligibility 
criteria to be enrolled on the protocol. Eligibility criteria will be reviewed and confirmed by the 
Principal Investigator/Sub Investigator prior to subject being enrolled into the study. 
Patient is considered enrolled into the study on the day of apheresis and will be assigned a unique 
study number. Each study number will be assigned consecutively in increasing order starting with 
“297-01-01”.
7.2
Description of Study Procedures
Planned study procedures and the timing of these procedures are outlined in Section 9.6.  
Medical History
A comprehensive medical history will be taken on all patients at Screening, as outlined in Section 
5.3. Changes in the grading of any previously recorded medical history must be recorded as an 
adverse event as defined in Section 17.
Physical Exams
A comprehensive physical exam will be taken on all patients at Screening, as outlined in Section 5.4.
Interval physical exams will be taken at all subsequent study visits according to Section 9.6.
The following assessments should be done in conjunction with the physical exam once the patient 
starts the conditioning regimen:
1. Mucositis Evaluation
2. Veno-occlusive disease (VOD)
Vital Signs
Vital signs including blood pressure, pulse, respiratory rate, and temperature will be assessed 
according to Section 9.6.

 
 
  
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7.3 
Standard Laboratory Assessments 
The following standard laboratory tests will be collected for recording according to Section 9.6: 
Hematology 
WBC (with Differential if WBC > 500/mm3), RBC, hemoglobin, hematocrit, platelet count, 
MCV, absolute neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils, 
absolute basophils. 
Serum Chemistry 
Sodium, potassium, chloride, carbon dioxide, BUN, glucose, creatinine, total protein, albumin, 
total bilirubin, direct bilirubin, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), AST 
(SGOT), ALT (SGPT), gamma-glutamyltransferase (GGT), calcium, magnesium, phosphorus. 
Infectious Disease 
Surveillance 
CMV, Adenovirus, BK virus, HHV6, EBV, Aspergillus galactomannan 
Chimerisms 
% donor whole blood (WB), % donor bone marrow (BM), CD3 WB & BM, CD15 WB & BM, 
CD19 WB & BM, CD34 WB& BM, CD56 WB& BM 
Other 
Pregnancy test for females of child-bearing potential; urinalysis 
 
 
 
 

 
 
  
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7.4 
Immune Function Tests 
Immune function testing will include the following tests as per standard of care and according to 
Section 9.6. All tests will be sent to the SHC laboratory. Table 7.4.1 describes the minimum required 
values that need to be reached before specific tests may be performed. Table 7.4.2 describes the 
frequency interval for each test once the minimum required values have been reached. 
Table 7.4.1 
Immune function test table describing minimum required values to initiate specific 
tests 
*For patients treated at SHC, their Immunization will occur at the one-year post HSCT mark and all 
activities post Td will be postponed. 
 
Table 7.4.2 
Immune function test frequency table  
Test 
Frequency 
T, B, & NK Lymphocyte Subsets 
Weekly until Day +60, then monthly. 
Lymphocyte mitogen proliferation panel 
Monthly until positive response. 
Immunization with Td 
1st immunization within 28 days after positive mitogen 
response; 2nd immunization 28 days (+/- 10 days) after 
the 1st immunization 
Lymphocyte antigen (Tetanus) Proliferation Panel 
Repeat test 1 month (+/- 10 days) after 2nd immunization 
if first test result is negative. 
 
 
 Minimum 
Required 
Values 
Lymph
ocyte > 
200/µL 
CD3 > 
200/µL 
CD4 > 300/µL or 
6 months post 
SCT whichever 
earlier 
Positive 
PHA 
response  
1 month 
post-1st 
immuniz
ation  
Positive in 
vitro Ag-
specific 
response  
Specific Test  
CD3 count abs. 
X 
X 
 
 
 
 
CD4 count abs. 
 
X 
 
 
 
 
CD8 count abs. 
 
X 
 
 
 
 
CD19 count abs. 
 
X 
 
 
 
 
CD3- /16+ 56+ 
count abs. 
 
X 
 
 
 
 
Lymphocyte 
Mitogen 
Proliferation Panel 
 
 
X 
 
 
 
Immunize with Td 
 
 
 
*X 
 
 
Lymphocyte 
antigen (Tetanus) 
Proliferation Panel 
 
 
 
 
X 
 
Quantitative 
Immunoglobulin 
(QIg)  and tetanus 
specific 
immunoglobulin 
titers 
 
 
 
 
 
X 

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7.5
Research sample collection and handling
Refer to Section 9.6 for timing and frequency of all research lab sample collections. Detailed 
instructions for collection, type of tubes, volumes, handling and processing of samples are found in 
the T-allo10 Laboratory Manual.
7.6
Bone Marrow Aspirate
Bone marrow aspirate will be performed at specific time points as outlined in Section 9.6.  
7.7
Recipient Apheresis
The recipient will undergo an apheresis procedure for the purpose of T-allo10 cell generation. The 
apheresis procedure will be performed according to institutional standards.
7.8
Screening and Baseline Assessments
Patient screening and baseline assessments are described in detail in Section 12.1 and Section 12.2.
7.9
Randomization Procedures
No randomization procedures will be followed.
7.10 Unblinding Procedure
This is an open label study; therefore, no unblinding procedure is required.
7.11 Graft-versus-Host Disease Assessments
Independent Evaluator
All patients who receive the T-allo10 investigational product will be evaluated by an independent 
evaluator. The GvHD evaluator will assess patients according to Section 9.6.
Physician Evaluations
In addition to the independent GvHD evaluator, patients will be assessed by the attending physician 
for GvHD according to Section 9.6 and according to standard of care and intuitional procedures. 

 
 
  
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8 Investigational Product Administration 
8.1 
Dose Calculation 
T-allo10 cell dosage will be calculated based on the patient’s weight in kilograms (at the time of 
apheresis) according to the cohort management plan outlined in Section 10. 
 
8.2 
Administration 
On Day -1, T-allo10 cells will be brought to the stem cell unit from the BMT-CTF and thawed at the 
patient’s bedside. Prior to cell infusion, the cell product identity will be double-checked by two 
authorized staff (MD or RN), and identification of the product and documentation of administration 
will be entered into the patient’s medical record, as is done for blood product administration. Patients 
will receive pre-medication 30 minutes prior to the T-allo10 cell infusion with acetaminophen at a 
dose of 15 mg/kg not to exceed 650 mg total dose and diphenhydramine 1 mg/kg not to exceed 50 
mg total dose. The cells will be infused within 30 minutes (or as appropriate for patient weight) and 
patients will be observed for infusion related reactions for the next 24 hours. All infusion related 
toxicities will be recorded, and grade 3 and 4 toxicities will be reported as per reporting guidelines in 
Section 17.3. 
 
8.3 
Safety Monitoring 
Patients will be closely monitored for infusion related toxicities. Vital signs will be recorded as 
described in Section 9.3. Safety monitoring will be performed according to Section 17. 
 
 

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9
PATIENT TREATMENT PLAN
Patient treatment will be divided into 4 phases:
•
Conditioning
•
T-allo10 Cell Infusion
•
Bone Marrow Infusion
•
Follow-up
Study visit details are described in Section 9.6 and Section 12.
9.1
Conditioning
Patients will receive fractionated total body irradiation (FTBI) and cyclophosphamide as per the 
schedule below. Supportive care for FTBI and cyclophosphamide will follow institutional guidelines. 
Cranial Spinal Boost (CSB)
Patients with central nervous system (CNS) disease at presentation or relapse will receive a CSB as 
per institutional guidelines.
Day
Agent
Dose
GvHD 
Prophylaxis
-8
FTBI
120cGy X3 doses
-7
FTBI
120cGy X3 doses
-6
FTBI
120cGy X3 doses
-5
FTBI
120cGy X2 doses
-4
Cyclophosphamide
60 mg/kg
-3
Cyclophosphamide
60 mg/kg
Start Sirolimus
-2
Rest
-1
T-allo10 Cell 
Infusion
0
Stem Cell Infusion
(TNC/kg)
BM: ≥1 x 108
PBSC: ≥3 x 108
+1
Start MMF

 
 
  
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9.2 
GvHD Prophylaxis 
Patients will be started on Sirolimus at a loading dose of 3 mg/m2 on Day -3 and then 1 mg/m2 daily 
thereafter. Drug levels will be monitored at least twice a week and dose adjusted to maintain levels 
between 8-12 ng/ml. See Section 13.4.1. Mycophenolate Mofetil will be started on Day +1 after 
transplant at a dose of 15 mg/kg every 8 hours. In case of GvHD occurrence, grading of GvHD and 
all treatments will be recorded in the CRF. Taper schedules can be found for both medications in 
Section 13.4. 
 
9.3 
T-allo10 Cell Infusion 
On Day -1, T-allo10 cells will be brought to the stem cell unit and thawed at the patient’s bedside. 
Patients will receive pre-medication 30 minutes prior to the T-allo10 cell infusion with 
acetaminophen at a dose of 15 mg/kg NTE 650 mg total dose and diphenhydramine 1 mg/kg NTE 50 
mg total dose. The cells will be infused within 30 minutes (or as appropriate for patient weight) and 
patients will be observed for infusion related reactions for the next 24 hours. All infusion related 
toxicities will be recorded, and grade 3 and 4 toxicities will be reported as per reporting guidelines in 
Section 17.3. 
Patients will have vital signs recorded as per table below:   
 
 
 
 
 
 
 
 
Patient must be monitored during infusion for ANY adverse reactions, including the following 
expected infusion related reactions: (see Section 17.3 for adverse event reporting) 
 
• Fluid overload 
• Chills (rigors) 
• Hypotension 
• Respiratory distress 
(shortness of breath, 
wheezing) 
• Fever 
• Back or flank pain 
• Nausea 
• Rash/hives 
• Bradycardia 
• Vomiting 
• Hypertension 
• Tachycardia 
• Chest pain 
• Anaphylaxis 
 
 
1. Pre-infusion 
5.    1 hour after the start of 
infusion 
2. 15 minutes after the start of 
infusion 
6.    2 hours after the start of 
infusion 
3. 30 minutes after the start of 
infusion 
7. 4 hours after the start of 
infusion 
4. 45 minutes after the start of 
infusion 
8. 24 hours after the start of 
infusion 

 
 
  
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9.4 
Bone Marrow or PBSC Infusion 
On Day 0, HSC (bone marrow or PBSC) will be collected from the donors as per institutional 
standards. The minimal target for bone marrow collection is 1 x 108 nucleated cells per kilogram. The 
minimal target for PBSC collection is 3 x 108 nucleated cells per kilogram. The HSC will be processed 
in the BMT-CTF for red cell or plasma depletion as indicated by the blood group incompatibility. 
The HSC will be transported to the stem cell unit by a courier. Patients will receive premedication 
with acetaminophen 15 mg/kg NTE 650 mg total dose and diphenhydramine 1 mg/kg NTE 50 mg 
total dose. The HSC will be released by the BMT-CTF after release criteria are met.  The cells will 
be infused, at least 24 hours after the T-allo10 cell infusion. The cells will be infused and patients 
will be observed for infusion related reactions for the next 24 hours. All infusion related toxicities 
will be recorded and grade 3 and 4 toxicities will be reported as per reporting guidelines in Section 
17.  
Patient must be monitored during infusion for ANY adverse reactions including the following 
infusion related reactions: (see Section 17 for adverse event reporting) 
 
• Fluid overload 
• Chills (rigors) 
• Hypotension 
• Respiratory distress 
(shortness of breath, 
wheezing) 
• Fever 
• Back or flank pain 
• Nausea 
• Rash/hives 
• Bradycardia 
• Vomiting 
• Hypertension 
• Tachycardia 
• Chest pain 
• Anaphylaxis 
 
 
9.5 
Follow up Phase 
The patient will be evaluated weekly according to the Schedule of Events through Day +60 following 
HSCT. After Day +60, the patient will be evaluated monthly, unless indicated otherwise on the 
Schedule of events (Section 9.6 for details). Specific details of the requirements of the individual tests 
are detailed in Section 7. 
Immune reconstitution will be evaluated per Section 7.4. 
Time points outlined in Schedule of Events should be closely followed. Visit windows up to Day +60 
will be +/- 3 days. Following Day +60 a tolerance of 10 days (+/-) is permitted. 
 

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9.6 
Schedule of Events (Recipient) 
Study Evaluations 
Screening 
Baseline 
Recipient apheresis 
Conditioning 
Day -1 (T-allo10 
infusion)  
Day 0 (HSCT 
infusion) 
Weekly until  
Day +60 
(+/- 3 days) 
Day +28 
(+/- 3 days) 
Day +42 
(+/- 3 days) 
Day +60  
 (+/- 3 days) 
Monthly until  
Day +365 
(+/-10 days) 
Day +90 
 (+/- 10 days) 
Day +180  
(+/- 10 days) 
Day +365  
(+/-10 days) 
Early  
Termination 
(+/-10 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Clinical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam i 
X 
X 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
Performance status (Lansky 
or Karnofsky) 
X 
X 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
Vital Signs 
X 
X 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
Echocardiogram or MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary function 
evaluation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard transplant work-up h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential 
X 
X 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
Serum Chemistry a 
X 
X 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
Urinalysis 
X 
(X) 
 
(X) 
(X) 
(X) 
(X) 
 
 
 
(X) 
 
 
 
(X) 
Infectious Disease 
Surveillance b  
 
X 
 
(X) 
(X) 
(X) 
X 
 
 
 
(X) 
 
X 
X 
(X) 
Pregnancy Test g 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 
Sirolimus Levels f 
 
 
 
X 
X 
 
2X 
 
 
 
 
 
 
 
 
Recipient apheresis 
(Enrollment) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
T-allo10 Cell Infusion c 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
HSCT Cell Infusion c 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 

 
 
  
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Study Evaluations 
Screening 
Baseline 
Recipient apheresis 
Conditioning 
Day -1 (T-allo10 
infusion) 
Day 0 (HSCT 
infusion) 
Weekly until 
Day +60 
(+/- 3 days) 
Day +28 
 (+/- 3 days) 
Day +42  
(+/- 3 days) 
Day +60 
(+/- 3 days) 
Monthly until  
Day +365 
(+/-10 days) 
Day +90   
(+/- 10 days) 
Day +180  
(+/- 10 days) 
Day +365  
(+/-10 days) 
Early  
Termination 
(+/-10 days) 
Infusion Toxicities 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
Disease (Re)staging –BM 
aspirate (+/- biopsy as indicated)j 
X 
 
 
 
 
 
 
X 
X 
(X) 
 
X 
X 
X 
(X) 
Chimerism-Bone Marrowj 
 
 
 
 
 
 
 
X 
X 
(X) 
 
X 
(X) 
X 
(X) 
Chimerism-Peripheral Bloodj 
 
 
 
 
 
 
 
X 
X 
(X) 
 
X 
X 
X 
(X) 
Immune Function Test d 
X 
 
 
 
 
 
(X) 
 
 
 
(X) 
 
 
 
(X) 
Research Lab Sample e 
X 
X 
X 
 
X 
X 
X 
 
 
 
X 
 
 
 
X 
GvHD evaluation 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Adverse Events Assessment 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
a 
 
See Section 7.3 for details regarding serum chemistry 
b 
 
Includes adenovirus, BK virus, CMV, EBV, HHV6 and fungal surveillance 
c 
 
See section 9 for details regarding T-allo10 and HSCT infusion 
d 
 
See Section 7.4 for details regarding Immune Function Test 
e 
 
See Section 7.5 for details regarding Research laboratory studies 
f 
 
Sirolimus levels will be performed at least twice weekly and as clinically indicated  
g 
 
Pregnancy test must be repeated prior to chemotherapy starting according to institutional standards 
h 
 
Standard transplant workup will follow institutional guidelines and must be completed prior to the start of conditioning. It does not need to be completed 
prior to enrollment. 
i 
 
Physical exams include review of systems and weight. Height taken at baseline. 
j 
 
If Day 28 peripheral blood and bone marrow meets all criteria of engraftment, Day 42 disease restaging and chimerism will not be performed. In 
replacement Day 60 disease restaging and chimerism to be done if clinically needed 
(X) 
 
As clinically indicated 
 

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10 COHORT MANAGEMENT PLAN 
Dose escalation will proceed in cohorts of 3–9 patients. Each dose cohort is expected to enroll a 
minimum of 3 patients and a maximum of 6 evaluable patients at each dose level to determine MTD. 
In addition, the study will allow for up to 3 additional patients to be enrolled in each of the dose cohorts 
(9 additional patients for complete study) due to inability to achieve target cell doses. If any patient is 
withdrawn from study for any reason (withdrawal of consent, relapse before start of chemotherapy, 
etc.) before receiving the T-allo10 cells, the patient will not be counted in total evaluable patients and 
will be replaced. Up to a maximum of 3 inevaluable patients may be replaced. The maximum number 
of patients that may be enrolled will be 30 (18 + 9 + 3).  
There will be a 28 day safety evaluation between the first and second subject in cohort one.  The 
second subject in cohort one will be treated no sooner than 29 days after the first subject’s infusion of 
T-allo10 (after safety assessment). Subsequent subjects in cohort one may be treated with T-allo10 at 
least 28 days after the preceding subject is treated with T-allo10 in the cohort.   
After infusion of T-allo10 in the last subject of each cohort, there will be a 28 day safety evaluation 
period. If the cohort meets safety and tolerability criteria, subsequent subjects may be enrolled in the 
cohort of the next higher cell dose.  
In cohorts two and three subjects may be treated with T-allo10 at least 28 days after the preceding 
subject is treated with T-allo10 in the cohort. Subjects 1 and 2 (in Cohort 1) will be ≥ 12 years’ old.  
  
 
 
 
 
 
 
 
   
Dose Escalation Schedule 
Dose Level 
Dose of (IND Agent)  
Cohort 1 
 1 X 106/kg (± 10%)  
Cohort 2 
 3 X 106/kg (± 10%)  
Cohort 3 
 9 X 106/kg (± 10%)  

 
 
  
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If de-escalation from the lowest dose of 1x106/kg is needed, we will follow the dose de-escalation 
schedule indicated in the table below.  
 
 
Dose escalation will follow the rules outlined in the table in section 10.1 below.  
  
10.1 Safety and tolerability: 
The MTD is the highest dose level that can be feasibly generated to meet established release criteria 
at which no more than 1 out of 6 patients experience a DLT from the infusion of T-allo10 cells, or the 
dose below that at which at least 2 (of ≤6) patients have a DLT as a result of the infusion of T-allo10 
cells.  
 
Number of Patients with DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
The cohort meets safety and tolerability criteria and 
we may enroll patients in next higher cohort. 
1 out of 3 
Enter up to 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, the 
cohort meets safety and tolerability criteria and 
we may enroll patients in next higher cohort. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared 
the maximally administered dose.  Up to three 
(3) additional patients will be entered at the next 
lowest dose level if only 3 patients were treated 
previously at that dose. 
 2 out of ≤ 6 
Dose escalation will be stopped.  This dose level 
will be declared the maximally administered dose 
Dose De-escalation Schedule 
Dose Level 
Dose of (IND Agent)  
Cohort -1  
 8 X 105/kg (± 10%)  
Cohort -2 
 6 X 105/kg (± 10%)  
Cohort -3 
 4 X 105/kg (± 10%)  

 
 
  
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(highest dose administered).  Up to three (3) 
additional patients will be entered at the next lowest 
dose level if only 3 patients were treated previously 
at that dose. 
If cohort 1 is unable to meet safety and tolerability 
criteria, dose de-escalation will occur and cohort -1 
should be tested for tolerability and safety by 
enrolling at least 3 patients in that cohort. 
<1 out of 6 at highest dose level below 
the maximally administered dose 
This is the MTD and would be recommended as the 
phase 2 dose.  At least 6 patients must be entered at 
the recommended phase 2 dose. 
 
If the third dose level is completed without DLT, an MTD may not be determined. This will be 
considered the ‘highest cell dose’ studied, and will be the dose level that may be considered for further 
study. Alternatively, if no toxicity or clinical activity is observed after completion of the 3rd dose 
level, consideration may be given to adding additional dose levels in a protocol amendment. 
In addition, if the targeted T-allo10 cell dose cannot be generated for at least 3 patients out of ≤ 6 
patients in a dose cohort, accrual to that dose level will stop and the dose escalation phase of the study 
will end as manufacturing will not be feasible for that dose level.  The highest dose level that can be 
feasibly manufactured tested for safety and tolerability will be the ‘highest cell dose’ studied, and the 
MTD may not be determined. 
If the targeted T-allo10 cell dose number for a dose cohort cannot be generated for any patient, the 
patient will receive the total manufactured T-allo10 cell dose, as the efficacious dose level is not 
known.  That patient will be considered a feasibility failure, and will be evaluated for safety in the 
dose cohort for the actual cell dose administered. For each patient who fails the feasibility criteria, 
another patient is enrolled in that cohort (up to a total of 9 patients). If additional patient(s) who receive 
cells in a previously defined safe dose cohort experience DLT(s) that meet the criteria for MTD (2 out 
of ≤ 6 patients experience DLT), dose escalation will pause pending discussions with the IRB and 
FDA regarding dose modification/escalation decisions.  
   
 
 

 
 
  
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11 DOSE LIMITING TOXICITIES 
11.1 Definitions 
A dose limiting toxicity (DLT) is defined as the following: 
• Any Grade 3 or 4 related TEAE 
• Any Grade 3 or 4 suspected AE 
The following exceptions will be made in Section 11.2. 
11.2 DLT Exceptions 
The following Infusion Reactions are expected with the infusion of cellular therapy. The following 
adverse events will be considered DLTs only if they occur as specified below:  
• Fluid overload that does not resolve within 24 hours 
• Chills that cannot be reversed after 6 hours with standard care 
• Hypotension that does not resolve after 3 fluid boluses of 10 ml/kg each  
• Respiratory distress (shortness of breath, wheezing) that does not resolve within 30 minutes 
following the T-allo10 cell infusion 
• Fever that cannot be reversed within 24 hours within standard care  
• Back or flank pain that cannot be reversed within 12 hours with standard care 
• Bradycardia that cannot be reversed within 24 hours 
• Rash/Hives that cannot be reversed within 24 hours with standard care 
• Hypertension that does not resolve within 2 hours with standard care 
• Tachycardia that does not resolve within 24 hours and is not associated with fever 
• Chest pain that does not resolve within 30 minutes of the infusion 
Acute GvHD will not be considered as DLT for the study but is followed as the secondary endpoint. 
To ensure safety of the patients, acute grade III and above GvHD is one element in the list of safety 
stopping rules. The stopping rule addresses excessive acute grade III and above GvHD in Section 3.2. 
 
11.3 DLT Assessment Window 
DLTs associated with the infusion of T-allo10 cells will be evaluate through 24 hours following the 
T-allo10 cell infusion.  Adverse events will be reported as described in Section 17. 
DLTs will be assessed from the time of T-allo10 cell infusion until 28 days following the infusion. 
 
11.4 DLT Reporting Procedures 
During the DLT assessment window, any DLTs should be reported to Sponsor-Investigator and 
DSMC as follows: 

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Sponsor-Investigator- DLTs will be reported to the sponsor within 24 hours.
Data Safety Monitoring Committee (DSMC)
•
Within 5 working days
Any DLT that is:
– Suspected: associated with the use of the study drug,
– unexpected,
– fatal or life-threatening, or serious (not fatal or life threatening) and
– places participants at greater risk of harm 

 
 
  
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12 PATIENT STUDY EVALUATIONS AND PROCEDURES 
12.1 Screening Evaluations and Procedures 
All screening assessments must be done prior to enrollment. 
• Informed consent and assent (if applicable) must be obtained prior to any study-related 
procedures. If an assessment was done prior to informed consent as part of standard of care 
it may be used for screening.  
• Complete medical/clinical history (including previous and concomitant diseases) using NCI 
CTCAEv4. 
• Physical examination per Section 7.2.2. 
• Performance status (Karnofsky or Lansky). 
• Complete Blood Count (CBC) with differential. 
• Serum Chemistry per Section 7.3. 
• Urinalysis 
• Vital signs per Section 7.2.3. 
• Standard transplant work up per institutional standards*.  
• Echocardiogram or MUGA with ejection fraction/shortening fraction as appropriate. 
• Pulmonary function evaluation: Pulmonary function tests (if age appropriate and feasible) 
or oxygen saturation. 
• HCV RNA testing and nucleic acid amplification test for HIV. 
• Bone marrow aspirate (and biopsy where appropriate) to evaluate disease status. 
• Immune function test per Section 7.4. 
• Research lab sample per Section 7.5. 
• Pregnancy test in all females of child-bearing potential. 
• Adverse events assessments using NCI CTCAEv4. 
• Concomitant medications. 
* Standard transplant workup will continue in baseline and does not need to be completed prior to 
enrollment.  
 
12.2 Baseline Evaluations and Procedures 
Baseline evaluations will occur from enrollment to start of conditioning for HSCT.   
• 
Recipient Apheresis per Section 7.7. 
• 
Continue remaining standard transplant work up per institutional standards. 
• 
Physical examination per Section 7.2.2. 
• 
Vital signs per Section 7.2.3. 
• 
Performance status (Lansky or Karnofsky). 
• 
CBC with differential. 
• 
Serum Chemistry per Section 7.3.  
• 
Infectious disease surveillance per institutional standards. 
• 
Pregnancy test for all females of child bearing potential. 
• 
Urinalysis if clinically indicated. 

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•
Research lab sample per Section 7.5.
•
Concomitant medications.
•
Adverse events assessments using NCI CTCAEv4.
12.3 Treatment Evaluations and Procedures
Treatment evaluations are divided into the following phases:
•
Conditioning:  Day -8 to Day -2
•
T-allo10 cell infusion day:  Day -1
•
HSC infusion day:  Day 0
•
Post-transplant Days: +1 until Day +365
Conditioning: Day -8 to Day -2
•
Physical examinations per Section 7.2.2.
•
Vital signs per Section 7.2.3.
•
Performance status (Lansky or Karnofsky).
•
Infectious disease surveillance if clinically indicated.
•
Serum Chemistry per Section 7.3.
•
CBC with Differential.
•
Urinalysis if clinically indicated.
•
Adverse events assessments using NCI CTCAEv4.
•
Concomitant medications.
T-allo10 Cell Infusion: Day -1
•
Physical examination per Section 7.2.2.
•
Performance status (Lansky or Karnofsky).
•
Vital signs during infusion as per Section 9.3.
•
Serum Chemistry as per Section 7.3.
•
CBC with Differential.
•
Urinalysis if clinically indicated.
•
Sirolimus level if clinically indicated.
•
Infectious disease surveillance if clinically indicated.
•
T-allo10 cell infusion as per Section 9.3.
•
Adverse events assessments using NCI CTCAEv4.
•
Infusion toxicities assessment per Section 9.3.
•
Research lab samples as per Section 7.5.
•
Concomitant medications.
HSC Infusion: Day 0
•
Physical examination per Section 7.2.2.
•
Performance status (Lansky or Karnofsky).

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•
Vital signs during infusion as per Section 9.4.
•
Serum Chemistry as per Section 7.3.
•
CBC with Differential. 
•
Urinalysis if clinically indicated.
•
Sirolimus level if clinically indicated.
•
Infectious disease surveillance if clinically indicated.
•
Stem cell infusion as per Section 9.4.
•
Adverse events assessments using NCI CTCAEv4.
•
Infusion toxicities assessment per Section 9.4.
•
Research lab samples as per Section 7.5.
•
Concomitant medications.
Post-Transplant follow up phase: 
Assessments to be done weekly (+/- 3 days) through Day +60, then monthly (+/- 10 days) through 
Day +365
•
Physical examination per Section 7.2.2.
•
Vital signs as per Section 7.2.3.
•
CBC w/differential.
•
Urinalysis if clinically indicated.
•
Serum Chemistry as per Section 7.3.
•
Sirolimus level.
•
Performance status (Lansky or score Karnofsky).
•
Graft versus host disease (GvHD) evaluations per Section 7.11.
•
Infectious disease surveillance if clinically indicated.
•
Immune function test as per Section 7.4.
•
Research lab samples as per Section 7.5.
•
Adverse events assessments using NCI CTCAEv4.
•
Bone marrow aspirate (and biopsy where appropriate) to evaluate engraftment/disease 
status per Section 9.6.
•
Chimerism-Bone marrow per Section 9.6.
•
Chimerism-Peripheral blood per Section 9.6.
•
Concomitant medications.
12.4 Early Termination
In the event the subject must come off study, every effort should be made to complete the early 
termination assessments.
•
CBC with differential.
•
Serum Chemistry per Section 7.3.
•
Urinalysis if clinically indicated.
•
Pregnancy test if clinically indicated.

 
 
  
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• 
Physical examination per Section 7.2.2. 
• 
Vital signs per Section 7.2.3. 
• 
Performance status per Lansky or Karnofsky 
• 
Research lab samples per Section 7.5. 
• 
Graft versus host disease (GvHD) evaluations per Section 7.11. 
• 
Immune function test per Section 7.4.  
• 
Infectious disease surveillance if clinically indicated. 
• 
Bone marrow aspirate (and biopsy where appropriate) to evaluate engraftment/disease 
status if clinically indicated. 
• 
Chimerism-Bone marrow if clinically indicated. 
• 
Chimerism-Peripheral blood if clinically indicated. 
• 
Adverse events assessments using NCI CTCAEv4. 
• 
Concomitant medications. 
 
12.5 Screen Failures 
If a subject does not meet eligibility requirements or withdraws from the study prior to enrollment, 
they will be considered a screen failure.  
 
 
 

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13 CONCOMMITANT MEDICATIONS
In general, concomitant medications deemed necessary for the support and safety of the patients are 
permitted in accordance with standard practice (such as medications for emesis, diarrhea, etc.). Use of 
neutrophil growth factors (G-CSF) or red blood cell growth factors (erythropoietin) are permitted per 
institutional policy.  Transfusions may be given in accordance with institutional policy. All supportive 
medications and interventions do not need to be recorded in the patient’s CRF unless specified below.
Prohibited medications are listed in Section 13.5.
13.1 Medications used to treat AE, SAE, TEAE, and TESAE
Medications used to treat any Grade 3 or 4 adverse event must be recorded on the case report form.
Any medication used to treat a TEAE will be reported on the case report form.
13.2 Immunosuppressive Medications
All medications used for immunosuppression, including prophylactic medications, must be recorded 
on the case report form.
13.3 Supportive Medications
Viral Prophylaxis
All patients will be treated as high risk and will receive viral prophylaxis according to institutional 
standards. 
Fever Prophylaxis 
Any temperature of > 38◦C will require initiation of the Fever work-up and treatment as per 
institutional standard operating procedures (SOPs).
Fungal Prophylaxis
All patients will be treated as high risk and will receive fungal prophylaxis according to institutional 
SOPs.
VOD Prophylaxis
Patients will receive Actigall 6 mg/kg as per institutional VOD SOP. Patients who develop VOD will 
be assessed and treated as per the VOD SOP.

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13.4 Medications for GvHD
Sirolimus
a) Sirolimus dosing: Sirolimus will begin on Day -3 with a 3 mg/m2 oral loading dose, followed 
by 1 mg/m2/day rounded to the nearest full milligram. Doses may be repeated if the patient 
vomits within 15 minutes of an oral dose.
b) Sirolimus monitoring: Sirolimus levels will be drawn twice weekly during hospitalization, with 
doses adjusted to maintain a target serum trough level of 8-12 ng/ml.  Thereafter, drug levels 
will be assessed weekly to Day +100 and as clinically indicated, such as in the setting of an 
acute change in renal function or a new medication with known drug-drug interactions.
c) Sirolimus tapering: Tapering of sirolimus will begin at Day +120 in the absence of GvHD and 
disease relapse. The goal of tapering is complete discontinuation of immunosuppression by 8
months post-HCT. Tapering by approximately 10% of the Day +120 dose per week will 
achieve discontinuation by approximately 8 months post-HCT. Sirolimus and MMF should be 
tapered in an alternate fashion every other week when clinically feasible with both drugs 
discontinued simultaneously. (See “MMF tapering” below).                        
d) Drug Interactions: Fluconazole and other azoles drugs are known to increase the sirolimus 
blood levels; therefore, sirolimus drug levels must be monitored closely and doses adjusted 
accordingly. Voriconazole has previously been contraindicated with the use of sirolimus. 
However, recent pharmacokinetic information supports the safe use of sirolimus at 90% of the 
dose if co-administered with oral voriconazole86.  To achieve appropriate dosing of sirolimus, 
a liquid formulation of sirolimus, available at 1 mg/ml concentration, may be required.  The 
liquid form can be taken directly or administered within gelatin capsules.
Mycophenolate Mofetil (MMF)
a) MMF Dosing:  MMF will begin intravenously (IV) on Day +1 at 15 mg/kg three times a day 
(TID).  For patients with Body Mass Index ≥ 30, MMF dose will be calculated based on the 
adjusted ideal body weight (Adjusted IBW = IBW + 0.25 X (Actual Body Weight – IBW). 
Maximum MMF dose not to exceed 3 g/24hrs. MMF may be changed to oral dosing at Day ≥ 
28, upon resolution of the patient’s regimen-related gastroenteritis and control of GvHD. The 
conversion to oral dosing is one-to-one with the IV dose. If the patient develops gastrointestinal 
symptoms believed to be due to MMF, such as large volume diarrhea, the dose may be reduced 
to 10 mg/kg three times/day. 
b) MMF Monitoring:  MMF will be administered IV or orally at fixed doses until the initiation 
of the taper schedule.
c) MMF tapering: Tapering of MMF will begin on Day +100 in the absence of GvHD and disease 
relapse.  The goal of tapering is complete discontinuation of immunosuppression by 8 months 
post-HCT.  Tapering by approximately 10% of the Day +100 dose per week will achieve 
discontinuation by approximately 8 months post-HCT.  Sirolimus and MMF should be tapered 
in an alternate fashion every other week when clinically feasible with both drugs discontinued 
simultaneously.
d) Drug Interactions: Oral magnesium and antacids should be avoided as they reduce the 
absorption of MMF. If needed, MMF should be given 2-3 hours prior to any oral magnesium 
or antacids.

 
 
  
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13.5 Prohibited Medications 
• Hydrocortisone is not allowed as a pre-medication for T-allo10 cells. It may be used for 
HSCT as per institutional guidelines. 
• Hydrocortisone may be used to treat grade 4 infusion reactions related to the T-allo10 cell 
administration 
• Patients may not receive any other investigational agents for 30 days prior to enrollment 
and while they are enrolled on study. 
 
 
 

 
 
  
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14 CRITERIA 
FOR 
SUBJECT 
REMOVAL 
FROM 
STUDY 
AND 
COMPLETION 
14.1 Dose Limiting Toxicity (DLT) 
Subjects who experience a DLT that in the opinion of the investigator would prohibit the subject from 
continuing in the study will be removed. All DLTs will be followed until resolution. 
14.2 Withdrawal of Consent 
Subjects may withdraw consent for participation in the study at any time.  However, if the patient 
decides not to participate once conditioning has started, the subject will not receive the T-allo10 cells, 
but will receive a HSCT as per standard of care and institutional guidelines and will be replaced in the 
accrual numbers. Subjects who withdraw consent following the HSCT infusion will be followed as 
per standard of care. 
14.3 Completion of Study Visits and Procedures 
All subjects who complete study visits and procedures will be removed from the study at the time of 
completion. 
14.4 Disease Relapse 
Subjects who experience relapse of their primary disease after T-allo10 infusion and after stem cell 
transplant will be removed from the study.  
14.5 Unable to receive T-allo10 cells 
Subjects who are not able to receive T-allo10 cells for any reason will be withdrawn from the study 
and will continue receive their transplant under standard of care. 
 
 
 
 
 

 
 
  
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15 CORRELATIVE STUDIES 
15.1 Laboratory Correlative Studies 
All correlative tests will be processed by/for the Roncarolo Laboratory located in the Lorry Lokey 
Stem Cell Institute, 265 Campus Drive West, Room 3015, Palo Alto, CA. The correlative tests 
include but not limited to: 
1. T helper cell panel 
2. T regulatory cell panel  
3. Recent Thymic Emigrants  
4. Cytokine production  
5. Functional host donor reactivity  
6. Memory / Naïve (CD45RA / CD45RO) cells 
 
 
 

 
 
  
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16 STUDY ENDPOINTS 
16.1 Primary Endpoint 
The primary endpoints are as follows: 
– Tolerability of T-allo10 cells as evidenced by the incidence and severity of treatment-emergent 
adverse events (TEAE), laboratory abnormalities, changes in vital signs, and changes in physical 
examination following infusion of T-allo10 cells, recorded and graded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (see link). 
– Safety of T-allo10 cells as evidenced by the time to stem cell engraftment after HSCT. Stem cell 
engraftment is defined as: 
• Absolute Neutrophil Count (ANC) above 500/mm3 for three consecutive days by Day 
+42. 
• Presence of hematopoiesis, by bone marrow examination, with cellularity > 5% and donor 
chimerism > 90% by STR analysis for the presence of donor cells by Day +42. 
• Absence of disease relapse as evidenced by minimal residual disease (MRD) assay < 0.1% 
by Day +42. 
– Feasibility defined by the rate of successful manufacture of the T-allo10 cells to satisfy the targeted 
dose level and meet the required release specifications. 
 
16.2 Secondary Endpoint 
The secondary endpoint for this study is the incidence of grade III and grade IV acute GvHD at Day 
+100 following the infusion of T-allo10 cells, assessed using the Modified Keystone scale 
administered by an independent evaluator on study visits through Day +100 according to schedule of 
events (Section 9.6) 
 
16.3 Exploratory Endpoint 
The exploratory endpoints for this study are as follows: 
• Incidence and severity of chronic GvHD after Day +100 through Day +365, assessed by the 
NIH consensus guidelines administered by an independent evaluator on study visits from Day 
+100 through Day +365 according to schedule of events (Section 9.6). 
• Time to immune reconstitution, assessed by time to reach >200/microliter CD3+ T cells. 
• Disease free survival at Day +365 assessed by bone marrow aspirate examination, morphology, 
MRD assay, and donor chimerism by STR analysis. 
 
16.4 Analysis of Safety 
Patients will be assessed for treatment emergent adverse events (TEAE) and treatment emergent 
serious adverse events (TESAE).  Patient assessments will include alterations in vital signs, changes 
in physical exam, clinical laboratory studies, and other tests like ECG, PFT, radiological studies and 
other studies being performed per protocol. 
 

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17    SAFETY REPORTING/DATA AND SAFETY MONITORING PLAN
17.1 Definitions
Adverse Event (AE)
An adverse event (AE) is an undesirable medical occurrence (sign, symptom, or diagnosis) or 
worsening of a pre-existing medical condition that occurs after Informed Consent whether or not it is 
considered to be related to the investigational product, or other protocol-imposed intervention, 
regardless of attribution. This includes the following: 
1. AE not previously reported in the Medical History 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 Attending Physician or designee to have 
worsened in severity, frequency, or increased in duration during investigational product 
treatment during the protocol-specified AE reporting period.  
Abnormal laboratory values or test results constitute recordable AE. The highest CTCAE grade (I-
IV) for the adverse event will be recorded.
An abnormal laboratory value will be considered a reportable AE if the laboratory abnormality is 
characterized by any of the following:
•
Results in interruption or discontinuation of the transplantation process
•
Is associated with clinical signs or symptoms 
•
Requires treatment or any other therapeutic intervention
•
Is judged by the Attending Physician or designee to be of significant clinical impact
•
If any abnormal laboratory result is considered clinically significant, the Attending Physician 
or designee will provide details about the action taken with respect to the test drug and about 
the patient’s outcome.
Treatment-Emergent Adverse Events (TEAE)
A Treatment-Emergent Adverse Event (TEAE) is any AE that occurs after initiation of the 
investigational product infusion (T- allo10 cell infusion) regardless of severity, or any event that was 
present at baseline and worsened in intensity. Adverse events that occur prior to the T-allo10 cell 
infusion but after the start of the conditioning regimen will be primarily attributable to the conditioning 
regimen, disease or extraneous causes. After T-allo10 cell infusion, toxicities will be evaluated for 
temporal and causal relationship to the conditioning regimen versus cell infusion. Some symptoms 
may overlap and attribution will not be clearly definable, in which case toxicities will be attributed as 
possibly related to conditioning and cell infusion.
Toxicities will be attributed to the T-allo10 cell infusion if: 
1. They were NOT present before the T-allo10 cell infusion; OR 
2. If they increase in Grade in temporal association with the T-allo10 cell infusion; AND 
3. They are not clearly explained by other factors.

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Similarly, after the stem cell infusion, symptoms that occur may overlap and attribution between the 
T- allo10 cell infusion and the stem cell infusion may not be clearly definable. If toxicities were not
present before the stem cell infusion or are known stem cell infusion toxicities, they will be attributable 
to the stem cell infusion. Any symptom that occurs after the T-allo10 cell infusion and increases in 
grade with the stem cell infusion could be possibly related to the T-allo10 infusion and will be reported 
as TEAE.
Serious Adverse Event (SAE)
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 AE that do not meet any of the criteria for serious should be regarded as non-serious AE. 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 AE and SAE on the CRF.
The Attending Physician or designee is responsible for ensuring that all AE and SAE are recorded on 
the CRF and reported to the Sponsor-Investigator in accordance with protocol instructions. 
Suspected Adverse Reaction
Suspected adverse reaction means any adverse event for which there is a reasonable possibility that 
the investigational therapy caused the adverse event. For the purposes of IND safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between the 
investigational therapy and the adverse event. A suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by an 
investigational therapy.

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Unexpected adverse reaction
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk information described 
in the general investigational plan or elsewhere in the current application. "Unexpected”, also refers 
to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as 
occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but 
are not specifically mentioned as occurring with the particular drug under investigation.
Pregnancies
Pregnancies occurring after the infusion of investigational product are considered immediately 
reportable events.  While not considered a serious adverse event unless a serious criterion is met, 
pregnancies occurring in subjects enrolled on the study must be reported and followed to outcome.  
The Attending Physician or designee should complete the pregnancy report form and provide it to the 
Sponsor-Investigator within one working day of knowledge of the pregnancy.  Following delivery or 
termination of pregnancy, the follow-up pregnancy report should be completed and provide it to the 
Sponsor-Investigator.  Spontaneous abortions should always be reported as SAE.  Follow-up 
information regarding the outcome of the pregnancy and any postnatal sequelae in the infant will be 
required.
Protocol Deviations
Any change, divergence or departure from the IRB approved protocol will be documented and reported 
to the Investigator-Sponsor.
17.2 Adverse Event Characteristics
Severity
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.
Relationship to Investigational Product
The Attending Physician must document their opinion of the relationship of the AE, TEAE or SAE to 
the investigational product as follows.
NOT RELATED: The event can be readily explained by the subject’s underlying medical condition, 
a concomitant therapy or other cause and the Investigator believes no relationship exists between the 
event and the investigational product.  In this case, the Investigator should document the condition, 

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concurrent/underlying illness, medication, study procedure, or other cause they believe to be the cause 
of the adverse event.
UNLIKELY: The event does not follow a reasonable temporal sequence from administration of the 
investigational product nor does the event follow a known or expected response pattern to the 
investigational product and may have another cause.  In this case, the Investigator should document 
the condition, concurrent/underlying illness, medication, study procedure, or causality believed to 
have contributed to the adverse event.
POSSIBLE: The subject’s condition, concurrent/underlying illness, medication, or study procedures 
cannot explain the event, and there is a plausible temporal relationship between the event and the 
investigational product administration.
PROBABLE: The temporal relationship between the administration of the investigational product 
and the adverse event strongly suggests a relationship, and/or the adverse event cannot be reasonably 
explained by another condition, concurrent/underlying illness, medication, study procedure or other 
cause, or the adverse event abates with discontinuation of the investigational product, and recurs with 
re-administration.
Adverse events that occur prior to the T-allo10 cell infusion but after the start of the conditioning 
regimen will be primarily attributable to the conditioning regimen, disease or extraneous causes. After 
T-allo10 cell infusion, toxicities will be evaluated for temporal and causal relationship to the 
conditioning regimen versus cell infusion. Some symptoms may overlap and attribution will not be 
clearly definable, in which case toxicities will be attributed as possibly related to conditioning and cell 
infusion.
17.3 Adverse Event and Serious Adverse Event Reporting
At each contact with the subject, the Attending Physician or designee must seek information on 
adverse events by specific questioning and, as appropriate, by examination.  Information on all adverse 
events should be recorded immediately in the source document, and also in the appropriate CRF.  
All AE and SAE occurring during the study period must be recorded.  The clinical course of each 
event should be followed until resolution, stabilization, or until it has been determined that the 
investigational product is not the cause or the subject is lost to follow-up.  SAE that are still ongoing 
at the end of the study period must be followed up to determine the final outcome.  Any SAE that 
occurs for up to 30 days after the study period and is considered to be at least possibly related to the 
study treatment or study participation should be recorded and reported immediately.
A TEAE is any AE that occurs after the investigational product infusion. After 24 hours, the patient 
will receive infusion of the stem cell making it more difficult to determine if the AE is related to the 
infusion of the T-allo10 cells or the stem cell transplantation. If it is not clear, then attribution may be 
attributed to both infusions. If it is an expected AE of the stem cell infusion, then it would be attributed 
to the stem cell infusion.
Type and Duration of Follow-Up of Adverse Events 
The Attending Physician or designee should follow all unresolved AE and SAE until the events are 

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resolved or stabilized, the subject is lost to follow up, or it has been determined that the study treatment 
or participation is not the cause of the AE/SAE. Resolution of AE and SAE (with dates) should be 
documented on the Adverse Event CRF or CRF and in the subject’s medical record to facilitate source 
data verification (SDV).  For some SAE, the Sponsor-Investigator will follow up with the Attending 
Physician or designee by telephone, fax, email, and/or a monitoring visit to obtain additional case 
details deemed necessary to appropriately evaluate the SAE report (e.g., hospital discharge summary, 
consultant report, or autopsy report).  
Post-Study Adverse Event 
The Attending Physician or designee should notify the study Sponsor-Investigator of any death or 
other SAE occurring at any time after a subject has discontinued or terminated study participation if 
felt to be related to prior study treatment. The Sponsor-Investigator should also be notified if the 
Attending Physician or designee should become aware of the development of cancer or of a congenital 
anomaly in a subsequently conceived offspring of a subject that participated in this study. The 
Attending Physician or designee should report these events to the Sponsor-Investigator on the study 
CRF. If the study CRF is no longer available, the Attending Physician or designee should report the 
event directly to the Sponsor-Investigator via phone or email.
Investigator Reporting Requirements 
Attending Physician or designee will submit reports of SAE to the Sponsor-Investigator within one 
working day of learning of the events. For initial SAE reports, Attending Physician or designee should 
record all case details that can be gathered in the SAE Report Form. Corresponding information should 
also be entered into the CRF as soon as possible. Relevant follow-up information should be submitted 
to the Sponsor-Investigator as soon as it becomes available and/or upon request. 
The Sponsor-Investigator must comply with the applicable regulatory requirements related to the 
reporting of SAE to the IRB. All IND Safety Reports will be reported to the IRB by the Sponsor-
investigator.
The Sponsor-Investigator will notify the IRB of AE/TEAE by the timeline for reporting and associated 
event type:
Within 5 working days
Any study event that is:
– suspected: associated with the use of the study drug,
– unexpected,
– fatal or life-threatening, and
– places participants at greater risk of harm 

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Within 10 working days:
Any study event that is:
– suspected: associated with the use of the study drug
– unexpected,
– places participants at greater risk of harm, and
– serious, but not fatal or life-threatening.
Annually on Continuing Review:
Any study event that is:
– expected, and
– All AE/TEAE determined not to meet the criteria of serious.
Fatal/Life-Threatening SAE Related to Investigational Product
Any life-threatening (i.e., imminent risk of death) or fatal SAE that is attributed by the Attending 
Physician or designee to the investigational product will be telephoned or emailed to the Sponsor-
Investigator immediately, followed by submission of case details on the SAE CRF within one working 
day. 
17.4
Sponsor-Investigator Reporting to FDA and DSMC
Suspected Unexpected Serious Adverse Reactions (SUSARs)
All events qualifying as Suspected Unexpected Serious Adverse Reactions (SUSARs) will be reported 
to the FDA and to the DSMC by the Sponsor-Investigator. SUSARs are required to be reported to the 
FDA within 7 calendar days for life threatening events and those resulting in death, or 15 calendar 
days for all others. SUSARs will be reported to the DSMC and IRB within 5 business days for life 
threatening events and those resulting in death, or 10 business days for all others. These timeframes 
begin with the first notification of the SUSAR to the Sponsor-Investigator from the Attending 
Physician or designee. 
The Sponsor-Investigator will notify FDA of SUSARs using FDA Form MedWatch 3500A. The 
following describes the safety reporting requirements by timeline for reporting and associated type of 
event:
Within 7 calendar days
Any study event that is:
– suspected: associated with the use of the study drug
– unexpected, 

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– fatal or life-threatening, and 
Within 15 calendar days
Any study event that is:
– associated with the use of the study drug,
– unexpected, and
– serious, but not fatal or life-threatening.
-or-
– a previous adverse event that was not initially deemed reportable but is later found to fit the 
criteria for reporting (reporting within 15 calendar days from when event was deemed 
reportable).
Serious Adverse Event Reporting on Cell Therapy Products to the FDA
A sample from all products that are non-conforming or do not meet release specifications will be used 
to conduct an out of specification investigation and the remainder either disposed of according to our 
facility biohazardous material disposal SOP or the FDA will be contacted by the PI and manufacturing 
team to determine whether the product is suitable for infusion. The manufacturing facility will report 
all products manufactured including those that did not meet release criteria or were otherwise not 
infused in the annual IND report and the annual facility report if the LCGM submits a facility master 
file with the FDA.
All HCT/P (Human Cells, Tissues, and Cellular and Tissue-Based Products) deviations involving 361 
cell products will be reported using MedWatch From FDA3500A according to FDA publication 
“Guidance for Industry: MedWatch Form FDA 3500A: Mandatory Reporting of Adverse Reactions 
Related to Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) available at:
http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/ucm153082.htm
Reporting to the DSMC
The Sponsor-Investigator will report:
1. Any death on the study regardless of expectedness within 24 hours of knowledge
2. Suspension of study for concerns of safety or Investigational Product related toxicity within 
24 hours
3. Investigational Product related SAEs and DLTs within five business days of knowledge
4. Clinical update prior to dose escalation including:
a.
Description of the cohorts
b. Dose levels
c.
Any Dose Limiting Toxicities observed
5. All other adverse events; protocol and subject deviations; Protocol specific data and safety 
monitoring reports, any internal and external audit reports every six months or as requested by 

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the DSMC.
17.5 Data Safety Monitoring Committee (DSMC)
The purpose of the DSMC is to provide an unbiased review of the safety data generated by the clinical 
trial.  The independent DSMC will review clinical trial data prior to dose escalation and on an as-
needed basis but not less than semi-annually, if there are subjects enrolled on the study.  The DSMC 
will review serious adverse events, adverse events, and protocol deviations associated with the 
research to ensure the protection of human subjects. The Sponsor-Investigator or designee will inform 
the Chairperson of the DSMC of the potential need for ad hoc meetings and will coordinate such 
meetings.   A statistician, serving as a non-voting member to the DSMC, will provide data preparation 
support to the DSMC.  The DSMC will assess the progress of the clinical trial, including the safety 
data and feasibility and will recommend to the sponsor whether to continue, modify, or stop the clinical 
trial. The DSMC recommendations will be provided to the Sponsor-Investigator for final disposition.
The Sponsor-Investigator will report DSMC recommendations to the IRB as required.
DSMC review for grade III-IV acute GvHD
If two consecutive patients in any cohort develop grade III-IV acute GvHD, we will consider a 
reevaluation and the DSMC will review the data. However, patients with grade III-IV GvHD 
improving after MMF withdrawal or after starting specific anti infectious treatment will be exempted. 
This exception will allow us to rule out confounding factors that might mimic gut GvHD symptoms, 
like the presence of preexisting/superimposed GI infections or drug-related toxicity (e.g. MMF). In 
addition, patients with a complete response within 4 weeks of GvHD standard treatment (per GvHD 
treatment guideline) will be exempted. In case of no improvement within 4 weeks from MMF 
withdrawal and/or anti infectious treatment start and GvHD standard treatment, the patient will meet 
the criteria requiring review by the DSMC.
17.6 Graft versus Host Disease (GvHD) Evaluator
An independent qualified physician will be appointed by the Protocol Sponsor and Protocol Director 
to evaluate acute and/or chronic graft versus host disease.

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18 INVESTIGATIONAL PRODUCT MANAGEMENT
18.1 T-allo10 
The product (T-allo10) will be transported to the BMT-CTF from where it will be taken to the bedside. 
ISBT128 labels will be used for packaging the product. The empty bags will be disposed of as per the 
standard operating procedures of the hospital.
18.2 Cyclophosphamide
Administration
Cyclophosphamide will be given according to LPCHS high dose cyclophosphamide administration 
guidelines at a dosage of 60 mg/kg on Days -4 and -3.  Mesna must be administered with 
cyclophosphamide on Days -4 and -3. Mesna is given as per institutional standards.
Dose adjustments 
Dose adjustments for the patients will be made as per institutional standards.
Patient Monitoring
Patients should receive an ECG prior to the first dose of cyclophosphamide as per high-dose 
cyclophosphamide administration guidelines.
18.3 Mesna
Administration
Mesna will be administered with cyclophosphamide on Days -4 and -3 as per institutional standards. 
18.4 Total Body Irradiation (TBI)
Total body irradiation (TBI) will be given by the Stanford Radiation Oncology department.  
•
Administration-TBI may be given outpatient prior to admission for the stem cell 
transplantation or inpatient as per institutional standards.  TBI will be given as 
fractionated dosing 120 cGy three times (3) daily for three (3) days Day -8, -7,-6; and 
twice (2) daily on Day -5 to total 1320 cGy.
•
Dose Adjustments- no dose adjustments will be made for TBI.
•
Patient Monitoring- patients must be instructed not to use lotions during the days of TBI.
Cranial Spinal Boost (CSB)
Patients with central nervous system (CNS) disease at presentation or relapse will receive a CSB as 
per institutional guidelines.
19 GENERAL CONSIDERATIONS
19.1 Basic Principles
This research will be carried out in accordance with the clinical research guidelines established by the 
Basic Principles defined in the U.S. 21 CFR Parts 50, 56, and 312, the principles enunciated in the 
Declaration of Helsinki concerning medical research in humans (“Ethical Principles for Medical 

 
 
  
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Research Involving Human Subjects,” Helsinki 1964, amended Tokyo 1975, Venice 1983, Hong Kong 
1989, Somerset West 1996, Edinburgh 2000 and clarifications, Washington 2002 and Tokyo 2004), 
and the Good Clinical Practice (GCP) guidelines of the International Conference on Harmonization 
(ICH) of the Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH E6 
(May 1996). 
19.2 Institutional Review Board (IRB) 
Prior to initiation of any study procedures, the Clinical Study Protocol, Informed Consent Form, and 
Product Information will be submitted to the IRB for review and approval.  In addition, any 
amendments to the protocol or informed consent document will be reviewed and approved (if 
necessary) by the IRB.  The Principal Investigator (PI) at the clinical site assumes responsibility for 
ensuring that the protocol is submitted to the IRB for any required periodic review.  The PI must 
receive a letter documenting the IRB approval at the clinical site prior to the initiation of the study.  
Any subsequent IRB correspondence must also be submitted to the Investigator.  The Investigator is 
responsible for providing the appropriate reports to the reviewing IRB during the course of the clinical 
study.  This will include the following: 
• 
Informing the IRB of the study progress periodically as required, but at least annually 
• 
Reporting any unanticipated adverse event per IRB Policies & Procedures 
• 
Reporting any deviations from the clinical protocol to protect the life or well-being of a 
subject in the case of an emergency within 5 working days after the emergency occurred 
• 
Providing any other reports requested by the IRB 
After the final visit of the last subject, a final report will be sent to the IRB per institutional Policies & 
Procedures that includes a summary of the results of the study by the PI. 
The IRB must be constituted and operate in accordance with the principles and requirements described 
in the U.S. Code of Federal Regulations (21 CFR Part 56). 
19.3 Informed Consent 
Participation in this trial incurs risks to the participant as well as the possibility of benefits afforded 
by the investigational agent.  Since the target population is pediatric, the consent process will involve 
both the Legally Authorized Representative (LAR) of the participant, usually the parents, as well as 
the participant him- or herself.  The assent process will be carried out per institutional policies.  The 
participant is not required to take part in the assent process if the parents/LAR, Principal Investigator 
(PI), or Medical Director (MD) does not think the child is capable of comprehension.  All parents or 
LAR of the subject must have the ability to understand and the willingness to sign a written informed 
consent.  
The PI, or designee will lead the consent process by describing the disease, the rationale for the 
proposed experimental therapy, the treatment plan, the timeline and logistics as well as the risks, and 
the potential benefits of the study.  Alternatives to the therapy including standard-of-care treatments 
will be described.  The Patient’s Bill of Rights will be reviewed.  The voluntary nature of participation 
will be explained, as well as the right to withdraw from the study at any point in time.  Adequate time 

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will be taken and questions will be asked of the participants to verify comprehension.  When possible, 
the participant and the parents or LAR will be sent home with a copy of the informed consent form 
(ICF) and where applicable, the Pediatric Assent Form, to read and review.  The PI or designee will 
be available for discussion at any time during the visit.  To authorize participation in the trial, the 
parents or LAR will need to sign the ICF.  A copy of the ICF, and where applicable, a Pediatric Assent 
Form (PAF), will be given to the participant, parents, or LAR.  If both parents are unable to sign the 
consent, the reasons for the omission of one parent should be documented in the patient’s medical 
record and Research Binder.  Where applicable, the PAF should also be signed and documented as for 
the ICF.
The consenting process for donors is outlined in Section 6.2.
Pediatric Assent Process
Where applicable, for children ≥7 and < 18 years of age, pediatric assent will be documented as 
described above. If an assented child turns 18 years of age while enrolled on study, they will be 
consented at the earliest opportunity.
19.4 Study Termination
The Investigator reserves the right to terminate the study in the interest of subject safety and welfare. 
The Sponsor reserves the right to terminate the study at any time for administrative reasons.
19.5 Regulatory Documentation
Documents that must be provided to the Sponsor and/or its designee prior to study initiation are as 
follows:
•
Up-to-date curriculum vitae for each investigator and sub-investigator
•
Applicable local regulatory documentation (e.g., FDA 1572 Form)
•
A copy of the formal written notification to the investigator regarding approval of the protocol 
by an IRB that is in compliance with regulatory guidelines. The written notification is to be 
signed by the chairman or authorized designee and must identify the specific protocol. In cases 
where an IRB member has a known conflict of interest, abstention of that individual from 
voting should be documented; an investigator (or sub-investigator) may be a member of the 
IRB, but may not vote on any research in which he or she is involved.
•
Name and address of the IRB with a statement that it is organized and operates according to 
GCP and the applicable laws and regulations, and a current list of the IRB members. If 
accompanied by a letter of explanation from the IRB, a general statement may be substituted 
for this list.
•
A copy of the IRB approved informed consent form and other adjunctive materials 
(e.g., advertising) to be used in the study, including written documentation of IRB approval of 
these items.

 
 
  
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• 
Name and address of any local laboratory conducting tests for the study, a dated copy of the 
laboratory reference values for tests to be performed during the study and a copy of the 
certification or other documentation establishing adequacy of the facility. 
• 
Required financial agreement. 
In addition to the documents required prior to the study, other documentation may be required during 
the course of the study. 
19.6 Study Documentation 
All documents pertaining to the study, including a copy of the approved protocol, copy of the Informed 
Consent Form, and case report forms, will be retained in the permanent archives of the study site.  
These will be available for inspection at any time by the Sponsor and/or its designee, or the U.S. Food 
and Drug Administration (FDA). 
19.7 Data Handling and Record Keeping 
As electronic trial data handling and/or remote electronic trial data systems will be used, the Sponsor 
and/or its designee will: 
• 
Ensure and document that the electronic data processing system(s) conforms to the Sponsor’s 
established requirements for completeness, accuracy, reliability, and consistent intended 
performance 
• 
Maintain a security system that prevents unauthorized access to the data 
• 
Maintain a list of the individuals who are authorized to make data changes 
• 
Maintain adequate backup of the data 
• 
An unambiguous subject identification code will be used that will allow identification of all 
the data reported for each subject 
• 
The Sponsor and/or its designee will retain all of the Sponsor-specific essential documents 
pertaining to the trial in conformance with the applicable regulatory requirement(s)  
• 
Documentation and records generated by this clinical trial will have a retention period not less 
than 2 years after all marketing applications in all regions where the drug is being developed 
and have been approved for the drug or 2 years after the last shipment / delivery of the 
investigational product under the IND, if a marketing application has not been approved for 
the drug.  Subsequent to the fulfillment of the record retention requirements, Stanford may 
destroy all records in a confidential manner.   
• 
The original data collection forms will be stored electronically in a secure server at Stanford 
University.  The server is password protected and all data are encrypted.  Access to the server 
is limited to those who have been granted permission by the PI and to whom Stanford grants 
access – these personnel will have a legitimate reason for accessing the data.  Physical access 
to the server is also restricted by lock and key.  When results of this study are reported in 

 
 
  
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journals, publications, or at meetings, identification of those taking part will not be disclosed.  
Medical records of subjects will be securely maintained in the strictest confidence, according 
to current legal requirements.  They will be made available for review, as required by the FDA, 
Health and Human Services (HHS), or other authorized users under the guidelines established 
by the Federal Privacy Act and rules for the protection of human subjects. 
19.8 Use of Information and Publication 
The use of data and information from this clinical investigation is only at the discretion of the PI.  All 
dissemination of trial data medical care and medical decisions related to the investigation and the 
conclusions of the investigation, by publication, public talks, or through any media will be made with 
the authorization of the PI.  
Publications and public material pertaining to the trial will not disclose patient PHI.  When referring 
to data from specific patients, the patient’s identification and PHI will be protected by coding with 
non-traceable identifiers. 
 
 
 

 
 
  
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20 STATISTICAL ANALYSIS METHODOLOGY 
A formal Statistical Analysis Plan (SAP) will be prepared and finalized before database lock for the 
final analysis for the study report. The SAP will provide details regarding the definition of analysis 
subjects (populations), analysis variables, and analysis methodology to meet all study objectives. 
The principle and key elements of the SAP are provided as follows: 
• In general, tolerability, safety and feasibility data will be summarized for each dose cohort with 
descriptive statistics, including means, standard deviations, medians, minimums and 
maximums for continuous variables, the number of subjects and percent in each category for 
categorical variables. 
• Data from each individual will be tabulated as appropriate. Tolerability, safety and feasibility 
endpoints will be tabulated by dose cohort and time point. 
20.1 Tolerability and safety endpoints 
The tolerability and safety of Investigational Product (IP) will be assessed by: 
• Treatment-emergent adverse events. 
• Treatment-emergent serious adverse events. 
• Changes in clinical laboratory tests (clinical chemistry, hematology). 
• Changes in vital signs (blood pressure, pulse, respiratory rate and body temperature). 
• Changes in physical exams. Signs and symptoms assessed may require additional testing as 
clinically indicated such as ECG, PFT, radiographic studies, etc. 
• Time to stem cell engraftment after HSCT. 
Tolerability data will be analyzed per standard methods and interpreted descriptively. Tolerability data 
will be summarized for each dose cohort separately and for all dose cohorts combined. Adverse events 
will be assessed using the CTCAE version 4.0 for type and severity of event. Serious Adverse Events 
will be summarized for each dose cohort and for all dose cohorts combined. Reasons for 
discontinuation will be tabulated. 
Laboratory includes hematology, serology, serum chemistry, and urinalysis; laboratory collected prior 
to T-allo10 infusion will be the baseline laboratory. The study will utilize local lab for all clinical 
laboratory testing. Laboratory data will be tabulated based on the following result class. 
• 
Normal: result is within the local lab normal range 
• Abnormal: result is either higher or lower than the normal range 
All abnormal values will be assessed for clinical significance; clinical significance will be captured in 
the case report form. Number and percent of subjects within each result class will be tabulated by time 
point for each lab test without formal inferential statistics. If data permits, shift in result class from 
baseline to post baseline may also be tabulated. 
Vital signs collected immediately prior to receiving study drug will be the baseline vital signs. 
Observed vital sign values and change from baseline in vital signs at each visit will be summarized 
without formal statistical testing. 

 
 
  
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Vital sign result may also be tabulated based on the following result class. 
• Normal: result is within the normal range. 
• Abnormal: result is either higher or lower than the normal range. 
All abnormal values will be assessed for clinical significance; clinical significance will be captured in 
the case report form. Number and percent of subjects within each result class will be tabulated by time 
point for each vital sign. 
Findings of physical examinations will be tabulated by treatment groups and abnormal values will be 
assessed for clinical significance; clinical significance will be captured in the case report form. 
Safety data will be analyzed per standard methods and interpreted descriptively. Safety data will be 
summarized for each dose cohort separately and for all dose cohorts combined.  
For stem cell engraftment, time to engraftment and rate of engraftment will be tabulated for each dose 
cohort and for all dose cohorts combined. 
20.2 Feasibility endpoint 
In addition to tolerability and safety, establishing feasibility of manufacturing T-allo10 cells that meet 
release criteria is essential to evaluating the primary objective of this study.  Feasibility will be defined 
as the rate of successful manufacture of the T-allo10 cells to satisfy the targeted dose level and meet 
the required release specifications.  Patients will be enrolled on a given dose level until adequate 
number of patients are enrolled to complete the safety evaluation at that dose level. Specifically, dose 
escalation will proceed as long as an adequate cell dose can be manufactured that meets release 
specifications to reach the number of patients required for the safety evaluation at the targeted dose 
level. For example, this might mean that 6 to 9 patients may need to be enrolled to result in 6 patients 
evaluable for safety in that dose cohort level. However, if an adequate T-allo10 cell dose can only be 
manufactured for a small fraction (< 3) of the initial 6 patients at a given dose level, evaluation of that 
level and beyond will not take place. Specifically, if after the first 6 patients have been enrolled at a 
given dose level, and the cell dose generated for more than 3 patients is less than the targeted dose for 
the given dose level, accrual to that dose level will stop and the dose escalation phase of the study will 
also end, as manufacturing will not be feasible for that dose level. Since the upper 90% one-sided 
confidence interval for 3/6 is 79.9%; thus, it would be unlikely that the true feasibility rate is 80% or 
greater for a given, which would be desirable. 
20.3 Efficacy endpoints 
Although a secondary endpoint, the efficacy analysis will focus on rate of acute grade III or IV GvHD. 
We will report descriptive data of rate of acute grade III or IV GvHD and its comparison with historical 
data on rate of acute grade III or IV GvHD in similar population. This analysis will be used to 
determine if a phase 2 study whose primary endpoint will be efficacy is warranted. 
 
20.4 Analysis Datasets 
All patients who receive experimental treatment will be analyzed for safety and efficacy. 
Subjects not treated for any reason will be included in the disposition tabulation but will be excluded 
from the tolerability and safety analysis. 

 
 
  
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20.5 Disposition and Study Population Characteristics 
Disposition summaries will be prepared to include number and percent of subjects screened, treated, 
and subjects that completed the study, or if not, the reason for discontinuation. Reason for screening 
failure will also be tabulated. 
Subject characteristics summaries will include demographics (age, gender, race, and ethnicity), 
baseline characteristics (weight, height, BMI), diagnosis, donor age and relationship to patient, and 
medical history. 
Disposition summary will be based on treatment group (i.e., planned treatment) whereas the baseline 
characteristics summaries will be based on the actual treatment group. 
Subjects with protocol deviations will be identified. The nature of the deviation and potential impact 
on the deviation on study outcome will also be assessed. 
 
 
 

 
 
  
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24. Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F, et al. Treatment of high-risk 
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22 APPENDICES  
 
22.1 Lansky Performance Score 
 

 
 
  
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22.2 Karnofsky Performance Score