Post Transplant Infusion of Allogeneic CD8 Memory T-Cells as Consolidative Therapy After Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients With Leukemia and Lymphoma
Phase: PHASE2
Conditions: Acute Myeloid Leukemia, B-Cell Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, Hodgkin Lymphoma, Myelodysplastic Syndrome, Myeloproliferative Neoplasm, T-Cell Non-Hodgkin Lymphoma
Sponsor: Robert Lowsky

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Post Transplant Infusion of Allogeneic CD8 Memory T-Cells as Consolidative 
Therapy After Non-Myeloablative Allogeneic Hematopoietic Cell 
Transplantation in Patients with Leukemia and Lymphoma  
Coordinating Center 
Stanford Cancer Center 
875 Blake Wilbur Dr 
Stanford, CA 94305 
Protocol Director 
Robert Lowsky, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA 94305  
rlowsky@stanford.edu  
              
  NCT02424968      Version date: 23 August 2019 
 
Co-Investigators 
Wen-Kai-Weng, MD, PhD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
 wkweng@stanford.edu  
Robert Negrin, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr MC5623, Stanford, CA  94305 
negrs@stanford.edu 
Sally Arai, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
sarai1@stanford.edu 
Laura Johnston, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
korb@stanford.edu 
David Miklos, MD, PhD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
dmiklos@stanford.edu 
Judith Shizuru, MD, PhD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA 94305 
Jshizuru@stanford.edu 
Everett Meyer, MD 
Division of Blood and Marrow Transplantation 
and Cellular Therapeutics Facility Laboratory 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
evmeyer@stanford.edu 
Andrew Rezvani, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr , Stanford, CA  94305 
 
arezvani@stanford.edu 
Lori Muffly, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
lmuffly@stanford.edu 
Samuel Strober, MD 
Divisions of Immunology & Rheumatology 
CCSR Building, Stanford, California 94305 
sstrober@stanford.edu 

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Michael Spinner, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Drive, Stanford, CA 94305 
mspinner@stanford.edu 
Philip Lavori, PhD (Biostatistician) 
Department of Health Research and Policy 
Biostatistics Shared Resource, 
Redwood Building, Stanford, CA 94305 
 
lavori@stanford.edu 
 
IRB number: 
IRB-33058  
OnCore number 
BMT288 
Version date: 
 23 August 2019 
IND number: 
IND 014844 
SRC Approval  
 20 April 2019 

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TABLE OF CONTENTS 
 
 
Protocol Synopsis 
4 
Schema 
5 
1. 
Objectives 
6 
2. 
Background 
6 
3. 
Participant Selection and Pre-Enrollment Requirements 
16 
4. 
Treatment Plan 
20 
5. 
Investigational Agent Information 
21 
6. 
Dose Modifications 
23 
7. 
Adverse Events and Reporting Procedures 
23 
8. 
Correlative / Special Studies 
25 
9. 
Study Calendar 
26 
10. 
Measurement and Statistical Methods 
27 
11. 
Regulatory Considerations 
28 
12. 
Statistical Considerations 
28 
References 
30 
Appendices 
34 
 

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Protocol Synopsis 
TITLE  
A post-transplant infusion of CD8 memory donor T-cells as 
consolidative therapy after allogeneic non-myeloablative hematopoietic 
cell transplantation in patients with leukemia and lymphoma. 
STUDY PHASE 
Phase 2 efficacy study 
STUDY SITE 
Stanford University Medical Center, CA 94305 
INDICATION 
Patients with leukemia and lymphoma who are not eligible for full dose 
transplantation 
INVESTIGATIONAL 
PRODUCT  
Allogeneic CD8 memory T-cells infused 30 to 75 days after 
hematopoietic cell transplant 
PRIMARY 
ENDPOINT and 
OBJECTIVE(S) 
To determine the proportion of patients with full dose donor T-cell 
chimerism within 3 months after the CD8+ memory T-cell infusion. 
SECONDARY 
ENDPOINTS AND 
OBJECTIVE(S) 
1. To determine the risk of disease progression, overall and event free 
survival, and non-relapse mortality following treatment with 
allogeneic CD8+ memory T-cells. 
2. To determine the incidence of acute and chronic GVHD following 
infusion of allogeneic CD8 memory T-cells. 
STUDY 
OBSERVATION 
PERIOD 
Patients will be followed for 6 months from the time of transplant 
(about 4 month after the CD8+ memory T-cell infusion) 
TREATMENT 
SUMMARY 
The efficacy of non-myeloablative allogeneic transplantation is 
mediated in part by the establishment of an alloreactive donor T-cell 
compartment following transplant with minimal toxicity.  A 
post-transplant infusion of allogeneic CD8+ memory T-cells may 
facilitate the conversion to full donor chimerism without an increase in 
graft versus host disease.  This is a single institution open-labeled 
single treatment study evaluating the efficacy of allogeneic CD8+ 
memory T-cell infusion derived from HLA-matched sibling donors.   
SAMPLE SIZE  
20 patients plus 20 sibling donors 
SUMMARY OF 
SUBJECT 
ELIGIBILTY 
Patients with the following histologically-confirmed disease: 
1. Acute myeloid leukemia (AML) 
2. Chronic lymphocytic leukemia (CLL) 
3. Non-Hodgkin lymphoma (NHL) 
4. Hodgkin lymphoma (HL) 
5. Myelodysplastic syndrome (MDS) /  
Myeloproliferative disease syndrome  (MPD) 
Patients not undergoing a full dose transplant conditioning 
Patients with HLA-matched or single antigen/allele mismatched related 
donors. 
CONTROL GROUP 
Historically-matched control patients 

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SCHEMA 
 
Day -11 
TLI 1 120 cGy 
ATG 2 1.5 mg/kg 
 
Day -10 
TLI 120 cGy 
ATG 1.5 mg/kg 
 
Day -9 
TLI 120cGy 
ATG 1.5 mg/kg 
 
Day -8 
TLI 120 cGy 
ATG 1.5 mg/kg 
 
Day -9 
TLI 120 cGy 
ATG 1.5 mg/kg 
 
Day -4 
TLI 120 cGy 
 
 
Day -3 
TLI 120cGY 
 
oral CsA 3 
Day -2 
TLI 120 cGy 
 
 
Day -1 
TLI 
120 cGy x 2 
 
 
Day 0 
 
infusion of 
mobilized PBSC 4 
oral MMF 5 
Day 25 to 70 
On study 
enrollment date 
Cyclophosphamide 
1.5 g/m2 IV x1 
 
Day 30 to 75 
 
CD8 memory 
T-cell infusion 
 
 Age ≤ 80 
 Not eligible for a 
myeloablative preparative 
regimen 
 Available HLA-matched or 
single allele/antigen 
mismatched related donor 
 Estimated creatinine clearance 
≥ 50 mL/min 
 LVEF ≥ 30%,  
 DLCO ≥ 40% predicted 
(adjusted for Hgb) 
 TBili < 3mg/dL 
 AST/ALT < 3X ULN 
 KPS ≥ 70 
Screening / Eligibility 
 AML 
 CLL 
 NHL 
 HL 
 MDS/MPD 
HLA-matched or single antigen/allele 
mismatched related donor 
G-CSF 16 mcg/kg x 5 days 
Collection of hematopoietic cells by 
apheresis, desired goal of ≥ 5 million 
CD34+ cells/kg recipient weight for 
infusion on Day 0 
Collection of unstimulated donor lymphocytes by  
apheresis with infusion of fresh column enriched  
CD8 memory T-cells between Days 30 to 75 
post-transplant, desired dose of 5 million/kg recipient 
weight 
1  TLI = total lymphoid irradiation 
2  ATG = anti-thymocyte globulin  
3  CsA = cyclosporine 
4  PBSC = peripheral blood stem 
cells.  The PBSC infusion 
procedure is called a 
hematopoietic cell transplant 
(HCT) or donor leukocyte 
infusion (DLI)  
5  MMF = mycophynelate mofitel 

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1. 
OBJECTIVES 
1.1 Primary Objective 
To determine the rate of conversion to full donor chimerism (FDC) following a post-transplant 
infusion (Day 30 to 75) of freshly enriched allogeneic CD8+ memory T-cells in patients with 
AML, NHL CLL, or HL, who received non-myeloablative TLI ATG transplant conditioning. 
1.2 Secondary Objectives 
1.  To determine the risk of disease progression, overall and event free survival, and non-relapse 
mortality. 
2.  To determine the incidence of acute and chronic GVHD following the infusion of allogeneic 
CD8+ memory T-cells. 
2. 
BACKGROUND 
2.1 Allogeneic Hematopoietic Cell Transplantation 
Allogeneic hematopoietic cell transplantation (HCT) is proven effective therapy for patients with a 
variety of hematolymphoid malignancies.  Following allogeneic HCT, a significant percentage of 
patients who were otherwise considered to have incurable cancers using best of care 
non-transplantation therapies have long-term disease free control and appear cured.  These patients 
are characterized by developing donor type hematopoiesis and have complete resolution of all 
disease-related signs, symptoms and markers.  Generally, patients who undergo allogeneic HCT 
are doing so as a “last ditch” effort for long-term disease control and possibly cure after exhausting 
all chemotherapy, and radiation therapy based treatment strategies.  Often many of the patients 
who undergo allogeneic HCT for treatment of their lymphoma have had disease relapse even after 
high dose chemotherapy and autologous stem cell rescue (autologous HCT). 
2.2 Relapse of Disease following Allogeneic HCT 
The main cause for treatment failure following allogeneic HCT is disease relapse.  Depending, in 
part, on the disease, disease status at the time of transplantation, and the intensity of the 
transplantation regimen, disease relapse occurs in roughly 25 to 80% of patients.  For example, 
following a full dose transplant in younger patients with acute leukemia in 1st or 2nd complete 
remission (CR) and using a graft from an HLA-matched sibling, the 2-year risk of disease relapse 
was < 30% [1-8].  In contrast, the 2-year risk of disease relapse for younger patients with 
refractory acute leukemia who received a full dose transplant was > 70% [9-11].  Older (> 55 years 
of age) patients or younger patients with medical co-morbidities that preclude full dose 
conditioning undergo reduced intensity conditioning (RIC) allogeneic HCT.  The 2-year risk of 
disease relapse in patients with acute leukemia in CR who received RIC allogeneic HCT was 
> 50% [12, 13].  Similarly, disease relapse remains the major cause of treatment failure for patients 
with T-cell, large B-cell and Hodgkin lymphomas and chronic lymphocytic leukemia (CLL) and 
occurs in > 40% who undergo RIC allogeneic HCT with chemotherapy, sub-lethal total body 
irradiation (TBI), or total lymphoid irradiation combined with anti-thymocyte globulin (TLI/ATG) 
[13-18].   
2.3 Treatment for Disease Relapse Following Allogeneic HCT 
Disease relapse following allogeneic HCT remains an ominous clinical event, which usually 
results in progressive disease and death.  Treatment strategies of patients with relapse following 

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allogeneic HCT can often be further complicated by the overall general poor clinical status of the 
patient.  Strategies for the treatment of disease relapse in these patients include the cessation of 
post-transplantation immune suppression medication, salvage chemotherapy with or without 
irradiation, a second allogeneic HCT, or the infusion of donor leukocytes (DLI).  Despite these 
interventions few patients beyond those with chronic myelogenous leukemia (CML) can be 
returned to durable remissions and the overall survival (OS) at 2 years following disease relapse 
was < 20% [19, 20].  Given that disease relapse is relatively common after transplant, and that few 
if any patients can be returned to durable remission once relapse has occurred, a desired goal 
would be to improve the transplant strategy and avoid the serious problem of post-transplant 
disease relapse. 
2.4 Graft Versus Tumor Reactions 
A major mechanism of cancer eradication following allogeneic HCT is the immunological-based 
recognition of residual host tumor cells by donor-derived immune cells contained in the donor 
graft.  This phenomenon, termed graft-versus-tumor (GVT) reactions, is supported by various lines 
of evidence.  The initial observations in support of GVT reactions stemmed from studies that used 
T-cell depleted (TCD) donor grafts whereby graft-versus-host disease (GVHD) was eliminated; 
however, without donor T-cells in the donor inoculum patients suffered a high incidence of disease 
recurrence [21].  The importance of GVT reactions was further demonstrated by improved disease 
control and fewer relapses following HLA identical sibling (allogeneic) transplantation compared 
to syngeneic (identical twin) transplantation for patients with hematologic malignancies [22].  The 
three year probability for relapse of leukemia was substantially higher following syngeneic 
compared to allogeneic HCT in acute myelogenous leukemia (AML) (52% vs 16%) and CML 
(40% vs 7%) following treatment using full dose transplant conditioning regimens [22].  The 
increased risk of relapse in syngeneic transplants counterbalanced the beneficial effect of the lack 
of GVHD.  Perhaps the most compelling evidence comes from the observation that the infusion of 
donor leukocytes obtained from the original donor in patients who have disease relapse following 
allogeneic HCT resulted in a GVT effect (23).   
2.5 Reduced Intensity Transplant Conditioning 
Following the recognition that a main mechanism of disease control after allogeneic HCT is by 
donor derived immune mediated GVT reactions, multiple groups, including our own at Stanford,  
developed reduced intensity transplant conditioning (RIC) regimens that shifted the burden of 
disease control from high doses of chemoradiotherapy to the donor immune system (24-28).  The 
low intensity transplant conditioning has allowed older patients and those with medical 
co-morbidities to proceed with transplant whereas, before these patients were excluded from 
allogeneic transplantation as the full dose conditioning regimens were associated with prohibitive 
toxicities.  As a consequence of the low dose conditioning, host hematopoietic and immune cells 
persist and result in a state of mixed hematopoietic and lymphoid chimerism (MC) that may 
convert to full donor chimerism (FDC) over a variable time course (13, 28-30).  Importantly, the 
achievement of early (before Day 60) FDC appears to be a necessary precondition for disease 
control (13, 28-30).  We and others have reported that irrespective of the specific type of RIC 
regimen used, the relapse risk is significantly higher in patients with persistent MC compared to 
those with FDC, and likely reflects tolerance of donor cells to recipient tissues (13, 28-30).  In a 
report detailing the outcomes of 111 allogeneic HCT recipients from HLA-matched and single 
antigen mismatch donors following TLI-ATG conditioning for leukemia and lymphoma there was 
a very low incidence of severe (Grade 2 to4) acute GVHD (< 5%), and a low incidence of 

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non-relapse related mortality at 1 year (< 5%) (13).  Whereas almost all patients who failed to 
achieve FDC experienced disease relapse, the actuarial event free survival was more than 55% in 
the patients who achieved > 95% donor type chimerism, with observations extending up to 6 years 
(13).  
2.6 Strategies to Convert MC to FDC 
Attaining FDC relatively early post-transplant is desirable because of its significant association 
with a reduced risk of disease relapse (13, 28-36).  A commonly used strategy to convert MC to 
FDC has involved the use of low dose, or escalating doses, of donor lymphocyte infusions (DLI) at 
designated early time points post-transplant [31-36].  These studies confirmed that prophylactic 
DLI (i.e.  before disease progression) induced conversion to FDC and was associated with a 
reduced risk of disease relapse, yet overall survival was not improved in these trials due to the 
increased risk of significant acute GVHD (31-36). 
In summary, disease relapse is the main cause of treatment failure following allogeneic HCT and is 
an ominous event as most patients cannot be returned to durable remission.  A significant 
percentage of patients who receive reduced intensity conditioning remain as MC for months and 
there is a significant association of MC with increased risk of disease relapse.  Conversion of MC 
to FDC following low dose or escalating doses of DLI was associated with a reduced risk of 
disease relapse yet OS was not improved due to the limiting toxicity of severe acute GVHD.  A 
pre-emptive strategy that would promote conversion of MC to FDC and retain immune mediated 
GVT reactions yet without promoting GVHD has the potential to benefit patients and may improve 
the cure rate in patients following allogeneic HCT. 
2.7 Preclinical Strategies to Overcome GVHD with DLI in a Murine Model Memory T-cells 
Induce Significantly Less GVHD than Naïve T-cells 
Recent murine studies showed that in many strain combinations memory T-cells, including 
memory CD4+, and memory CD8+ T-cells induce significantly less GVHD than naive T-cells 
(CD62LhiCD44lo) or combinations of naive and memory T-cells [37-43]. 
Accordingly, our group at Stanford compared freshly isolated naive CD4+, CD8+, or total T-cells, 
and/or memory CD4+CD44hi, CD8+CD44hi, and total memory T CD44hi cells from unprimed 
donors for their capacity to induce GVHD, and mediate antitumor activity against a naturally 
occurring B-cell lymphoma (BCL1) in an MHC-mismatched model where CD4 is predominant yet 
CD8 also can induce lethal GVHD (44).  Only the CD8+CD44hi memory T-cell subset containing 
both central and effector memory cells was capable of eradicating the lymphoma cells without 
inducing GVHD.  In contrast, CD4+ and CD8+ naïve T-cells, memory CD44hi CD4+ T-cells, 
naive total T-cells, and memory CD44hi total T-cells either induced lethal GVHD or lacked potent 
antitumor activity.  The tumor-bearing recipients of CD8+CD44hi T-cells had a clear survival 
advantage over those given CD8+ naive T-cells because of the lethal GVHD induced by the latter.  
The CD8+CD44hi T-cells were also used in a model of treatment of progressive lymphoma growth 
after BMT, and were able to promote complete chimerism and eradicate the tumor without GVHD. 
In other preclinical murine models of bone marrow transplantation using various MCH-matched 
strain combinations conducted by our group, the only cell subset that we could identify that 
provided GVT reactions against FBL3 leukemia tumor cells without inducing lethal GVHD was 
CD44hiCD8+ memory T-cells [45]. 

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Taken together, our studies and those by others suggest that CD8+ memory T-cells will have 
retained promote donor cell engraftment and retain GVT reactions yet have markedly reduced 
GVHD capacity.  These studies support the hypothesis that a clinical trial of infusing CD8+ 
memory T-cells may be superior to DLI for the conversion of MC to FDC following allogeneic 
HCT. 
2.8 Purification of human CD8+ memory T-cells for use as DLI therapy 
 
Figure 1A, Representative flow analysis of peripheral blood apheresis collections from the 
pre-selection, post-CD45RA depletion, and CD8 enrichment steps and stained for 
expression of CD4, CD8, CD45RA, and CD45RO after gating on CD3+ cells.   
Since we were successful in treating progressive tumor growth after BMT without inducing 
GVHD in mice with enriched donor CD8+ memory T-cells, we attempted to purify a similar subset 
of freshly isolated T-cells from normal humans for use in the currently planned study.  
Accordingly, we used immunomagnetic bead separation on Miltenyi columns to enrich 
CD8+CD45RO+CD45RA- T-cells from PBMCs (46).  First, cells were incubated with Miltenyi 
Unfractionated 
CD45RA Depleted 
1A 
CD45RA depleted 
CD8 selected 
CD8 
 

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GMP grade anti-CD45RA mAb conjugated beads for negative selection.  Thereafter, the 
CD45RA- cells were incubated with Miltenyi GMP grade anti-CD8 mAb conjugated beads to 
positively select the CD8+ cells.  The resultant CD8+CD45RA- T-cells had over 95% purity as 
shown in the FACS pattern in Figure 1A that is representative of 6 independent separations.  
Almost all the CD45RA-CD8+ cells were CD45RO+CD8+.  Yields of the cells were also 
determined using apheresis products from normal HCT donors and the mean post-enrichment cell 
count obtained from a single apheresis product was 5 x 108 with a range of 3 to 8 x 108 
CD45RA-CD8+ cells.  Therefore, following 2 high volume aphereses per donor, the highest 
feasible dose of memory CD8+ T-cells available for infusion will be 10 x 108 cells.  Assuming 
most patients weigh less than 100 kg, attainable numbers of memory CD8+ T-cells for a phase 1 
dose escalation trial are 1 x 106/kg;  5 x 106/kg;  and 10 x 106/kg.  IND 014844 has been submitted 
to the FDA describing the use of manipulated donor lymphocyte infusion (DLI) cells in clinical 
trials. 
 
In further studies the enriched CD45RA-CD8+ human memory T-cells were tested for immune 
reactivity in vitro by stimulation with irradiated allogeneic PBMCs from normal donors.  The 
cultures were monitored for 3H-thymidine incorporation at 7 days and for IFN-γ and IL-2 
concentrations in the supernatants.  The responder T-cells increased the mean 3H-thymidine 
incorporation in cultures with allogeneic stimulator cells as compared to control cultures without 
allogeneic stimulators (data not shown).  In addition, the memory CD8+ T-cell supernatants had a 
marked increase in the concentration of IFN-γ after culture with allogeneic stimulator cells, and 
had a minimal increase in the concentration of IL-2 (Figure 1B).  The results of the human mixed 
Figure 1B, Cytokine secretion assessment in CD8
+/CD45RA
- and 
CD4
+ cells activated by co-culture with or without irradiated allogeneic 
stimulators (Stim).  Supernatants from 7-day cultures were analyzed by 
flow cytometry using Cytokine Bead Arrays for INFγ;  IL-2;  and TNFα 
(n = 4).  Results are shown with +/- standard deviation (SD) 
1B 

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leukocyte response (MLR) experiments were consistent with the responses observed with CD8+ 
memory T-cells from mice.  The murine responder cells also showed a marked increase in 
3H-thymidine incorporation after stimulation with allogeneic cells, and the production of IFN-γ 
was considerably greater than that of IL-2 [46]. 
In summary, these studies demonstrated that an enriched population of CD8+ memory T-cells can 
be obtained from healthy human donors that in MLR experiments were consistent with the 
responses observed with CD8+ memory T-cells from mice and provided evidence for clinical 
safety (limited GVHD) and efficacy (retained GVT reactions).   
2.9 Phase 1 Clinical Trial of CD8+ Memory T-cell Infusion for Disease Relapse after 
Allogeneic HCT 
We conducted a single institution open-labeled single treatment study evaluating the safety and 
potential efficacy of allogeneic CD8+ memory T-cell infusion derived from HLA-matched sibling 
donors.  The phase I study followed a standard 3+3 dose escalation format using a low CD8+ 
memory T-cell dose of 1 x 106 cells/kg, an intermediate dose of 5 x 106 cells/kg and a final dose of 
10 x 106 cells/kg.  The objectives of the protocol were:   
1. To determine the feasibility of purifying allogeneic CD8+ memory T-cells suitable for 
clinical application and to determine the safety and maximum tolerated dose (MTD) of 
these cells in patients with recurrent or refractory hematolymphoid malignancies following 
allogeneic HCT.   
2. To determine disease response, time to disease progression, event-free survival, and overall 
survival following treatment with allogeneic CD8+ memory T-cells.   
3. To assess donor specific chimerism before and at designated time points after treatment 
with allogeneic CD8+ memory T-cells. 
To date, 8 patients with disease relapse after allogeneic HCT have been enrolled on the study and 
were followed for safety and potential efficacy.  The Table below summarizes the patients.  
Pt Dose 
level 
Dx 
DOT 
Date of 
Relapse 
Status at CD8+ 
memory 
T-cell infusion 
Date of CD8+ 
memory 
T-cell  infusion 
AE or GVHD 
Follow-up 
(months) 
Status at last 
F/U 
1.1 
1 
AML 
2-27-09 
8-25-11 
CR2 
4-17-12 
none 
27 
Alive in CR 
1.2 
1 
AML 
4-6-12 
8-1-12 
Not in CR 
8-10-12 
none 
17 
Expired 
1.3 
1 
AML 
08-14-03 4-17-12 
CR3 
10-11-12 
none 
20 
Alive, 
Relapse 
2.1 
2 
AML 
07-17-12 
1-4-13 
CR2 
6-6-13 
none 
14 
Expired 
2.2 
2 
BC- CML 08-29-07 
2-1-13 
CR 
6-27-13 
none 
13 
Alive in CR 
2.3 
2 
CLL 
09-03-10 3-15-12 
Not in CR 
7-17-13 
none 
3 
Expired 
3.1 
3 
AML 
05-31-13 7-10-13 
Not in CR 
10-9-13 
AE*, no GVHD 
1 
Expired 
3.2 
3 
AML 
03-15-13 11-18-13 Not in CR 
4-2-14 
AE*, no GVHD 
6 
Alive, 
Relapse 
* The AE was unrelated to CD8+ memory T-cell infusion. 

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Detailed patient summaries are provided below and are divided by cell dose cohort, 
Cohort 1:  A dose of 1 x 106 CD8+ memory T-cells/kg 
Patient 1.1:  A 66-year-old female with AML relapse 910 days after TLI-ATG conditioned 
allogeneic transplant from her matched sibling donor.  For disease relapse she received 4 cycles of 
myelotarg combined with azacytadine and achieved a complete marrow remission with < 5% 
marrow blasts yet had incomplete count recovery.  She received the donor CD8+ memory T-cell 
infusion on 17 April 2012, and as per visit on 21 October 2014, she was 917 days post CD8+ 
memory T-cell infusion and continues in complete remission with normal blood counts and a 
marrow with no evidence of AML. 
Patient 1.2:  A 71-year-old female with AML who had disease progression 117 days after 
TLI-ATG conditioned allogeneic transplant from her matched sibling donor.  The patient declined 
chemotherapy her post-transplant disease relapse.  Therefore, CD8 memory T-cells were infused at 
a time of the patient had active disease.  Post CD8+ memory T-cell infusion, the patient developed 
stable disease and was transfusion independent for 455 days.  Fifteen months after the cell infusion 
the patient presented with leukemic cutis and declined therapy and she succumbed from 
progressive disease on Day 517 after the cell infusion. 
Patient 1.3:  A 40-year-old female with extra medullary leukemia relapse 3165 days after initial 
allotransplant.  She received involved field radiation therapy to the extra-medullary site of disease 
and 4 cycles of Azacytadine and was returned to remission.  On evaluation on 727 days after the 
CD8 memory T-cell infusion, she was alive yet had disease relapse 650 days after the cell infusion. 
Cohort 2:  A cell dose of 5 x 106 CD8+ memory T-cells/kg 
Patient 2.1:  A 37-year-old with AML who had disease relapse 169 days after allogeneic 
transplant from a matched sibling donor.  The patient received 7+3 re-induction with cytarabine 
and Daunorubicin and failed to achieve a remission.  Thereafter the patient received 2 cycles of 
G-CLAC (G-CSF, clofarabine and cytarabine) and achieved a marrow remission with incomplete 
blood count recovery.  Following the CD8+ memory T-cell infusion the patient continued in 
remission with normal blood counts for 9 months and thereafter had chemorefractory resistant 
recurrence and expired from AML 418 days after the cell infusion. 
Patient 2.2:  A 60-year-old who underwent allogeneic HCT from a matched sibling donor for blast 
crises CML and developed a return of chronic phase CML 1829 days after transplant.  The patient 
was returned to a complete remission with dasatinib and at last follow up continues in complete 
remission, 435 days after the CD8+ memory T-cell infusion. 
Patient 2.3:  A 53-year-old with multiply recurrent high risk CLL who had disease progression 
545 days post allotransplant that progressed on salvage bendamustine-rituximab, and was treated 
to a stable disease using 3 cycles of FCR (fludarabine, cyclophosphamide, and rituximab).  Shortly 
(32 days) after receiving the CD8+ memory T-cell infusion the patient had progressive disease and 
was transitioned to best supportive care and died 89 days after the cell infusion. 
Cohort3:  A cell dose of 10 x 106 CD8+ memory T-cells/kg  
Patient 3.1:  A 61-year-old woman with refractory AML at start of allotransplant conditioning 
despite several attempts to achieve remission using 3 different induction regimens.  The patient 
had progressive AML 65 days post allotransplant and received salvage FLAG (fludarabine, 
high-dose cytarabine, G-CSF) chemotherapy and continued with refractory disease.  For her 

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refractory disease the patient was infused with 7.8 x 106 CD8 memory T-cells/kg, instead of the 
desired cell dose of 10 x 106cells/kg.  The patient continued with progressive disease and was 
transitioned to best supportive care and died 42 days after the cell infusion. 
Patient 3.2:  A 67-year-old man with overlap Myeloproliferative Disease and Myelodysplastic 
syndrome who on azacitidine progressed to AML.  He failed to receive remission despite 2 courses 
of induction cytarabine and daunorubicin and underwent allogeneic HCT using his HLA-matched 
sibling donor.  He had progressive AML 236 days after transplantation and received several cycles 
of re-induction chemotherapy using vorinostat with temozolomide yet his disease failed to 
respond.  He received a CD8 memory T-cell donor lymphocyte infusion for his refractory disease; 
the dose of cells was 8 x 106 CD8 memory T-cells/kg, instead of the desired 10 x 106 CD8 memory 
T-cells/kg.  At last follow-up 185 days after the cell infusion, the patient continues with a stable 
low level of AML and has not received additional chemotherapy.   
Two adverse events, considered unrelated to the infused cell product were noted. 
Patient 3.1 had neutropenia prior to the cell infusion and continued with neutropenia after the cell 
infusion.  The neutropenia was related to active AML.  Eighteen days after the CD8 memory 
T-cell infusion, the patient developed a fever that was treated to resolution with short course broad 
spectrum intravenous antibiotics and anti-fungal therapy.  All cultures were negative.  The reported 
adverse event was most likely UNRELATED to the investigational product.  The serious adverse 
event (SAE) was reported to MedWatch on 6 November 2013.   
Patient 3.2 had neutropenia prior to the cell infusion and continued with neutropenia after the cell 
infusion.  The neutropenia was related to active AML.  The patient developed fevers 33 days after 
the cell infusion.  Imaging studies at the time revealed probable new onset pneumonia.  The 
pneumonia was treated to resolution with broad spectrum antibiotics.  A bronchoscopy revealed 
light growth of MSSA.  The patient completed a full course of rocephin, azithromycin, and 
fluconazole.  The PCP stain was negative.  The patient continues with active AML.  The adverse 
event was most likely UNRELATED to the investigational product. 
2.10 Lymphodepletion with cyclophosphamide to promote CD8+ memory T-cell expansion 
and persistence 
Lymphodepletion with cyclophosphamide administered several days prior to DLI has been shown 
to promote in vivo expansion and persistence of the infused donor lymphocytes by providing 
lymphoid space, eliminating anti-donor immune reactivity, and reducing competition for growth 
factors that promote expansion of the infused T-cells [47-49]. Lymphodepletion with 
cyclophosphamide is thus routinely utilized prior to the infusion of various autologous or 
allogeneic cellular therapies where it has been shown to augment the antitumor activity of 
unmanipulated DLI [50, 51], chimeric antigen receptor-modified T cells [52, 53], and adoptively 
transferred tumor-specific T cells [54, 55]. We therefore propose administering a single dose of 
cyclophosphamide 1.5 g/m2 intravenously 3-5 days prior to the CD8+ memory T-cell infusion in 
order to promote further expansion and persistence of the cells, augment GVT activity, and reduce 
relapse rates.  
 

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The Cell Processing and Quality Assurance data are highlighted below.  
Cell Processing Summary 
 
CD8+ memory T-cell Quality Assurance Assessment 
 
 

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From the clinical trial the following observations are made 
1. The CD8 memory T-cell infusion was not associated with any infusion related toxicities, or 
related adverse events such as the development of GVHD, or other. 
2. The CD8 memory T-cell infusion appeared to have some efficacy albeit patients who have 
relapse of disease after allogeneic transplant have a poor overall survival at < 20% at 
2 years [19, 20].  Among the 8 patients treated, one patient continues in CR more than 
2 years after the CD8 memory T-cell infusion, one patient with untreated relapse continued 
with disease that did not progress and transfusion independence for > 1 year, and 
2 additional patients remain alive but with disease relapse with observations extending to 
beyond a year. 
3. Although no toxicities were observed at any dose, the maximum cell dose of 
10 x 106 CD8+ memory T-cells/kg is not a feasible dose for use in a clinical trial due to our 
inability to obtain this high number of CD8 memory T-cells.  Rather, a dose of 
5 x 106 cells/kg is readily obtainable from all donors. 
2.11 Study Rationale 
The administration of CD8+ memory T-cells at doses of ≤ 10 x 106 cells/kg did not result in 
GVHD, or other related adverse events.  The persistence of mixed hematopoietic cell chimerism is 
associated with a significantly high risk of disease relapse after allogeneic HCT [13, 28-36].  Once 
the patient’s disease has relapsed after allogeneic HCT, the likelihood for long-term survival is 
poor.  Therefore, a strategy that can help promote conversion of mixed to complete hematopoietic 
cell chimerism prior to disease relapse, and does not promote significant GVHD has the potential 
to help improve the outcomes of allotransplant recipients by reducing the risk of disease relapse.  
The goal of the current proposed trial will be to determine if CD8+ memory T-cells administered 
prophylactically and prior to disease relapse can convert patients with mixed chimerism at 
30 to 75 days after transplant to complete chimerism.  We hypothesize that patients who convert 
from mixed to complete chimerism will have a reduced rate of relapse similar to patients who are 
complete chimeras.  This study will follow a single arm Simon 2-stage trial principle.  In 
Simon stage 1, we will enroll 8 patients, and if 3 or fewer patients respond, defined as the 
conversion from mixed to complete chimerism within 90 days of the CD8+ memory T-cell 
infusion, we will stop for futility.  If 4 or more respond in Simon stage 1, then in stage 2 we will 
continue to enroll a full sample of 20 patients and declare success if a total of 11 or more patients 
respond.  The time frame for the CD8+ memory T-cell infusion will be between 30 to 75 days after 
transplant, and all patients will continue with the planned immune suppression drug taper to 
discontinuation at 6 months after transplant providing no GVHD is observed.  The primary 
endpoints will be safety and determination of the rate of conversion from mixed to complete donor 
chimerism.  If > 2 patients among the first 6 enrolled experience any new Grade 3 to 4 toxicities or 
> 2 patients develop Grade 3 to 4 GVHD during the 60 days following the CD8+ memory T-cell 
infusion, we will de-escalate the dose to 1 x 106 CD8+ memory T-cells/kg.  Based on our 
preclinical data that CD8+ memory T-cells do not aggravate GVHD, and the data from the clinical 
phase 1 trial we do not expect toxicities at a dose of 5 x 106/kg.  Secondary endpoints will include 
the risk of acute and chronic GVHD, freedom from disease progression, event-free and overall 
survival, and the relapse rate.  The goal is to improve the rate of attaining complete chimerism 
without increasing the risk of GVHD.  If following the Simon 2-stage trial the results are 

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lncouraging, we will expand our experience to a broader trial to determine if the infusion of CD8+ 
memory T-cells is associated with significantly lower rates of disease relapse. 
Study Design 
This is a single institution open-labeled single treatment study evaluating the safety and efficacy of 
allogeneic CD8+ memory T-cell infusion derived from HLA-matched sibling donors.  Enrollment 
of 18 patients is expected to be completed in less than 3 years.  The study will involve a single 
non-randomized intervention arm of administering 5 x 106 cells/kg CD8+ memory T-cells 
30 to 75 days after allogeneic HCT using TLI ATG conditioning.  The total duration of patient 
study participation is 6 months.  Patients will be followed indefinitely for all outcomes including 
survival, event-free survival and late complications such as but not limited to late chronic GVHD 
and infections. 
3. PARTICIPANT SELECTION AND PRE-ENROLLMENT REQUIREMENTS 
Refer to the Participant Eligibility Checklist in Appendix A. 
3.1  
Patient Inclusion Criteria for Transplant (patients must have all of the following). 
3.1.1  Between 18 and 80 years of age, inclusive. 
3.1.2  Has a HLA-matched or single allele-mismatched adult sibling serving as donor. 
3.1.3 Has a myeloid or lymphoid malignant disease that is treated with TLI and ATG 
reduced-intensity conditioning for allogeneic transplant [any of the following:  acute 
myeloid leukemia (AML);  chronic lymphocytic leukemia (CLL);  B or T-cell 
non-Hodgkin lymphoma (NHL);  Hodgkin lymphoma (HL);  Myelodysplastic syndrome 
(MDS);  or Myeloproliferative disease syndrome  (MPD)] 
3.1.4  Patients who due to age, pre-existing medical conditions, or, prior therapy are considered to 
be at high-risk for regimen-related toxicity associated with fully ablative transplant 
conditioning, and therefore reduced intensity conditioning is recommended. 
3.1.5  Ability to understand and the willingness to sign a written informed consent document.  
Patients must have signed informed consent to participate in the trial. 
3.2  
Patient Exclusion Criteria for Transplant (excluded if any of the following) 
3.2.1.   Uncontrolled bacterial, viral or fungal infection defined as currently taking medication and 
progression of clinical symptoms. 
3.2.2.  Progressive hemato-lymphoid malignancy despite conventional therapy 
3.2.3.  Acute leukemia not in remission 
3.2.4.  Chronic myelogenous leukemia (CML)  
3.2.5.  Active CNS involvement of the underlying malignancy 
3.2.6.  HIV-positive 
3.2.7.  Pregnant or lactating  
3.2.8.  Prior malignancy (EXCEPTION:  diagnosed > 5 years ago without evidence of disease, OR 
treated ≤ 5 years ago but have a greater than 50% chance of life expectancy of ≥ 5 years for 
that malignancy). 
E.2.9.  Have a psychiatric disorder(s) or psychosocial circumstance(s) which in the opinion of the 
primary physician would place the patient at an unacceptable risk from transplant. 

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3.2.10. Organ dysfunction defined as follows: 
i.  Ejection fraction < 30%, or uncontrolled cardiac failure 
ii.  DLCO < 40% predicted 
iii.  Total bilirubin > 3 mg/dL 
iv.  SGOT or SGPT > 4 x ULN 
v.  Creatinine > 2 mg/dL and an estimated creatinine clearance < 40 mL/min  
j.  Poorly controlled hypertension despite multiple antihypertensive medication 
k.  KPS < 60% 
l.  Note:  Patients positive for hepatitis B and C will be evaluated on a case-by-case basis 
3.3  
Donor Inclusion/Exclusion Criteria (To be eligible to participate in this trial, donors must 
meet the following criteria): 
3.3.1 HLA-matched or single allele mismatched sibling of enrolled transplant patient 
3.3.2 18 to 80 years of age, inclusive 
3.3.3 In a state of general good health and have completed a donor evaluation with history, 
medical examination and standard blood tests within 60 days of starting the hematopoietic 
cell collection procedure.  In order to fairly represent the interests of the donor, the donor 
evaluation and consent will be performed by a study team member other than the 
recipient’s attending physician.  
3.3.4 White blood cell count >3.5 x 109/liter, platelets >150 x 109/liter and hematocrit > 35% 
3.3.5 Capable of undergoing leukapheresis 
3.3.6 Able to understand and sign informed consent 
3.3.7 Hepatitis A, B and C, HIV-1 and -2, HTLV, VZV, EBV, HSV, West Nile virus, Syphilis 
Treponema, T cruzi (Chagas), CMV, and the MPX NAT IDT (HIV/HCV/HBV) will be 
tested as per national standard of care guidelines for transplant donors.  Donors who are 
HIV-positive will be excluded.  Donors who are positive by serology for Hepatitis B or C 
are eligible as long as PCR for RNA/DNA is negative.  
3.3.8 Females must not be pregnant or lactating 
3.3.9 
No psychological traits or psychological or medical conditions which make them unlikely to 
tolerate the procedure 
3.3.10 Has not developed a new malignancy requiring chemotherapy or radiation in the interval since 
apheresis for initial HCT 
3.4 
Patient Criteria for Proceeding with CD8+ Memory T-cell Infusion:  On Study 
enrollment date. 
3.4.1 Patients must be beyond Day 30 and before Day 75 after transplant. 
3.4.2 Patients must have evidence of mixed CD3 T-cell chimerism based on the Day +28 
(+/- 7 days) blood sample showing ≥ 30% and <90% donor type cells. 
3.4.3 Patients must have no evidence of active graft-versus-host disease at the time of the CD8+ 
memory T-cell infusion.  Patients with a history of acute GVHD overall Grade 2 based on 
skin only involvement or upper GI tract involvement only will be eligible.  Patients with a 
history of Liver or lower GI tract GVHD will not be eligible. 

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3.4.4 Patient must not have clinical evidence of disease progression prior to the CD8+ memory 
T-cell infusion. 
3.4.5 Patients must be on single immune suppression therapy with either Tacrolimus or 
Cyclosporine at the time of CD8+ memory T-cell infusion.  Prednisone at a physiologic 
dose of 5mg per day or less is allowed. 
3.4.6 Patients must have a Karnofsky performance status of ≥ 60% at the time of the CD8+ 
memory T-cell infusion. 
3.4.7 Patients must not have an uncontrolled bacterial, fungal or viral infection, defined as 
progressive symptoms despite therapy, at the time of the CD8+ memory T-cell infusion.  
Asymptomatic viremia is allowed. 
3.4.8 Patients must have adequate organ function and performance status at the time of the CD8+ 
memory T-cell infusion, defined by the following: 
i. Total bilirubin ≤ 4 mg/dL 
ii. SGOT or SGPT ≤ 4 x ULN 
iii. Creatinine ≤ 3 mg/dL or estimated creatinine clearance ≥ 40 mL/min  
3.5 Donor Evaluation for CD8+ Memory T-Cell Collection 
Donors must be the HLA-matched sibling who served as the donor for the allogeneic transplant.  
Within 7 days of cell collection, donors will be screened to confirm eligibility.  Screening will 
consist of the following evaluations and procedures.   
- 
A transplant physician together with the study coordinator will review the prior medical 
record that was performed for the initial transplant. 
- 
Under the direction of the study coordinator, donors will fill out a standard Stanford BMT 
self-assessment form that highlights all new medications prescribed from the time of initial 
donation, as well as any new medical diagnosis or surgeries. 
- 
Any newly prescribed medication, new medical diagnosis, or surgery since the time of the 
initial collection for transplant will initiate a formal medical re-evaluation. 
- 
If no new medications or new diagnosis have occurred, and no surgery, then just as what is 
done for the NMDP and collection of a DLI, the prior medical evaluation will suffice 
providing it is ≤ 120 days from date of initial medical evaluation to the date of starting the 
CD8+ memory T-cell collection. 
Documentation of vital signs (temperature, blood pressure, pulse rate, weight). 
Donors will be evaluated with the following laboratory tests within 14 days of starting apheresis 
for the collection of CD8+ memory T-cells:   
• CBC with complete blood count. 
• Clinical chemistry assessments including sodium, potassium, chloride, creatinine, random 
glucose, total calcium, total protein, albumin, total bilirubin, alkaline phosphatase, SGOT, 
SGPT.   
• A coagulation profile including PT and PTT  
• Female donors of child-bearing potential will undergo serum HCG testing which must be 
negative to proceed. 

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Donors will be screened within 7 days of the CD8 memory T-cell collection to confirm eligibility 
by undergoing repeat testing for: 
• Hepatitis A, B and C, HIV-1 and -2, HTLV, VZV, EBV, HSV, West Nile virus, Syphilis 
Treponema, T cruzi (Chagas), CMV, and the MPX NAT IDT (HIV/HCV/HBV) will be 
tested as per national standard of care guidelines for transplant donors.  Donors who are 
HIV-positive will be excluded.  Donors who are positive by serology for Hepatitis B or C 
are eligible as long as PCR for RNA/DNA is negative. 
• ABO/Rh will be performed. 
Once donors have been appropriately screened, they will proceed to cell harvest.   
3.6 Informed Consent Process 
A conference will be held with the patient and family to discuss this study and alternative 
treatments available for treatment of the underlying disease.  The attending physician will conduct 
the conference.  All potential risks associated with the use of TLI, ATG, immunosuppressive drugs 
and allogeneic hematopoietic cell infusions including and CD8+ memory T-cell cells will be 
discussed as objectively as possible.  It will be explained that patients offered this protocol have an 
underlying malignancy that render them either at high risk of relapse or that will result in life 
expectancies of several months to no more than one to two years with conventional treatments.  
These patients would be unlikely to benefit from, or tolerate an autologous transplant, and are at 
high risk of early transplant mortality from conventional allogeneic transplant.  Informed consent 
from the patient will be obtained using a form approved by the Administrative Panel on Human 
Subjects in Medical Research of the Stanford University Medical Center.  The participant will 
receive a copy of the signed and dated consent document.  The original signed copy of the research 
consent document must be retained in the subject’s research file.   
3.7 Study Timeline 
It is expected the study will accrue 7 patients per year and therefore the target goal of 20 patients 
will be completed within 2.5 years of the study opening. 
Patients will be followed for 6 months after the mobilized PBSC infusion on Day 0.  Patients’ 
End-of-Study Visit will be scheduled for approximately Day 180 post-PBSC infusion, +/- 3 weeks.  
Therefore, it is expected the study will be complete within 36 months of opening.  All patients will 
be followed for outcomes beyond the 6 months study observation period for determination of 
secondary outcome measures and as per institutional standards for transplant patients. 

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4. 
TREATMENT PLAN 
4.1 
Study Treatment Schedule 
Transplant Schedule 
Week 1 
Monday 
Day -11 
Tuesday 
Day -10 
Wednesday 
Day -9 
Thursday 
Day -8 
Friday 
Day -7 
Saturday 
Day -6 
Sunday 
Day -5 
TLI 120 cGy 
TLI 120 cGy 
TLI 120 cGy 
TLI 120 cGy TLI 120 cGy 
Rest 
Rest 
ATG  
1.5 mg/kg + 
solumedrol 
1.0 mg/kg 
ATG  
1.5 mg/kg + 
solumedrol 
1.0 mg/kg 
ATG  
1.5 mg/kg + 
solumedrol 
1.0 mg/kg 
ATG  
1.5 mg/kg + 
solumedrol 
1.0 mg/kg 
ATG  
1.5 mg/kg + 
solumedrol 
1.0 mg/kg 
 
 
Week 2 
Monday 
Day -4 
Tuesday 
Day -3 
Wednesday 
Day -2 
Thursday 
Day -1 
Friday 
Day 0 
Saturday 
Day +1 
Wednesday 
Day 25-70 
Friday 
Day 30-75 
TLI 
120cGy 
TLI  
120 cGy 
TLI  
120 cGy 
TLI  
120cGy  
x 2 doses 
Mobilized 
PBMC 
 
Cytoxan 
1.5 g/m2 IV 
x1  
CD8+ 
memory 
T-cell 
infusion 
 
Start Oral 
CSP 
CSP 
CSP 
CSP 
CSP 
CSP 
CSP 
 
 
 
 
Start Oral 
MMF 
MMF 
MMF 
stopped     
Day +28 
 
4.2 Apheresis 
HLA-matched donors will undergo unmobilized apheresis for collection of CD8+ memory T-cells.  
Sufficient numbers of cells will be obtained following 1 to 2 apheresis procedures on consecutive 
days such that the target cell dose at the end of the selection will be achieved.  Plasmapheresis, 
including volumes and frequency of collections, will be in accordance with 21CFR§640.65.  
4.3 Cyclophosphamide lymphodepletion 
Patients will receive a single dose of cyclophosphamide 1.5 g/m2 intravenously over 2 hours as 
lymphodepletion 3-5 days prior to the CD8+ memory T-cell infusion in order to promote further 
expansion and persistence of the infused T cells (see section 2.10). 
4.4 Administration of Study Drug  
Selected CD8+ memory T-cells meeting the release criteria (described below) will be infused no 
more than 48 hours after the harvest.  CD8+ memory T-cells will be taken to the recipient and 
infused fresh without cryopreservation.  The cells will be infused through a central venous catheter 
or peripheral IV of at least 19 gauge.  CD8+ memory T-cell infusion will take place over 10 to 20 
minutes, just like unmodified DLI.  

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IN Patients will be monitored for vital signs (temperature, blood pressure, pulse rate) every 
30 minutes following infusion and for at least two hours afterwards with evaluation every 
30 minutes.  WHO toxicity will be performed as described.  Recipients will be monitored for 
infusion related toxicities and treated as needed.  Premedication is not required and, if possible, 
should be avoided.  If clinically indicated, Benadryl and Tylenol can be given as needed.  Benadryl 
and will be utilized should a reaction occur and epinephrine and solumedrol will be available at the 
bedside. 
4.5 Criteria for Removal from Study and not proceeding with the Planned CD8+ memory 
T-cell Infusion 
All adverse events will be reviewed by Stanford Cancer Institute Data and Safety Monitoring 
Committee (DSMC) and patients will be removed from the study for the following reasons: 
• Excess toxicities are observed such as acute GVHD beyond Grade 2 skin or upper GI tract 
only GVHD, uncontrolled infection or organ performance status not meeting criteria for 
cell infusion. 
• Any other cconcurrent illness that prevents further administration of CD8 + memory T-cell 
Infusion 
• Non-compliance with the protocol (defined as inability to receive all scheduled treatments, 
follow-up appointments, and tests) 
• Patient request to withdraw from the study 
The number of patients who do not receive the planned CD8 memory T-cell infusion will be 
followed.  If for any reason more than 1 of the first 3 patients, or more than 2 of the first 6 patients, 
or more than 3 of the first 10 patients do not receive the planned infusion, the trial will temporarily 
close pending a DSMC audit to determine the cause.  A patient enrolled on the trial but who does 
not proceed with the planned infusion will be replaced with another enrolled patient as the goal is 
to evaluate 20 patients who receive the CD8+ memory T-cell product. 
4.6 Alternatives 
Alternative therapies will be discussed with each patient and would potentially include allogeneic 
transplantation using TLI and ATG conditioning without a planned CD8+ memory T-cell infusion 
or allogeneic transplantation using other transplant conditioning or other investigational therapies, 
or best of care non-transplantation therapy. 
4.7 Compensation 
There will be no compensation for participation on study. 
5. 
INVESTIGATIONAL AGENT INFORMATION 
5.1 
 Investigational Agent  
CD8+ Memory T-Cell Selection 
The patient’s original HLA-matched donor will undergo apheresis with collection of blood 
mononuclear cells as for standard DLI.  No mobilization agents will be administered.  Donor 
CD8+/CD45RA- T-cells will be isolated by tandem immunomagnetic selection using the 
CliniMACS Cell Selection System (Miltenyi Biotec).  Depletion of CD45RA expressing cells uses 
CliniMACS CD45RA Reagent (BB-MF-11872).  The CD45RA depleted fraction is enriched for 

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CD8 expressing cells by positive cell selection with CliniMACS CD8 Reagent (BB-MF-11704).  
In our phase 1 study, we evaluated the CD45RA-CD8+ cell yield from 8 normal donors that 
underwent either 1 or 2 aphereses.  The mean starting TNC count was 6.8 x 1010, the mean 
post-CD45RA depletion cell count was 4.5 x 1010, and the mean post-CD8 enrichment cell count 
was 6.6 x 108 with a range of 1.5 to 18.0 x CD45RA-CD8+ cells.  The lower end range cell yields 
were in donors who underwent 1 apheresis and the higher end range cell yields were following 
2 consecutive days of apheresis.  In combination, we completed 4 validation runs, combined with 
8 donor runs for the phase 1 protocol, our efficiency of percent CD8+ memory T-cell recovery has 
dramatically increased from < 20% to > 50%.  Therefore, following 1 or 2 consecutive days of 
aphereses per donor, we have data to validate that we will achieve the target cell dose of 5 x 106 
CD8+ memory T-cells/kg for all patients, assuming most patients weigh less than 120 kg.  If the 
number of CD8+ memory T-cells be below the desired threshold of 5 x 106/kg, the infusion will 
proceed as planned as the aggregate data support the importance of conversion from mixed to 
complete chimerism to decrease the risk of post-transplant disease relapse (13, 28-36).  Therefore 
we believe it is in the patient’s best interest to receive the additional cell infusion as this has the 
potential to help achieve complete chimerism.  It is expected that a cell yield of less than the 
desired cell dose will be obtained less than 10% of the time. 
Stability 
Prior to initiating the phase 1 study we completed four validation runs and found > 90% viability 
based on the immediate post selection viability.  We also have stability data on the 4 validation 
runs that extend to 48 hours of storage and found minimal loss in cell viability and all validation 
products continued with > 90% viability.  The phase 1 study added stability data from an 
additional 8 donors that extended to 48 hours of storage and confirmed > 94% viability in all cases.   
Reagents for cells for immediate release and conditions for storage 
For post selection products infused the same day the Miltenyi Biotech Selection Buffers that 
contain PBS with 1mmolar EDTA and 0.5% HSA will be used.  The CD8 and CD45 reagent 
systems are pharmaceutical grade and both have Master Files which are BB-MF-11704 and 
BB-MF-11872, respectively.  For post selection products that will be stored for 24 or 48 hours 
prior to infusion, the product will be diluted for storage with 1 volume of Normosol-R with 
2% HSA.  For patient comfort the volume will be reduced to < or equal to 200 mL and the 
CD8+memory T-cell concentration will range between 1 x 106 to 1 x 108 cells/mL.  The overnight 
storage temperature will be 4 degrees Celsius. 
Release Requirements of the Product 
Release of the selected cell products for fresh infusion includes: 
• negative Gram staining (no organisms detected) 
• endotoxin levels ≤ 0.5 EU/milliliter of infused product volume 
• > 90% cell viability 
• ≥ 80% of the CD3+ cells express the CD8 memory T-cell phenotype, here defined as 
CD8+/CD45RA-/CD45RO+ 
• ≤ 5% of cells with the CD3+/CD45RA+/CD45RO- phenotype 
• sufficient cells with the CD8 memory T-cell phenotype to meet the desired dose, or at least 
the minimum dose of > 2 x 106 CD8+ memory T-cells/kg 

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Release Criteria for products stored 24 or 48 hours:  due to the logistics of donor cell collection, 
cell processing and patient schedule, it is possible that some products may be stored for 24 or 48 
hours before their infusion.  Cell viability >90% is required for infusion of products not being 
stored.  Release criteria for products stored 24 or 48 hours require >80% viability as assessed by 
trypan blue or 7-AAD dye exclusion. 
In addition, post-selection sterility cultures in accordance with sterility testing guidelines 
(21CFR§610.12) will be conducted to confirm the sterility of the selected cells.  Any positive 
growth results obtained will be documented in the processing record of the selection and 
immediately communicated to the patient’s attending physician in accordance with the plan of 
action for the infusion of cellular products with microbial contamination.  Ancillary studies may 
include phenotypic analysis of the selected cells and cytokine secretion profiles from MLR assays 
may be used to further our understanding of the CD8+ memory T-cell population characteristics 
but do not constitute release criteria at this time. 
If the cell product does not meet release criteria after manipulation, the product will not be infused.  
In the case(s) where the manipulated cell product does not meet release criteria, the donor may 
undergo subsequent apheresis procedure(s) to collect a new product in an attempt to achieve a 
releasable fresh product for infusion.  If at any dose level the minimum cell dose is not achieved 
the patient and donor may be taken off study.  A patient removed from the study due to a failure to 
achieve the minimum CD8+ memory T-cell dose will be replaced with another patient. 
5.2 
Availability 
CD8+ memory T-cell products will be prepared in the Stanford Blood and Marrow Transplantation 
Cellular Therapy Facility under the direction of laboratory director, Kevin Sheehan, PhD.  
Dr Sheehan oversaw the manufacturing of the CD8+ memory T-cells for the phase 1 trial. 
5.3 
Agent Accountability 
CD8+ memory T-cells meeting the release criteria will be administered according to the 
instructions specified in the approved study protocol.  Infusions will be prepared and administered 
by a trained person designated by the investigator in response to orders written by the investigator. 
6. 
DOSE MODIFICATIONS 
The primary endpoints will be safety and determination of the rate of conversion from mixed to 
complete donor chimerism.  In the first 6 enrolled patients (i.e., infused with CD8+ memory 
T-cells), if > 2 patients experience any new Grade 3 to 4 toxicities, or > 2 develop Grade 3 to 4 
GVHD during the 60 days following the CD8+ memory T-cell infusion, we will de-escalate the 
dose to 1 x 106 CD8+ memory T-cells/kg.  In the first 12 enrolled patients, if > 3 patients develop 
Grade 3 to 4 GVHD during the 60 days following the CD8+ memory T-cell infusion, or after the 
first  12 enrolled patients if > 4 patients develop Grade 3 to 4 GVHD during the 60 days following 
the CD8+ memory T-cell infusion, the dose will be de-escalated as per above.  
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Adverse Events 
Hematopoietic cell transplantation (HCT) is an aggressive therapy for the treatment of a number of 
life-threatening disorders, including cancer.  In this setting, a very large number of Grade 1 and 2 
adverse events (AEs) are expected to occur, regardless of whether or not a patient is participating 
in a research study.  In order to minimize the “background noise” and to focus on 

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clinically significant, impactful adverse events useful in the assessment of treatment effect, the 
following AE reporting schema is proposed.  This schema is intended to capture all AEs that are 
clinically significant and/or impactful, but minimize “not informative” AE collection.  
• Grade 3 and higher AEs will be collected and documented with causality attribution 
(see Section 7.2 Adverse Event Attribution) on an adverse event log (AE log).   
• In addition, all AEs meeting the criteria of “serious” as defined at 21CFR§312.32(a), 
including any that are otherwise Grade 1 or 2,  will be collected;  identified as serious; and 
documented on an AE log, including causality attribution.   
o An adverse event is considered serious if it fulfills one of the following criteria per 
21CFR§312.32(a): 
▪ Results in death 
▪ Life-threatening (patient at risk of death at the time of the event) 
▪ Requires inpatient hospitalization or prolongation of existing hospitalization 
▪ Results in persistent or significant disability 
▪ Other medical events that may not be immediately life-threatening or result in death 
or hospitalization by may jeopardize the patient or require intervention to prevent 
one of the outcomes listed above 
• Laboratory values without a clinical consequence or outcome will not be tracked as 
adverse events, unless deemed serious. 
• Grade 1 and 2 AEs not meeting these criteria will not be collected, except as follows.  
Grade 1 and 2 AEs resulting in subject dose modification (including dose termination) or 
withdrawal from the study will be collected. 
All Serious Adverse Events (SAEs) will be tracked until resolution or at least 60 days after the last 
dose of the study treatment.  
Vital signs for all subjects enrolled on the trial will be monitored for infusion-related toxicities 
(AEs) during the CD8 memory T-cell infusion, and every 30 minutes for 2 hours afterwards.  
Observed events will be recorded on the AE log.  In particular, subjects will be observed for 
hemodynamic instability, allergic reactions (eg, hives, rashes, angioedema), and fevers 
(> 38.3º po).  
The development of acute GVHD, its date of onset and overall grade, is a key secondary outcome 
measure for patients on this trial.  Please refer to Section 6 “Dose Modifications” that highlight the 
safety rules with respect to GVHD development.  Acute GVHD will be recorded on an AE log.  
7.2 
Adverse Event Attribution 
As noted, HCT is an aggressive therapy for the treatment of cancer, and a large number of AEs are 
expected in this setting, including a number of specific AEs that are associated with the underlying 
disease;  therapies administered prior to HCT;  health status of the transplant recipient including 
co-existing conditions;  the preparative regimen for transplant;  concomitant therapies intended to 
reduce transplant-related complications (eg,  immunosuppressants for the prevention of GVHD);  
and treatment for complications of HCT.   

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The Protocol Director (PD) or designee will assess each Adverse Event (AE) to determine whether 
it is unexpected according to the Informed Consent, Protocol Document, or 
Investigator’s Brochure, and related to the investigation.  Unless specifically determined otherwise 
by the investigator, the following events are considered anticipated in this setting.  
• Alopecia  
• Anemia  
• Anorexia  
• Bleeding, including requiring transfusions  
• Cardiac arrhythmias   
• Central venous catheter infections  
• Constipation  
• Diarrhea  
• Edema  
• Fatigue  
• Febrile episodes  
• Gastritis  
• Graft failure  
• Graft versus host disease  
• Hematuria   
• Hypertension  
• Hypotension  
• Hypoxia  
• Incontinence  
• Infections, including sepsis 
• Insomnia  
• Laboratory abnormalities  
• Mental status changes and mood alterations  
• Mucositis  
• Nausea  
• Neutropenia  
• Pain  
• Pleural effusion  
• Pneumonitis  
• Rash  
• Seizures  
• Sinusoidal obstructive syndrome  
• Tachycardia  
• Thrombocytopenia  
• Thrombotic microangiopathy  
• Tremor  
• Vomiting 
7.3 
Adverse Event Reporting 
All serious adverse events (SAEs) related to study procedures will be collected from signing of 
informed consent through CD8+ Memory T-cell infusion.  Adverse events, both non-serious and 
serious, will be collected as outlined in Section 7.1 from date of CD8+ Memory T-cell infusion 
through 60 days.  Beyond 60 days post-cell infusion, SAEs related to study treatment will be 
collected through the Week 20 follow-up visit. 
All serious adverse events (SAEs) will be reported to the IRB;  to the IND;  and to the DSMC, 
either in an annual review or as an expedited report, in accordance with the applicable guidelines 
and regulations.  
AEs meeting the criteria specified for an IND Safety Report as defined at 21CFR§312.32(c)(1) 
will be collected;  documented in the adverse event log;  and reported to the IND (on a 
MedWatch 3500A form) in the timeframe specified. 
The IND annual report will include summaries of the collected AEs, as specified by 
21CFR§312.33.  
8. 
CORRELATIVE/SPECIAL STUDIES  
N/A 

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9. 
STUDY CALENDAR 
Pre enrollment 
requirements  
                           HCT 
                          Day = 0 
On study 
enrollment = 
CD8+ Memory 
T-cell Infusion 
Weeks from on study 
enrollment 
 
±5 days 
Weeks from on study 
enrollment 
 
±2 weeks 
(Day 30-75) 
Wk 1 
Wk 2 
Wk 4 
Wk 8 
Wk 12g 
Wk 20g 
HCT Infusion 
 
X 
 
 
 
 
 
 
 
Infusion of CD8+ 
memory T-cells 
 
 
X 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
X 
X 
X 
X 
X 
X 
Concurrent meds 
X 
 
X 
X 
X 
X 
X 
X 
X 
Donor Evaluation 
X 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs a 
X 
 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
Performance status 
X 
 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff 
X 
 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry b 
X 
 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse 
Event evaluation 
 
 
X 
Disease Status 
Assessment c 
X 
 
X 
B-HCG d 
X 
 
 
 
 
 
 
 
 
Cyclophosphamide 
 
 
Xf 
 
 
 
 
 
 
STR analysis e 
X 
 
X 
 
a: 
Temperature, blood pressure, and pulse.  On day of infusion, vital signs to be taken any time prior to infusion, then 
immediately after infusion and every 30 minutes thereafter until 2 hours post-infusion. 
b: 
Albumin, alkaline phosphatase, total bilirubin, calcium, chloride, creatinine, glucose, potassium, total protein, AST, 
ALT, sodium 
c 
Response assessment as per disease histology, and may include CT, PET, and/or MRI imaging, and bone 
marrow biopsy or aspiration (refer to Appendix C), and is typically performed around Day 90 post transplant 
(Day 0)  
d: 
Women of childbearing potential only 
e: 
Short tandem repeat (STR) analysis relative to transplant date Day 0.  Therefore, performed on Day 28 +/- 7 days, 
Week 8 +/- 2 weeks, Week 12 +/- 2 weeks, and Week 20 +/- 2 weeks, and thereafter as per standard of care  
f: 
A single dose as lymphodepletion given 3-5 days prior to the CD8+ memory T-cell infusion 
g: 
As necessary, data for the Week 12 or Week 20 visit, which is considered part of routine medical care for 
post-transplant patients, may be collected by phone contact to the subject and/or their regular physician. 

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10. 
MEASUREMENT and STATISTICAL METHODS 
Our extensive experience with the TLI ATG conditioning for allogeneic HCT in cancer patients 
showed a 30% incidence of FDC at Day 90, with a 95% confidence interval of 10 to 49%.  The 
non-relapse mortality (NRM) was 3% (95% CI:  0 to 14%) at 100 days and 6% (95% CI:  
1 to 28%) at 1 year.  The incidence of acute GVHD by Day 100 was 6% (0.7 to 22%). 
10.1  Primary and Secondary Outcome measures 
Following the infusion of CD8+ memory T-cells to promote the conversion of mixed chimerism to 
full donor chimerism and ultimately reduce the risk of disease relapse a variety of outcome 
measures will be followed. 
The primary outcome is to determine the proportion of patients with full dose donor chimerism 
within 3 months of receiving the CD8+ memory T-cell infusion.  Successful conversion from 
mixed to complete chimerism is defined as achieving ≥ 95% donor type in the CD3+ lineage or 
whole blood within 90 days of cell infusion.    
The secondary outcome measures include the 1 year time-to-disease progression;  
overall survival (OS);  and event-free survival (EFS);  and non-relapse mortality.  The incidence of 
acute and chronic GVHD following the infusion of allogeneic CD8+ memory T-cells will be 
determined. 
Recipients will be monitored for infusion related toxicities and the rates of GVHD or marrow 
aplasia.  Typically following an unmanipulated DLI the timing for acute GVHD or marrow 
hypoplasia onset is about 30 days post-infusion [32-38].  GVHD, if it occurs, will be treated 
promptly.  First line therapy will include corticosteroids at a dose of 1-2 mg/kg depending upon 
severity.  Additional immunosuppressive medications will be added as clinically indicated.   
Evaluations will be performed to assess infusion related toxicity according to the following:   
• Post-infusion toxicity evaluations (including physical exam, vitals, and weight) will be 
performed on days +7;  +14;  +28;  and weeks 8;  12;  20;  and 26 (+/- 5 days for the first 
4 weeks post-infusion;  +/- 14 days for dates thereafter) using CTCAE v4.0.   
• STR analysis will be performed prior to the CD8+ memory T-cell infusion (within 35 days 
prior) and then will follow the scheduled events calendar assessment visits until 6 months 
post-transplant. 
• GVHD will be according to Appendix B for GVHD Grading.   
• CBC performed within 7 days prior to the CD8+ memory T-cell infusion and then will follow 
the scheduled events calendar until 6 months. 
• Chemistries including Albumin, alkaline phosphatase, total bilirubin, calcium, chloride, 
creatinine, glucose, potassium, total protein, AST, ALT, and sodium will be performed within 
7 days prior to the cell infusion and thereafter follow the scheduled events calendar until 6 
months.   
• The level of tumor burden will be evaluated at 3 and 6 months after transplant by standard 
imaging and blood evaluation procedures specific for the patient disease (refer to 
Appendix C). 
Beyond 6 months all patients will be followed as per standard as per our institutional practice for 
HCT recipients (on average about every 6 weeks until 12 months post-transplant and regularly 

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thereafter) and data and laboratory tests including disease burden assessment will be recorded to 
determine the 1 year overall survival and event-free survival, NRM and for the development of 
infections and chronic GVD. 
11. 
REGULATORY CONSIDERATIONS 
11.1 
Institutional Review of Protocol 
The protocol, the informed consent and all forms of participant information related to the study 
(eg, advertisements used to recruit participants) will be reviewed and approved by the Stanford 
IRB and Stanford Cancer Center Scientific Review Committee (SRC).  Any changes made to the 
protocol will be submitted as a modification and will be approved by the IRB prior to 
implementation.  The Protocol Director will disseminate the protocol amendment information to 
all participating investigators. 
11.2 
Data and Safety Monitoring Plan 
The Stanford Cancer Center Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study.  The DSMC will audit study-related activities to determine 
whether the study has been conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  In addition, the DSMC will 
regularly review serious adverse events and protocol deviations associated with the research to 
ensure the protection of human subjects.  Results of the DSMC audit will be communicated to the 
IRB and the appropriate regulatory authorities at the time of continuing review, or in an expedited 
fashion, as needed. 
11.3 
Data Management Plan 
The Protocol Director, or his designee, will prepare and maintain adequate and accurate participant 
case histories with observations and data pertinent to the study.  The Stanford BMT data 
monitoring team along with the study coordinator will collect the information required in the Study 
calendar of events and maintain records for data analysis.  The data will be reviewed by the study 
PI for accuracy against source document data. 
11.4 Confidentiality  
Patient records will be kept in a secure location at Stanford University Medical Center accessible 
only to research authorized personnel.  Patient identity will be kept as confidential as possible as 
required by law.  The patient will not be identified by name, social security number, address, 
telephone number, or any other personal direct identifier.  Study patients will be assigned an 
identification code.  Information about the code will be kept in a secure location and access limited 
to research study personnel.  The results of this study may be presented at scientific or medical 
meetings or published in scientific journals, however patient identity will not be disclosed.  
Personal data included in the investigators’ database will be maintained in compliance with all 
applicable laws and regulations. 
12. 
STATISTICAL CONSIDERATIONS 
Statistical Analysis 
Analysis of 50 consecutive previous patients with persistent mixed chimerism after HCT using 
TLI-ATG conditioning confirmed the observed rate of conversion to complete chimerism without 

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an additional cell infusion was 25% (n = 12), and assume the upper limit of conversion is likely 
35%.  The sample size determination for the clinical trial will follow a single arm Simon 2-stage 
trial principle, with a null hypothesis of 35% (p0), and an alternative hypothesis of 70% (p1).  We 
will use a significance level of 0.05 () and power of 0.9 (1-).  In Simon stage 1, we plan to 
enroll 8 patients and if 4 or more patients respond by converting to complete chimerism we will 
proceed to stage 2 where we will continue to enroll a full sample of 20 patients and declare success 
if a total of 11 or more patients respond.  We will not start enrollment in Simon stage 2 until at 
least 3 successes are observed. 
Patients will receive a CD8+ memory T-cell infusion 30 to 75 days after their initial HCT.  The 
desired dose of CD8+ memory T-cells will be 5 x 106 cells/kg.  It is fully expected this dose will 
be safe and not provoke or increase the risk of GVHD or other complications.  In the phase 1 trial 
we infused this dose, or exceeded it, in 5 patients and observed no infusion related, early or late 
toxicities. 
Patients will be evaluated for toxicities, defined as new Grade 3 to 4 toxicities, according to the 
Common Toxicity Criteria v.4 and Grade 3 to 4 GVHD (Appendix B) during the 60 days 
following the CD8+ memory T-cell infusion.  If 2 of the first 6 patients develop DLTs, the dose 
will be lowered to 1 x 106 CD8+ memory T-cells/kg.  If 2 of the first 6 patients infused with this 
lower dose develop DLTs, then the trial will be stopped for safety reasons. 
For the first 3 enrolled patients, the CD8+ memory T-cell infusion will be staggered by at least a 
30-day interval between patients to allow for an assessment of DLTs for each patient.  Thereafter, 
if no DLTs are observed, the CD8+ memory T-cell infusion will be staggered by 10-day intervals 
between patients.  For added safety, if there is any incidence of a DLT observed the wait period 
will be extended to 60 days between the patients.   
If a Grade 5 toxicity or death occurs and is at least likely related to the cell infusion, the trial will 
stop.  Consideration for trial modifications will depend on institutional IRB and DSMC reviews.  
The appropriate regulatory offices including FDA will be notified within 5 business days of such 
an event. 
Statistical considerations for the revised protocol  
 
We have infused phenotypic CD8+ memory T cells in a total of 29 patients (as a treatment in 15 
patients who had disease relapse after transplant, and as a prophylactic intervention in 14 patients 
with mixed chimerism to convert to  complete chimerism to reduce the risk of subsequent disease 
relapse).  We have confirmed the safety; there have been no infusion reactions, and no grade 3 or 
higher adverse events attributable to the infusion, and no aggravation or precipitation of acute 
GVHD. 
 
We now propose to amend the protocol by administering a single dose of cyclophosphamide 
(1500mg/m2 BSA) 2-5 days prior to the CD8+ memory T cell infusion. The primary reason to 
amend the protocol to include cyclophosphamide is the desire to take advantage of the new clinical 
and pre-clinical information available that strongly suggests an increase in efficacy (success rate) 
with the addition (see section 2.10 in the revised Protocol). In addition to the obvious ethical 
impetus to provide trial participants with the optimal version of an experimental treatment, we note 
a scientific rationale: since the use of cyclophosphamide in this context will very likely become the 
new standard prior to infusing a cellular therapy, it is advisable to adapt our protocol to that reality.  

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The compelling ethical and scientific rationale notwithstanding, we must remain attentive to the 
extra assumptions required for statistical integration of the data from the patients treated without 
Cyclophosphamide early in the study and those treated with Cyclophosphamide after the change. 
Here is a review of the new design, the main issues it raises, and the analysis that led us to our new 
strategy: 
 
1. The original Simon optimal, 2-stage design was predicated on a historical control success rate of 
35% and an alternative success rate of 70%. There is no reason to alter the historical assumption. 
We propose a new embedded but independent 2-stage design (see below for details) with a single 
arm treated with the addition of Cyclophosphamide to the current regimen, predicated on an 80% 
alternative. The 10% increase in the alternative is based on the pre-clinical and clinical results 
cited above.  The original design entertained a Type 1 error rate of 5% and a Type 2 error rate of 
10%; in the new embedded trial we allow a 10% Type 1 error rate (which is more usual in phase 2) 
and retain the 10% Type 2 error rate.  
 
2. We considered simply finishing the trial with the remaining 6 patients in the original design now 
being treated with cyclophosphamide, which would address the ethical dimension. However, the 
interpretation of a positive result would rest on an assumption that the alternative under 
Cyclophosphamide cannot be less than that without Cyclophosphamide. This is a reasonable 
assumption, but at the end of the trial we would likely not have strong evidence to support it, so the 
interpretation would still rely on a largely untested assumption. In addition, we would have little 
new evidence for safety, always an important consideration. By adding only 2 patients to the entire 
study, we are able to treat up to 8 patients with the Cyclophosphamide-containing regimen, which 
leads to the 2-stage design (details below) predicated on the 80% alternative assumption.  
 
Why is this better? We have converted an assumption necessary for interpretation of a positive 
overall result into an assumption that drives the design of the embedded trial whose results will test 
the assumption at high power (90%). A positive result in the embedded trial is statistically definite, 
once it is completed, since the design assumption has been subject to test.  A positive independent 
result in the embedded trial will buttress the overall result obtained by pooling the initial 14 and 
new 8 patients and calculating the one-sided 95% lower confidence limit for the success rate. It 
should be noted that because the embedded trial “stands alone” and does not include the initial 
cohort of patients treated without Cyclophosphamide, the fact that the interim results in the initial 
patients are known does not affect the type 1 error of the embedded trial.  
 
3. The details of the embedded trial: Assuming a 35% historical control rate, and an 80% 
alternative, for 10% Type 1 and 2 error rates, the Simon optimal 2-stage design calls for a first 
stage with 2 patients, going on if there is at least 1 success, to the second stage with a cumulative 
total of 8 patients, rejecting the historical control rate (declaring a positive result) if there are at 
least 5 successes out of 8. 
 
The output for the file is: 
 
clinfun::ph2simon(pu=0.35,pa=0.80,ep1=0.1,ep2=0.1) 
 Simon 2-stage Phase II design  

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Unacceptable response rate:  0.35  
Desirable response rate:  0.8  
Error rates: alpha =  0.1 ; beta =  0.1  
 
                r1 n1 r n EN(p0) PET(p0) 
Optimal  0  2 4 8  5.465  0.4225 
 
 
 
12.1  Sample Size and On-Study Enrollment Date  
At least 20 patients will be required to complete the study (plus two additional patients as per 
above)  The on-study enrollment date for this trial will be the day the recipient is infused with 
CD8+ memory T-cells.  Prior to this date transplant recipients will be in a screening phase.  
12.2 
Accrual estimates 
Approximately 6 to 7 patients will be enrolled annually.  Time to complete enrollment will be 
3 years.  Time to complete the trial will be about 3.5 years. 

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Shook D, Pillai A, Pui CH, Leung W.  Risk-adapted donor lymphocyte infusion based 
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APPENDICES 
APPENDIX A:  Participant Eligibility Checklist  
Protocol Title: 
Post Transplant Infusion of Allogeneic CD8 Memory T-Cells as 
Consolidative Therapy After Non-Myeloablative Allogeneic Hematopoietic 
Cell Transplantation in Patients with Leukemia and Lymphoma. 
Protocol Number: 
IRB-33058 / BMT288 
Principal Investigator: 
Robert Lowsky, MD 
II.  Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
III.  Inclusion/Exclusion Criteria 
Transplant Patient Inclusion Criteria 
(From IRB-approved protocol) 
Must have all of the following 
Yes 
No 
Supporting Documentation* 
1. Between 18 and 80 years of age, inclusive 
 
 
      
2. Has a HLA-matched or single allele-mismatched 
adult sibling serving as donor 
 
 
      
3. Has a myeloid or lymphoid malignant disease that 
is treated with TLI and ATG reduced-intensity 
conditioning for allogeneic transplant [any of the 
following:  acute myeloid leukemia (AML);  
chronic lymphocytic leukemia (CLL);  B or T-cell 
non-Hodgkin lymphoma (NHL);  
Hodgkin lymphoma (HL);  Myelodysplastic 
syndrome (MDS);  or Myeloproliferative disease 
syndrome  (MPD)] 
 
 
      
4. Patients who due to age, pre-existing medical 
conditions, or, prior therapy are considered to be at 
high-risk for regimen-related toxicity associated 
with fully ablative transplant conditioning, and 
therefore reduced intensity conditioning is 
recommended. 
 
 
      
5. Ability to understand and the willingness to sign a 
written informed consent document.  Patients must 
have signed informed consent to participate in the 
trial. 
 
 
      

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Transplant Patient Exclusion Criteria 
Excluded if any of the following are yes 
 
 
 
1. Uncontrolled bacterial, viral or fungal infection 
defined as currently taking medication and 
progression of clinical symptoms. 
 
 
      
2. Progressive hemato-lymphoid malignancy despite 
conventional therapy. 
 
 
      
3. Chronic myelogenous leukemia (CML)  
 
 
      
4. Acute leukemia not in remission 
 
 
      
5. Active CNS involvement of the underlying 
malignancy 
 
 
      
6. HIV-positive 
 
 
      
7. Pregnant or lactating  
 
 
      
8. Patients with a prior malignancy (EXCEPTION:  
diagnosed > 5 years ago without evidence of 
disease, OR treated ≤ 5 years ago but have a 
greater than 50% chance of life expectancy of 
≥ 5 years for that malignancy) 
 
 
      
9. Has a psychiatric disorder(s) or psychosocial 
circumstance(s) which in the opinion of the 
primary physician would place the patient at an 
unacceptable risk from transplant. 
 
 
      
10. Organ dysfunction defined as follows: 
i. Ejection fraction < 30%, or uncontrolled 
cardiac failure 
ii. DLCO < 40% predicted 
iii. Total bilirubin > 3 mg/dL 
iv. SGOT or SGPT > 4 x ULN 
v. Creatinine > 2 mg/dL and an estimated 
creatinine clearance ≤ 40 mL/min  
vi. Poorly controlled hypertension despite 
multiple antihypertensive medication  
vii. KPS < 60% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
      
      
      
      
 
      
 
      

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Donor Eligibility Criteria 
(From IRB-approved protocol) 
 
 
 
1. HLA-matched or single allele-mismatched sibling of 
enrolled transplant patient 
 
 
      
2. 18 to 80 years of age, inclusive 
 
 
      
3. State of general good health with completed donor 
evaluation with history, medical examination and 
standard blood tests within 60 days of starting the 
hematopoietic cell collection procedure 
 
 
      
4. White blood cell count  
> 3.5 x 109/liter,  
platelets > 150 x 109/liter and  
hematocrit > 35% 
 
 
 
 
 
 
 
 
 
      
      
      
5. Capable of undergoing leukapheresis 
 
 
      
6. Able to understand and sign informed consent 
 
 
      
7. Hepatitis A, B and C, HIV-1 and -2, HTLV, VZV, 
EBV, HSV, West Nile virus, Syphilis Treponema, 
T cruzi (Chagas), CMV, and the MPX NAT IDT 
(HIV/HCV/HBV) will be tested as per national 
standard of care guidelines for transplant donors.  
Donors who are HIV-positive will be excluded.  
Donors who are positive by serology for 
Hepatitis B or C are eligible as long as PCR for 
RNA/DNA is negative. 
 
 
      
8. Females must not be pregnant or lactating 
 
 
      
9. No psychological traits or psychological or medical 
conditions which make them unlikely to tolerate the 
procedure 
 
 
      
10. Has not developed a new malignancy requiring 
chemotherapy or radiation in the interval since 
apheresis for initial HCT 
 
 
      
*All subject files must include supporting documentation to confirm subject eligibility.  The method 
of confirmation can include, but is not limited to, laboratory test results, radiology test results, 
subject self-report, and medical record review.   
IV.  Statement of Eligibility 
This subject is [ 
 eligible / 
 ineligible ] for participation in the study. 
 
Signature: 
Date: 
Printed Name: 
 

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Signature: 
Date: 
Printed Name: 
 
Signature: 
Date: 
Printed Name: 
 

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APPENDIX B:  Glucksberg clinical stage and grade of acute GVHD 
 

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APPENDIX C. 
RESPONSE CRITERIA by DISEASE HISTOLOGY 
 
AML Response Criteria (Cheson, et al.  2003) 
 
  In this study day of assessment is 12 weeks and 24 weeks post stem cell infusion.  For patients who are in a pathologically confirmed remission 
prior to infusion, a bone marrow biopsy and/or aspirate are not required; disease can be followed by confirmatory CBCs 
 
NHL Response Criteria (Cheson, et al.  2007) 
 
    In this study day of assessment is 12 weeks and 24 weeks post stem cell infusion. 
 

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CLL Response Criteria (Hallek, et al.  2008) 
 
  In this study day of assessment is 12 weeks and 24 weeks post stem cell infusion. 

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MDS Response Criteria (Cheson, et al. 2006)