A Phase 2 Study of Nonmyeloablative Conditioning With Transplantation of Partially Human Leukocyte Antigen (HLA)-Mismatched Bone Marrow and Post-transplant Cyclophosphamide for Patients With Hematologic Malignancies
Phase: PHASE2
Conditions: Hematologic Malignancies
Sponsor: University of California, San Diego

A Phase 2  Study of Nonmyeloablative or Myeloablative 
Conditioning with Transplantation of Partially HLA-
Mismatched Peripheral Blood or Bone Marrow and Post-
transplant Cyclophosphamide for Patients with 
Hematologic Malignancies
NCT02623439
Document Date: 6/12/2014

PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
______________________________________________________________________________ 
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Haplo Orig. Protocol 8-2-12 
Am1 8-7-13; Am 2 11-8-13; Am3 2-3-14; Am4 06-12-2014 
02/14mam, 06/14mam 
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A Phase 2  Study of Nonmyeloablative or Myeloablative Conditioning with Transplantation 
of Partially HLA-Mismatched Peripheral Blood or Bone Marrow and Post-transplant 
Cyclophosphamide for Patients with Hematologic Malignancies 
Original Protocol: August 2, 2012 
Amendment 1:  August 7, 2013 
Amendment 2:  October 28, 2013 revised 11-8-13 
Amendment 3:  February 03, 2014 
Amendment 4:  June 12, 2014 
Principal Investigators:   
Grace Ku, MD 
Moores UCSD Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA 92093 
Tel: 858-822-6600 
Fax: 858-822-6398 
Email:  gku@ucsd.edu 
Carolyn Mulroney, MD 
Moores UCSD Medical Center 
3855 Health Sciences Drive 
La Jolla, CA 92093 
Tel: 858-822-6600 
Fax: 858-822-6398 
E-mail: camulroney@ucsd.edu
Sub Investigators: 
Edward Ball, MD 
Januario Castro, MD 
Peter Curtin, MD 
Matthew Wieduwilt, MD, PhD. 
Caitlin Costello, MD 
Statistician:
Karen Messer, PhD., UCSD Biostatistics Program, Shared Resource 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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Haplo Orig. Protocol 8-2-12 
Am1 8-7-13; Am 2 11-8-13; Am3 2-3-14; Am4 06-12-2014 
02/14mam, 06/14mam 
 
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SYNOPSIS 
 
Study Design: This is a single center Phase 2 study of myeloablative (MA) and 
nonmyeloablative (NMA) conditioning, transplantation of partially HLA-mismatched bone 
marrow or peripheral blood stem cells and post-transplantation cyclophosphamide (Cy) in 
patients with hematologic malignancies including: 
1)  Acute lymphoblastic leukemia/lymphoma, acute myelogenous leukemia, and Burkitt’s 
lymphoma in remission. 
2) Relapsed lymphoma, including marginal zone B cell lymphoma, follicular lymphoma, and 
chemotherapy-sensitive large-cell or Hodgkin lymphoma. 
3) Myelodysplastic Syndrome (MDS) 
4) Blastic plasmacytoid dendritic cell neoplasm 
5) Multiple myeloma 
 
Primary Objective:  
The primary objective is to determine overall survival 180 days after transplantation involving 
MA and NMA conditioning, HLA-haploidentical marrow or peripheral blood stem cell grafts, 
and post-transplant Cy.   
 
Secondary Objectives: 
Secondary objectives include estimating overall and progression-free survival at 100 days, 180 
days, and one year after transplantation, treatment-related mortality, incidence of neutrophil and 
platelet recovery or engraftment, incidence of graft failure, cumulative incidence of acute and 
chronic GVHD, incidence of infections, and cumulative incidence of relapse/progression.  We 
will also examine the amount of time to transplant (day of unrelated search initiation to day 0). 
 
Eligibility Criteria:   
 Age: Subjects 18-75 years old. 
 Donor must be  18 years of age. 
 HLA typing will be performed at high resolution (allele level) for the HLA-A, -B, Cw, 
DRB1, and –DQB1 loci. A minimum match of 5/10 is required.    
With high resolution typing, the donor and recipient must be identical at a minimum of at least 
one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and 
HLA-DQB1.  Meeting this criterion will be considered sufficient evidence that the donor and 
recipient share one HLA haplotype, and typing of additional family members is not required. 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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 Acute Leukemias 
 Acute Lymphoblastic Leukemia in high risk CR1 as defined by at least one of the 
following: 
 
Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), MLL rearrangements, 
 
White blood cell counts of greater than 30,000 wbc/µL, 
 
Patients over 30 years of age, or 
 
Time to Complete Remission was greater than 4 weeks. 
 Acute Myelogeneous Leukemia in high risk CR1 as defined by at least one of the 
following: 
 Greater than 1 cycle of induction therapy required to achieve remission, 
 Preceding myelodysplastic syndrome (MDS), 
 Secondary leukemia (history of chemotherapy or radiation treatment as 
precursor to development of leukemia), 
 Presence of Flt3 internal tandem duplication (ITD), 
 FAB M6 or M7 leukemia, or 
 Adverse cytogenetics for overall survival such as 
 those associated with MDS 
 Complex karyotype ( 3 abnormalities) 
 Any of the following: inv(3) or t(3;3), t(6;9), t(6;11), + 8 [alone or with 
other abnormalities except for t(8;21), t(9;11), inv(16) or t(16;16)], 
t(11;19)(q23;p13.1) 
 
Acute Leukemias in 2nd or subsequent CR (see remission definition in Chapter 3). 
 
Biphenotypic/Undifferentiated Leukemias in 1st or subsequent CR. 
 
Burkitt’s lymphoma: second or subsequent CR. 
 
Myelodysplastic Syndrome (MDS) 
 
Blastic plasmacytoid dendritic cell neoplasm 
 Lymphoma: 
Chemotherapy-sensitive (complete or partial response; see response criteria in 
Chapter 3) aggressive lymphoma or Hodgkin’s lymphomas that have failed at least 1 
prior regimen of multi-agent chemotherapy and are ineligible for an autologous 
transplant. They may have received prior autologous transplant if greater than three 
months prior to enrollment. 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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Haplo Orig. Protocol 8-2-12 
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Or 
Marginal zone B-cell lymphoma or follicular lymphoma that has progressed after at 
least two prior therapies (excluding single agent Rituxan). 
 Multiple myeloma 
 Patients with adequate physical function as measured by: 
 Cardiac: Left ventricular ejection fraction at rest must be  40%,  
 Hepatic: Bilirubin, ALT, AST ≤ twice the upper limits of normal and Alkaline 
Phosphatase < 5 x ULN. 
 Renal: 24 hour creatinine clearance≥ 40 mL/min 
 Pulmonary: FEV1 ,of ≥ 50% of predicted and , DLCO (diffusion capacity)≥ 40% of 
predicted.  If unable to perform pulmonary function tests, then O2 saturation > 92% 
on room air. 
 Performance status: Karnofsky score 70-100%. 
 
Treatment Description: 
 
The preparative regimen will consist of: 
NMA: 
- Fludarabine 30 mg/m2 IV Days –6, –5, –4, –3, –2 
- Cyclophosphamide (Cy) 14.5 mg/kg IV Days –6, –5 
- Total body irradiation (TBI) 200cGy Day –1 
- Day 0 will be the day of infusion of non-T-cell depleted bone marrow or peripheral blood stem 
cells. 
 
MA: 
- Fludarabine 25 mg/m2 IV Days -–6, –5, –4, –3, –2 
- Busulfan 110 mg/m2 days -7,-6,-5,-4 
- Cyclophosphamide (Cy) 14.5 mg/kg IV Days –3, –2 
- Day 0 will be the day of infusion of non-T-cell peripheral blood stem cells with CD34 dose 
capped at 5 million per Kg recipient weight. 
 
 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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Haplo Orig. Protocol 8-2-12 
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The GVHD prophylaxis regimen will consist of: 
- Cy 50 mg/kg IV Days +3, +4  
- Tacrolimus (1 mg IV given as continuous infusion daily) beginning Day +5 with dose adjusted 
to maintain a level of 5-10 ng/mL.  Switch to PO when tolerating POs well and levels are stable. 
- Mycophenolate mofetil (MMF) 15 mg/kg po TID beginning Day + 5, maximum dose 1 g po 
TID 
- GCSF 5 mcg/kg/day beginning Day + 5 until ANC  1,000/mm3 for 3 consecutive days 
 
Study Duration: Patients will be followed for one year after transplantation for purposes of this 
study.  
 
Accrual Objective:  15 patients 
 
Accrual Period:  3 years 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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Haplo Orig. Protocol 8-2-12 
Am1 8-7-13; Am 2 11-8-13; Am3 2-3-14; Am4 06-12-2014 
02/14mam, 06/14mam 
 
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NON-MYELOABLATIVE TREATMENT SCHEMA 
 
 
Days –6, –5 
Fludarabine 30 mg/M2 IV daily 
Cyclophosphamide (Cy) 14.5 mg/kg IV daily 
Mesna 11.6 mg/kg IV daily 
           
Days –4  –2 
Fludarabine 30 mg/M2 IV daily 
 
 
Day –1 
TBI 200 cGy 
 
 
Day 0 
Infuse non-T cell-depleted marrow or non T cell depleted peripheral 
blood stem cells 
 

Days +3, +4 
Cy 50 mg/kg (IBW) IV daily 
Mesna 40 mg/kg IV daily 
(First dose of Cy must be administered 60-72 hour after infusion of marrow) 
 
 
Day +5    
Begin tacrolimus 1mg IV continuous infusion daily and 
MMF 15 mg/kg PO TID with maximum daily dose 3 gm/day 
Begin G-CSF 5 mcg/kg/day SC or IV, continue until ANC  1000/mm3 x 3 days 
 
 
Day ~28 
Assess chimerism in peripheral blood 
 

Day +35 
 
 
Discontinue MMF (optional if GVHD is active) 
 
 
Day ~56 
Assess chimerism in peripheral blood 
 
 
Day +180 
Discontinue tacrolimus (optional if GVHD is active) 
Assess chimerism in peripheral blood 
Evaluate disease 
 
 
1 yr  
Evaluate disease 
Assess chimerism in peripheral blood 
 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
______________________________________________________________________________ 
vii 
Haplo Orig. Protocol 8-2-12 
Am1 8-7-13; Am 2 11-8-13; Am3 2-3-14; Am4 06-12-2014 
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Myeloablative TREATMENT SCHEMA* 
 
Day – 7  Busulfan 110 mg/m2/day 
 
Days –6, –5, -4 
Fludarabine 25 mg/M2 IV daily 
     Busulfan 110 mg/m2/day 
 
 
 
                                                    
Day -3 and -2  Fludarabine 25 mg/M2 IV daily 
                                                          Cyclophosphamide (Cy) 14.5 mg/kg IV daily 
Mesna 11.6 mg/kg IV daily 
 
 
 
 
 
Day 0 Infuse non-T cell-depleted peripheral blood stem cell s with total CD34 dose capped 
at 5 million per kg 
 
 
Days 3, 4 
Cy 50 mg/kg (IBW) IV daily 
 
Mesna 40 mg/kg IV daily 
(First dose of Cy must be administered 60-72 hour after infusion of marrow) 
 
Day 5    
Begin tacrolimus 1mg IV qd and 
                
MMF 15 mg/kg PO TID with maximum daily dose 3 gm/day 
 
Begin G-CSF 5 mcg/kg/day SC or IV, continue until ANC  1000/mm3 x 3 days 
 
 
Day ~28 
Assess chimerism in peripheral blood 
 
 
Day 35 
 
Discontinue MMF (optional if GVHD is active) 
No taper 
 
 
Day ~56 
Assess chimerism in peripheral blood 
 
 
Day 180 
Discontinue tacrolimus (optional if GVHD is active) 
Without taper 
Assess chimerism in peripheral blood 
 
Evaluate disease 
 
 
1 yr,  Evaluate disease 
Assess chimerism in peripheral blood 
 
TABLE OF CONTENTS 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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1. 
BACKGROUND AND RATIONALE ............................................................................ 1 
1.1. 
Background ....................................................................................................................... 1 
2. 
STUDY DESIGN ............................................................................................................... 9 
2.1. 
Study Overview ................................................................................................................. 9 
2.2 
Hypotheses and Specific Objectives ................................................................................ 9 
Hypotheses 9 
Study objectives .............................................................................................................................. 9 
2.3 
Patient Inclusion Criteria ................................................................................................. 9 
2.4 
Patient Exclusion Criteria .............................................................................................. 11 
2.5 
Donor Inclusion Criteria ................................................................................................ 12 
2.6 
Donor Exclusion Criteria ............................................................................................... 12 
2.7 
Donor Prioritization Schema ......................................................................................... 12 
2.8 
Treatment Plan................................................................................................................ 13 
2.8.1  Indwelling Central Venous Catheter ................................................................................. 13 
2.8.2  Fludarabine ....................................................................................................................... 14 
2.8.3  Pre-transplantation Cyclophosphamide ............................................................................ 14 
2.8.4  Busulfan ............................................................................................................................ 15 
2.8.5  Total Body Irradiation ....................................................................................................... 16 
2.8.6  Bone Marrow and peripheral blood stem cell Transplantation ......................................... 16 
2.8.7  Post-transplantation Cyclophosphamide with Mesna ....................................................... 17 
2.8.8  Tacrolimus ........................................................................................................................ 17 
2.8.9  Mycophenolate Mofetil (MMF) ........................................................................................ 17 
2.8.10  Supportive Care ................................................................................................................ 18 
2.8.11  Transfusion Support .......................................................................................................... 18 
2.8.12  Anti-Ovulatory Treatment ................................................................................................ 18 
2.8.13  Post-transplant  Evaluation ............................................................................................... 18 
2.9 
Risks and Toxicities ........................................................................................................ 18 
2.10 
Growth Factor Support .................................................................................................. 22 
2.11 
Management of Slow Engraftment and Graft Failure ................................................ 22 
3. 
STUDY ENDPOINTS ..................................................................................................... 23 
3.1 
Primary Endpoint ........................................................................................................... 23 
3.2 
Secondary Endpoints ...................................................................................................... 23 
 
Neutrophil Recovery ......................................................................................................... 23 
 
Primary graft failure .......................................................................................................... 23 
 
Secondary graft failure ...................................................................................................... 23 
 
Platelet recovery ................................................................................................................ 23 
 
Donor Cell Engraftment .................................................................................................... 23 
 
Acute Graft-versus-Host Disease ...................................................................................... 23 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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 
Chronic Graft-versus-Host Disease .................................................................................. 25 
 
Progression-free Survival.................................................................................................. 25 
 
Treatment-Related Mortality (TRM) ................................................................................ 25 
 
Infections........................................................................................................................... 25 
 
Time from initiation of unrelated donor search to Day 0. ................................................ 25 
 
Relapse and Residual Disease ........................................................................................... 25 
4.PATIENT ENROLLMENT AND EVALUATION .............................................................. 27 
Enrollment Procedures ............................................................................................................... 27 
Screening and Eligibility Procedures ............................................................................................ 27 
Study Monitoring ........................................................................................................................ 28 
Follow-up Schedule: ..................................................................................................................... 28 
Adverse Event Reporting ........................................................................................................... 28 
Patient Assessments .................................................................................................................... 30 
Pre-transplant evaluations ............................................................................................................. 30 
Post-transplant evaluations ........................................................................................................... 31 
5. 
STATISTICAL CONSIDERATIONS .......................................................................... 32 
5.1 
Study Design .................................................................................................................... 32 
5.2 
Accrual ............................................................................................................................. 33 
5.3 
Study Duration ................................................................................................................ 33 
5.4 
Randomization ................................................................................................................ 33 
5.5 
Primary Objective ........................................................................................................... 33 
5.6 
Sample Size and Power Considerations ........................................................................ 33 
5.7 
Demographic and Baseline Characteristics .................................................................. 34 
5.8 
Analysis of Primary Endpoint ....................................................................................... 34 
5.9 
Analysis of Secondary Endpoints .................................................................................. 34 
 
 
LIST OF APPENDICES 
APPENDIX A – HUMAN SUBJECTS 
APPENDIX B – LABORATORY EVALUATIONS 
APPENDIX C – GUIDELINES FOR DONOR TYPING AND SELECTION 
APPENDIX D – REFERENCES 
APPENDIX E – DSMB Monitoring and Verification 
 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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1. 
BACKGROUND AND RATIONALE 
 
1.1. 
Background 
 
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers a curative treatment option 
for patients with hematologic malignancies.  An important component of this strategy involves an 
effect exerted by the T cells within the donor graft known as “graft-versus-malignancy” effect.1, 2  
While the best outcomes are shown in transplantation with HLA-matched sibling donors, only 25-
30% of patients have this option.  For the majority of patients, alternative donors are an important 
source of stem cells.  However, several obstacles exist in finding a successful unrelated donor.  
First, the likelihood of finding a matched unrelated donor for Caucasians is about 70% but can be 
10 -50% for ethnic minorities.3  Second, the interval of time between the initiation of a donor 
search to graft procurement is approximately 4 months.  Clearly this option is less than ideal for 
patients with high risk disease who are in urgent need of a transplant.  Umbilical cord blood 
overcomes some of these obstacles.  It is available within a few weeks. Greater than 95% of 
patients have at least a 4/6 potential matched cord blood unit and the majority have a potential 5/6 
match (http://marrow.org).  However, the use of cord blood units also has disadvantages.  Most 
adult recipients require double cord transplantation.  There are some recipients who are too large 
to even qualify for a double cord.  Other issues include the difficulty of procuring more stem cells 
in case of graft failure or DLI.  Additionally there is a prolonged engraftment time which leads to 
increased infection risk.  Transplantation with HLA-haploidentical relatives offers at least two 
advantages compared to unrelated donors.  First, there is a high likelihood of identifying an eligible 
donor since all biological parents and children share one HLA haplotype. Second, potential donors 
can be identified promptly, whereas the time from initiation of search to unrelated donor 
identification takes a median of 49 days4.  
 
While haploidentical stem cell transplantation has been studied since the late 1980s-early 1990s, 
early results showed high rates of graft rejection and severe graft-versus-host disease (GVHD).5, 6  
Groups at Johns Hopkins and Seattle have investigated the effect of administration of high dose, 
post-transplantation cyclophosphamide (Cy) on the incidence and severity of these complications 
in animal models7, 8 and then in humans9.  The rationale for administering Cy after transplantation 
is that recently activated, alloreactive T cells (the cells most responsible for GVHD) are selectively 
sensitive to the toxic effects of this drug.10  Also, Cy is known to be stem cell sparing. Pre-clinical 
studies demonstrated that engraftment of major histocompatibility complex (MHC)-mismatched 
bone marrow could be achieved by conditioning mice with the combination of pre-transplantation 
fludarabine and low dose (200 cGy) total body irradiation, and post-transplantation Cy.7 
 
Two independent clinical trials, one at Johns Hopkins (n=60) and the other at the Fred Hutchinson 
Cancer Research Center in Seattle  (n=28), evaluated the safety and efficacy of high-dose, post-
transplantation Cy in prevention of graft rejection and GVHD after outpatient NMA conditioning 
and T cell-replete bone marrow transplantation from partially HLA-mismatched related donors.  
Eighty-eight consecutive patients were accrued to these trials between 1999 and 2006. 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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Patients on the two protocols were treated in three separate groups (Hopkins A, Hopkins B, and 
Seattle) which differed in postgrafting immunosuppression (Figure 1.1).  Conditioning consisted 
of Cy 14.5 mg/kg/day IV on Days –6 and –5, fludarabine 30 mg/m2/day IV on Days –6 to –2, and 
200 cGy of TBI on Day –1.  On Day 0, patients received donor marrow.  The marrow was obtained 
in a targeted collection of 4 x 108 nucleated cells/kg recipient weight and depleted of red blood 
cells.  On Day +3, 50 mg/kg Cy was administered over 90 min together with Mesna (80% dose of 
Cy in 4 divided doses over 8 hr) by IV infusion (Hopkins A and Seattle).  The Hopkins B group 
received an additional dose of Cy on Day +4.  Pharmacologic prophylaxis of GVHD was initiated 
on the day following completion of post-transplantation Cy.  All patients received tacrolimus, 
initiated at a dose of 1 mg IV daily and adjusted to a therapeutic level of 5-15 ng/ml.  Tacrolimus 
was converted to oral form until discontinuation.  If there was no active GVHD, tacrolimus was 
tapered after Day 90 (Seattle) or discontinued on Day 50 or 180 (Hopkins A and B, respectively).  
All patients received mycophenolate mofetil (MMF) until Day+ 35 at a dose of 15 mg/kg PO twice 
daily (Hopkins A) or thrice daily (Hopkins B and Seattle), with a maximum daily dose of 3 g in 
the Hopkins B group.  Patients received filgrastim, 5 g/kg/day by subcutaneous injection starting 
on Day 1 (Hopkins) or Day 4 (Seattle) and continuing until recovery of neutrophils to >1000/L 
for three days. 
 
 
 
Figure 1.1 Treatment Schema 
 
Engraftment and chimerism.  By high resolution typing, donors differed from their recipients by a 
median of 3 of 8 (HLA-A, -B, -Cw, and DRB1) HLA alleles in both the host-versus-graft (HVG) 
and graft-versus-host (GVH) directions.  About one-third of donor-recipient pairs were 
mismatched for all four of these HLA antigens.  There were no differences in the three groups with 
respect to the donor age, donor-patient relationship, or total number of HLA allele mismatches in 
either the HVG or GVH directions. 
 
Median times to neutrophil and platelet recovery were 15 and 24 days, respectively.  Multivariate 
analysis showed that the factors associated with significantly delayed recoveries of neutrophils 
and platelets were lower graft CD34+ cell content and administration of a second dose of post-
transplantation Cy. 
 
Graft failure occurred in 15 of 84 evaluable patients (18%): 6 of 19 (32%) in the Hopkins A group, 
3 of 26 (12%) in the Seattle group, and 6 of 39 (15%) in the Hopkins B group.  Engrafting patients 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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achieved full donor chimerism rapidly.  With few exceptions, donor chimerism in patients with 
sustained engraftment was virtually complete (>95%) by 2 months post-transplantation. 
 
As a result of these encouraging single center studies the BMT CTN opened a phase 2 multicenter 
clinical trial, BMT CTN 0603.11  This involved nonmyeloablative (NMA) conditioning 
(fludarabine, cyclophosphamide, TBI) with HLA haploidentical bone marrow (haplo-marrow) 
transplantation followed by post-transplant Cy.  This trial was run in parallel to BMT CTN 0604 
using NMA conditioning and double umbilical cord blood (dUCB) transplantation.  These data 
were published in Blood in 2011 and the results are summarized below. 
 
 
 
 
 
Figure 1.2 BMT CTN 0604 and 0603 Treatment Schema 
 
In BMT CTN 0603, 50 patients were treated according to protocol and accrued between December 
2008 and May 2010.  Median age of recipients was 48 years (range 7-70 years).  More than 75% 
of the HLA haploidentical donors were mismatched for at least 4 HLA alleles. 
The median time of neutrophil recovery to >500 µL was 16 days and platelet recovery ≥ 20,000/µL 
was 24 days. There was one case of primary graft failure.  All engrafted patients had 100% donor 
chimerism at day +56 after transplant. 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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Targeted grade 3-5 toxicities were reported in 30% of the haplo-marrow recipients and these are 
noted below in Table 1.1. There were no grade 5 toxicities reported in either study. 
 
 
 
Table 1.1 Targeted Toxicities in BMT CTN 0604 and 0603 
 
 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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Cumulative incidence of grade 2-4 aGVHD at day +100 was 32% in the haplo-marrow group.  
There were no cases of grade 3-4 aGVHD. One year cumulative incidence of cGVHD was 13%.  
These results were comparable and perhaps superior to the earlier single center haploidentical 
transplant trials at Johns Hopkins and Seattle.  In the concurrently run dUCB trial, BMT CTN 
0604, the cumulative incidence of grade 2-4 and 3-4 aGVHD at day +100 were 40% and 21% 
respectively.  One year cumulative incidence of cGVHD was 25%. GVHD incidence for the two 
trials is shown in Figure 1.3. 
 
 
Figure 1.3 GVHD in BMT CTN 0603 and 0604 
 
With median follow up 357 days for surviving haplo-marrow recipients the one year cumulative 
incidence of NRM was 7% and relapse/progression was 45%.  One year PFS and OS were 48% 
and 62% respectively.  In dUCB group the median follow up was 365 days with a 1 year 
cumulative incidence of NRM of 24% and relapse/progression of 31%.  The one year PFS and OS 
in the dUCB trial were 46% and 54% respectively.  In both groups, relapse was the most frequent 
cause of death. Long term outcomes are shown in Figure 1.4. 
 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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Figure 1.4 Long term outcomes in BMT CTN 0603 and 0604 
 
Data have also been reported for Myeloablative strategies in patients who are considered to be 
candidates for an ablative transplant based on very high risk disease and comorbidity analysis.  
Solomon et al [Biol Blood Marrow Transplant 18: 1859-1866 (2012)](16) reported on a series of 
patients treated with an ablative regimen utilizing Busulfan, cyclophosphamide, and fludarabine.  
Post transplant immunosuppression included the same strategies as noted in the CTN trials.  Donor 
egraftment occurred in all patients with full donor chimerism in all patients at day+30.  The 
cumulative incidence of GVHD grade 2-4 was 30% with the incidence of grade 3-4 acute GVHD 
only 10%.  The cumulative incidence of chronic GVHD was 35%. The nonrelapse mortality at 100 
days and 1 year was 10%.  The estimated 1 year survival overall was 69% and disease free survival 
was 50%.  These outcome data with respect to NRM and aGVHD compare favorably to the 
outcome for nonmyelablative double umbilical cord blood transplants but the incidence of chronic 
GVHD are increased as compared to double umbilical cord blood transplants.  While the overall 
outcome as compared to the nonmyelablative regimens is similar there is a risk of more severe 
grade 3-4 acute GVHD and an increased risk of chronic GVHD. The overall similarity in survival 
at 1 year may be related to the potential benefit for chronic GVHD in decreasing relapse.    
 
In summary, HLA-haploidentical BMT after both ablative and non-myeloablative conditioning 
and using 2 doses of post-transplantation Cy followed by TID MMF is a well-tolerated procedure.  

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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The toxicity of the procedure compares favorably to the toxicity of ablative and non-myeloablative 
transplantation using unrelated donors. 
 
To place these results in context, the table below (Table 1.2) compares major outcomes of patients 
in BMT CTN 0603 and 0604 to those in a report containing the largest number of patients receiving 
unrelated donor grafts after NMA conditioning (n= 89)12.  The table demonstrates that the two 
procedures appear roughly equivalent in terms of time to neutrophil engraftment.  It appears that 
haplo-marrow transplant recipients may have had superior outcomes in the incidences of sustained 
donor chimerism, acute GVHD, and NRM.  The recipients of unrelated grafts fared somewhat 
better in terms of overall and disease-free survival at 1 year, but it is not possible in a retrospective 
comparison to know whether these differences are attributable to the relative efficacies of the 
treatment or to differences in the patient populations. 
 
 
BMT CTN 0603 
HLA-
haploidentical 
(n=50) 
BMT CTN 
0604 
dUCB  
(n=50) 
Solomon 
et al 
N=20 
Unrelated 
(n=89)* 
Median age (years) 
48 
58 
44 
53 
Time to ANC > 500/mL 
(days) 
16 
15 
16 
15 
Time to platelets > 
20K/mL (days) 
24 
38 
27 
4 
Sustained donor 
engraftment (total) 
98% 
88% 
 
79% 
Among recipient of PBSCs 
- 
- 
100% 
85% 
Among recipients of 
marrow 
98% 
- 
 
55% 
aGVHD II-IV 
32% 
40% 
30% 
52% 
aGVHD III-IV 
0% 
21% 
10% 
10% 
1 year non-relapse 
mortality (NRM) 
7 % 
24% 
20% 
17% 
1 year survival 
62 % 
54% 
69% 
52% 
1 year disease-free survival 
(DFS) 
48 % 
46% 
50% 
38% 
*Maris MB et al, Blood 102: 2021-2030, 2003 
Table 1.2 Comparison of Donor Sources.  Matched unrelated donor peripheral blood stem 
cell and bone marrow transplants as compared to dUCB and haplo-marrow transplant.  
All NMA conditioning. 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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Based upon the encouraging safety and efficacy data from CTN 0603 and Solomon et al we wish 
to offer haplo-marrow and peripheral blood stem cell transplants using the same conditioning 
regimens with post-transplant Cy to our patients who do not otherwise have a suitable donor.  In 
doing so, we would like to assess safety and anti-tumor efficacy of this treatment protocol when 
done at our center.  Although we participated in CTN 0603 we accrued only one patient prior to 
study completion.  In addition we have completed 3 other haploidental transplants at UCSD prior 
to the opening of this trial.  This includes one NMA bone marrow graft which failed to engraft 
and was subsequently salvaged by a NMA peripheral blood stem cell graft from the same donor.  
In addition we have recently completed one MA haplidentical transplant in a 60 year old man 
with very high risk leukemia.  Patient accrual in CTN 0603 occurred rapidly.  We believe that 
there could potentially be center based differences that could impact the outcome measures.  
Center based differences can result from both patient and system characteristics.  Local 
transplant centers may attract higher risk patients due to their inability to travel to larger centers.  
In addition there may be logistical factors which interfere with donor collections that might result 
in delays in treatment.  While direct comparisons between BMT 0603 and 0604 cannot be made, 
the haplo-marrow results look promising.  BMT CTN 1101, a phase 3 randomized multicenter 
trial comparing dUCB to HLA-haploidentical related bone marrow is in development.  Based on 
the results of this trial, HLA- haploidentical related bone marrow may become the preferred 
alternative donor source and may become a widely offered transplant option.  

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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2. 
STUDY DESIGN 
 
2.1. 
Study Overview 
 
This is a single center Phase 2 study to assess our institution’s outcomes in terms of safety and 
efficacy of haploidentical bone marrow transplantation (haplo-marrow) using a nonmyeloablative 
(NMA) or a myeloablative (MA)preparative regimen and post-transplant cyclophosphamide (Cy).  
The purpose is to determine if these transplants performed at UCSD would show similar outcomes 
to those published by the recent trials. If the results of this therapy are acceptable, we plan to offer 
this therapy as a routine option to patients who do not have a related sibling, matched unrelated 
donor, or cord option.  We plan on following clinical parameters that are routinely gathered for all 
our transplant patients here as part of the CIBMTR/NMDP/NMDP data registry, which all patients 
undergoing transplantation here provide consent for separately and routinely.  The only additional 
information that is not specifically gathered for CIBMTR/NMDP is time from unrelated donor 
search to Day 0. 
 
2.2      Hypotheses and Specific Objectives 
 
Hypotheses 
 
Primary Hypothesis: This is a Phase 2 study assessing 180 day survival after MA and NMA 
haplo- marrow or peripheral blood stem cell transplantation.  We hypothesize that we will have a 
180 day survival of about 60% which is the benchmark for reduced intensity transplant 
outcome.13  
Based on the data published by Solomon et al (16) we would expect the MA haploidentical 
peripheral blood stem cell grafts would fall within this benchmark as well. 
 
Study objectives 
 
The primary objective is to determine overall survival 180 days after transplantation involving 
MA or NMA conditioning, HLA-haploidentical marrow or peripheral blood graft, and post-
transplant Cy.  Secondary objectives include estimating overall and progression-free survival at 
100 days, 180 days, and one year after transplantation, treatment-related mortality, incidence of 
neutrophil and platelet recovery or engraftment, incidence of graft failure, cumulative incidence 
of acute and chronic GVHD, incidence of infections, and cumulative incidence of 
relapse/progression.  We will also examine the amount of time to transplant (day of unrelated 
search initiation to day 0). 
 
2.3        Patient Inclusion Criteria 
 
Patients fulfilling the following criteria will be eligible to enroll on this study: 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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1.  Age: Subjects 18-75 years old. 
2. Donor must be  18 years of age. 
3.  HLA typing will be performed at high resolution (allele level) for the HLA-A, -B, Cw, 
DRB1, and –DQB1 loci. A minimum match of 5/10 is required.   
With high resolution typing, the donor and recipient must be identical at a minimum of at 
least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-
DRB1, and HLA-DQB1.  Meeting this criterion will be considered sufficient evidence 
that the donor and recipient share one HLA haplotype, and typing of additional family 
members is not required. 
4. Acute Leukemias. 
 Acute Lymphoblastic Leukemia in high risk CR1 as defined by at least one of the 
following: 
 Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), MLL rearrangements, 
 White blood cell counts of greater than 30,000 wbc/µL, 
 Patients over 30 years of age, or 
 Time to Complete Remission was greater than 4 weeks. 
 Acute Myelogeneous Leukemia in high risk CR1 as defined by at least one of the 
following: 
 Greater than 1 cycle of induction therapy required to achieve remission, 
 Preceding myelodysplastic syndrome (MDS), 
 Secondary leukemia (history of chemotherapy or radiation treatment as 
precursor to development of leukemia), 
 Presence of Flt3 internal tandem duplication (ITD), 
 FAB M6 or M7 leukemia, or 
 Adverse cytogenetics for overall survival such as 
 those associated with MDS 
 Complex karyotype ( 3 abnormalities) 
 Any of the following: inv(3) or t(3;3), t(6;9), t(6;11), + 8 [alone or with 
other abnormalities except for t(8;21), t(9;11), inv(16) or t(16;16)], 
t(11;19)(q23;p13.1) 
 
Acute Leukemias in 2nd or subsequent CR (see remission definition in Chapter 3). 
 
Biphenotypic/Undifferentiated Leukemias in 1st or subsequent CR. 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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5.  Myelosdysplastic Syndrome 
6.  Burkitt’s lymphoma: second or subsequent CR. 
7.  Blastic plasmacytoid dendritic cell neoplasm 
8.   Lymphoma that is: chemotherapy-sensitive (complete or partial response; see response 
criteria in Chapter 3) aggressive lymphoma or Hodgkin’s lymphomas that have failed at least 1 
prior regimen of multi-agent chemotherapy and are ineligible for an autologous transplant. They 
may have received prior autologous transplant if greater than three months prior to enrollment. 
or 
Marginal zone B-cell lymphoma or follicular lymphoma that has progressed after at least two 
prior therapies (excluding single agent Rituxan). 
9.   Multiple myeloma 
10. Patients with adequate organ function as measured by: 
 Cardiac: Left ventricular ejection fraction at rest must be  40%,  
 Hepatic: Bilirubin, ALT, AST ≤ twice the upper limits of normal and Alkaline 
Phosphatase < 5 x ULN. 
 Renal: 24 hour creatinine clearance ≥40 mL/min 
 Pulmonary: FEV1 ,of ≥ 50% of predicted and , DLCO (diffusion capacity)≥ 
40% of predicted.  If unable to perform pulmonary function tests, then O2 
saturation > 92% on room air. 
11. Performance status: Karnofsky score 70-100%. 
 
2.4 Patient Exclusion Criteria 
 
Patients fulfilling the following criteria are ineligible for this study: 
1. Autologous hematopoietic stem cell transplant < 3 months prior to enrollment. 
2. Pregnancy or breast-feeding. 
3. Evidence of HIV infection or known HIV positive serology. 
4. Current uncontrolled bacterial, viral or fungal infection (currently taking medication with 
evidence of progression of clinical symptoms or radiologic findings). 
5. Prior allogeneic hematopoietic stem cell transplant. 
6. Patients with a history of primary idiopathic myelofibrosis. 
 
 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
______________________________________________________________________________ 
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2.5 Donor Inclusion Criteria 
1. Donors must be HLA-haploidentical first-degree relatives of the patient.  Eligible donors 
include biological parents, siblings, children, or half-siblings. 
2. Age  18 years. 
3. Donors must meet the selection criteria as defined by the Foundation for the 
Accreditation of Cell Therapy (FACT) and will be screened per the American 
Association of Blood Banks (AABB) guidelines. 
4. Donors must be willing and able to donate bone marrow product or peripheral blood stem 
cells. 
 
2.6  Donor Exclusion Criteria 
1. A donor is excluded if the recipient has anti-donor HLA antibody. This is because of a 
concern for engraftment failure. 
 
2.7 Donor Prioritization Schema 
Also see Appendix C, Guidelines for Donor Typing and Selection. 
 
In the event that two or more eligible donors are identified, the following order of priority: 
1. For CMV seronegative recipients, a CMV seronegative donor 
2. Red blood cell compatibility 
a. RBC cross-match compatible 
b. Minor ABO incompatibility 
c. Major ABO incompatibility 
 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
______________________________________________________________________________ 
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2.8 Treatment Plan 
 
Non-Myeloablative Treatment Plan: 
 
Day –6, -5 
Fludarabine 30 mg/M2 IV over 30-60 minutes 
Cyclophosphamide 14.5 mg/kg IV over 1-2 hours* 
Day –4-2 
Fludarabine 30 mg/M2 IV over 30-60 minutes 
Day –1 
TBI 200 cGy 
Day   0 
T cell replete BMT or T cell replete peripheral 
blood stem cell infusion 
Days +3,+4 
Cyclophosphamide 50 mg/kg IV 
Mesna 40 mg/kg IV 
Day   +5 
Begin tacrolimus, mycophenolate mofetil, and G-
CSF 
*Uroprophylaxis per institutional standard-see Section 2.5.3 
 
 
Myeloablative Treatment Plan: 
 
Day -7 
Busulfan 110 mg/m2/d 
Day –6, -5, -4 
Fludarabine 25 mg/M2 IV over 
30-60 minutes 
Busulfan 110 mg/m2/d 
Day -3 and -2 
Fludarabine 25 mg/M2 IV over 
30-60 minutes 
Cyclophosphamide 14.5 mg/kg 
IV over 1-2 hours* 
 
Day   0 
T cell replete PBSC 
Days 3,4 
Cyclophopshamide 50 mg/kg IV 
Mesna 40 mg/kg IV 
Day   5 
Begin tacrolimus, mycophenolate 
mofetil, and G-CSF 
 
 
*Uroprophylaxis per institutional preference (see 2.5.3 below) 
 
2.8.1 Indwelling Central Venous Catheter 
 
Placement of a double lumen central venous catheter will be required for administration of IV 
medications and transfusion of blood products. 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
______________________________________________________________________________ 
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2.8.2 Fludarabine 
 
A. NMA Fludarabine 30 mg/m2/day will be administered over 30-60 minutes intravenous 
infusion on Days –6 through –2. 
 
For decreased creatinine clearance (< 61 mL/min) determined by the Cockcroft Formula: 
 
CCr = (140 – age) x ideal body weight (IBW) (kg)   x   0.85 (for women) 
PCr x 72 
 
Fludarabine dosage should be reduced as follows: 
 
CCr  46-60 mL/min, fludarabine = 24 mg/m2 
CCr 40-45 mL/min, fludarabine = 22.5 mg/m2 
 
 
B.MA Fludarabine 25 mg/m2/day will be administered over 30-60 minutes intravenous 
infusion on Days –6 through –2.   
 
For decreased creatinine clearance (< 61 mL/min) determined by the Cockcroft Formula: 
 
 
 
CCr = (140 – age) x ideal body weight (IBW) (kg)   x   0.85 (for women) 
 
 
                       PCr x 72 
 
Fludarabine dosage should be reduced as follows: 
 
 
 
CCr  46-60 mL/min, fludarabine = 20 mg/m2 
 
 
CCr 40-45 mL/min, fludarabine = 18.75 mg/m2 
 
2.8.3 Pre-transplantation Cyclophosphamide 
 
A. NMA:  Cy 14.5 mg/kg/day will be administered as a 1-2 hour intravenous infusion with a 
high volume fluid flush on Days –6 and –5.  Cy will be dosed according to the recipient’s 
ideal body weight (IBW), unless the patient weighs more than 125% of IBW, in which 
case the drug will be dosed according to the adjusted IBW (AIBW; see below for 
formulas).   
 
Mesna will be given as uroprophylaxis according to our institutional practice: 
 
 
Mesna 11.6 mg/kg/day (80% of Cy dose) given as a continuous infusion beginning 30 
minutes prior to Cy administration.  Total volume of 500 mL volume to be run at 22 mL/hour x 
24 hours daily with each dose of Cy. 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
______________________________________________________________________________ 
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B. MA:  Cy 14.5 mg/kg/day will be administered as a 1-2 hour intravenous infusion with a 
high volume fluid flush on Days –3 and –2.  Cy will be dosed according to the recipient’s 
ideal body weight (IBW), unless the patient weighs more than 125% of IBW, in which case 
the drug will be dosed according to the adjusted IBW (AIBW; see below for formulas).  
Mesna will be given in the following manner:______________   
Mesna will be given as uroprophylaxis according to our institutional practice: 
 
 
Mesna 11.6 mg/kg/day (80% of Cy dose) given as a continuous infusion beginning 30 
minutes prior to Cy administration.  Total volume of 500 mL volume to be run at 22 mL/hour x 
24 hours daily with each dose of Cy. 
 
2.8.4 Busulfan 
 
MA:  Busulfan  
Give on days -7,-6,-5,-4 
 
-Avoid acetaminophen 72 hours prior to and 72 hours after the administration of 
Busulfan.  
Use Ideal or Actual body weight,  whichever is lower. For obese or severely obese 
patients (25% above Ideal body weight), an Adjusted "Ideal" Body  
Dose is 110 mg/m2 administered in saline with final concentration approximately 0.5 
mg/ml.  Infuse over 2 hours 
 
 
Ideal Body Weight (IBW) Formulas: 
 
Males IBW = 50 kg + 2.3 kg/inch over 5 feet 
 
Females IBW = 45.5 kg + 2.3 kg/inch over 5 feet 
 
 
Adjusted Ideal Body Weight Formula: 
 
AIBW = IBW + [(0.25) x (ABW - IBW)] 
 
 
 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
______________________________________________________________________________ 
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2.8.5 Total Body Irradiation 
 
NMA: Total body irradiation in the NMA conditioning : 200 cGy will be administered in a single 
fraction on Day –1. 
 
Patients undergoing MA conditioning will not receive TBI 
 
2.8.6 Bone marrow and peripheral blood stem cell transplantation 
 
On Day 0, patients will receive unprocessed marrow or peripheral blood stem cells unless there 
is a major ABO incompatibility, in which case red blood cell depletion will be performed.   
Minor ABO incompatibilities will be processed per our institutional standards in conjunction 
with the blood bank consultation. Donor bone marrow will be harvested with a target yield of 4 x 
108 total nucleated cells (TNC)/kg recipient IBW.  A sample of the product to be infused will be 
sent for flow cytometry to determine the content of CD34+ CD3+, CD4+, and CD8+ cells. This is 
done routinely. Donor peripheral blood stem cells shall be collected and the total infused CD34 
count will be capped at 5x10^6 CD34/kg. 
 
Marrow collection will be performed per UCSD policy/standard of operation (SOP) [BMTP-
22.5]. At UCSD and other transplant programs, the standard marrow cell dose target is 4 x 108 
TNC/kg of recipient body weight. This target is standard for all our bone marrow transplants.  
There has not been an established absolute minimum number of cells needed for engraftment of 
marrow.  As per UCSD standard practice, the bone marrow donor is usually harvested the day of 
planned infusion.  However, there may be rare instances due to donor factors (such as 
availability) that the treating physician may elect to harvest the donor on a different day. In this 
case the marrow may be cryopreserved and handled according to UCSD stem cell processing 
laboratory (SCPL) SOPs. 
 
For the bone marrow grafts there is not a maximum amount of TNC/kg to be infused. Per UCSD 
standards, there is a maximum amount of marrow product that can be collected from the donor 
for safety reasons (maximum 20 mL/kg donor weight). The stem cell processing laboratory 
(SCPL) will calculate a mid-run TNC (done approximately once half of the maximum marrow 
volume has been collected).  The mid-run will then be used to calculate how much more volume 
needs to be collected to meet the target (again not exceeding a maximum volume of 20mL/kg 
donor weight).  
 
UCSD marrow processing and storage will be performed per UCSD policy/SOP set forth by the 
SCLP (SCPL-0515, SCPL-0523, SCPL-0528, SCPL-0529). Marrow product is intended to be 
infused “fresh,” i.e. non-cyropreserved. It may be red cell depleted or plasma depleted depending 
upon ABO compatibility and with blood bank consultation. As mentioned, in rare cases, it may 
be cryopreserved if the harvest is done prior to day of planned infusion. 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
______________________________________________________________________________ 
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Proprietary and Confidential 
Peripheral blood stem cell collection will be performed per UCSD policy/standard operation . 
The peripheral blood stem cell target is 5 million per kg recipient weight  
 
2.8.7 Post-transplantation Cyclophosphamide with Mesna 
 
Hydration prior to Cy will be given in the following manner: A minimum of one liter normal 
saline will be given to patients the night prior to cyclophosphamide administration. The rate is at 
the inpatient team’s discretion.  Two hours prior to the start of cyclophosphamide, hydration with 
normal saline at 3 ml/kg/hr IV will begin. One hour prior to cyclophosphamide, the rate will be 
reduced to 2 ml/kg/hr and continued for 8 hours post-cyclophosphamide. Maximum rate will not 
exceed 200 mL/hr. 
 
Mesna uroprophylaxis will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours 
post-cyclophosphamide.  Mesna dose will be based on the Cy dose being given.  The total daily 
dose of mesna is equal to 80% of the total daily dose of Cy. 
 
Cy [50mg/kg IBW] will be given on Day 3 post-transplant (between 60 and 72 hours after 
marrow infusion) and on Day 4 post-transplant (approximately 24 hours after Day 3 
cyclophosphamide).  Cy will be given as an IV infusion over 1-2 hours (depending on volume). 
 
It is crucial that no immunosuppressive agents are given until 24 hours after the completion of 
the post-transplant Cy.  This includes corticosteroids as anti-emetics. 
 
2.8.8 Tacrolimus 
 
Tacrolimus will be given at a dose of 1 mg IV continuous infusion daily.  Tacrolimus begins on 
Day + 5. Dosing will be changed to oral dosing schedule once a therapeutic level is achieved and 
oral medications are well tolerated.  Serum levels of tacrolimus will be measured around Day 7 
and then checked weekly.  The dose will be adjusted to maintain a level of 5-10 ng/mL.  
Tacrolimus will be discontinued around Day 180 but may be continued if active GVHD is 
present.  Cyclosporine (target concentration 200-400 ng/ml) may be substituted for tacrolimus if 
the patient is intolerant of tacrolimus. 
 
2.8.9 Mycophenolate Mofetil (MMF) 
 
MMF will be given at a dose of 15 mg/kg PO TID (based upon actual body weight) with the 
maximum total daily dose not to exceed 3 grams (1 gram PO TID).  MMF prophylaxis begins  
Day+ 5 and will be discontinued after the last dose on Day +35 but may be continued if active 
GVHD is present. 
 
 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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2.8.10 Supportive Care 
 
Patients will receive transfusions, infection prophylaxis and nutritional support according to our 
institutional standards.  Infection prophylaxis includes, but is not limited to, agents or strategies 
(e.g., PCR screening and preemptive therapy) to prevent herpes simplex, cytomegalovirus 
(CMV), Pneumocystis carinii, and fungal infections. 
 
2.8.11 Transfusion Support 
 
Platelet and packed red cell transfusions will be given per current institutional standards. 
 
2.8.12 Anti-Ovulatory Treatment 
 
Menstruating females should be started on an anti-ovulatory agent prior to the initiation of the 
preparative regimen. 
 
2.8.13 Post-transplant Evaluation 
 
Patients will be followed by their transplant physician as per our institutional standards. 
Immediately post-transplant, they are followed out through a minimum of day 100 (if patient 
referred from outside institution) or longer if transplant related issues arise.  Additional follow-
up at 6 months and 1 year after transplantation is performed here if patient is from an outside 
institution. 
 
2.9 Risks and Toxicities 
 
Cyclophosphamide: 
 Cyclophosphamide side effects include: nausea/vomiting, cardiomyopathy, skin 
rash, mucositis, stomatitis, sterility, diarrhea, hemorrhagic cystitis, fluid weight 
gain/edema, alopecia and cytopenias. 
 
Fludarabine: 
 Neurotoxicity: Agitation or confusion, blurred vision, loss of hearing, peripheral 
neuropathy or weakness has been reported.  Severe neurologic effects, including 
blindness, coma, and death are seen in 36% of patients treated with doses 
approximately four times greater than recommended; severe CNS toxicity is rarely 
seen with doses in the recommended range for nontransplant therapy of hematologic 
malignancies.  Effect of chronic use on the CNS is unknown, although patients have 
received recommended doses for up to 15 courses.  The dose used in this study is 
approximately 1.5 times the usual one-course dose given in non-transplant settings.  
Doses and schedules such as those used in this study have been used in adult and 
pediatric patients and increased neurotoxicity has not been observed. 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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 Anemia: Life-threatening and sometimes fatal autoimmune hemolytic anemia has 
been reported after one or more cycles of therapy in patients with or without a 
previous history of autoimmune hemolytic anemia or a positive Coombs’ test and 
who may or may not be in remission; no mechanisms for development of this 
complication have been identified.  Corticosteroids may or may not be effective in 
controlling these episodes.  The majority of patients re-challenged developed a 
recurrence of the hemolytic process. 
 
 Cardiovascular: Deep venous thrombosis, phlebitis, transient ischemic attack, and 
aneurysm (1%) are reported. 
 
 Fever: 60% of patients develop fever. 
 
 Skin Rash: 15% of patients develop a skin rash, which may be pruritic. 
 
 Digestive: Gastrointestinal side effects include: nausea/vomiting (36%), diarrhea 
(15%), stomatitis (9%), anorexia (7%), GI bleeding and esophagitis (3%), mucositis 
(2%), liver failure, abnormal liver function test, constipation, dysphagia (1%) and 
mouth sores. 
 
 Some other effects are: Chills (11%), peripheral edema (8%), myalgia (4%), 
osteoporosis (2%), pancytopenia, arthralgia (1%), dysuria (4%), urinary tract 
infection and hematuria (2%); renal failure, abnormal renal function test, and 
proteinuria (1%); and, very rarely, hemorrhagic cystitis and pulmonary toxicity. 
 
 Late effects may include secondary malignancy. 
 
Total Body Irradiation: 
 TBI can cause: nausea and vomiting, diarrhea, parotitis (rapid onset within 24-48 
hours, usually self-limited), generalized mild erythema, hyperpigmentation, fever, 
mucositis, and alopecia. 
 
 Late effects include: possible growth retardation, vertebral deformities, cataracts, 
probable increased risk of secondary malignant neoplasms, sterility, nephropathy, 
interstitial pneumonitis and veno-occlusive disease. 
Busulfan:   
 Hematologic: Pancytopenia 
 Hepatic and Gastrointestinal: moderately emetogenic and require antiemetic therapy; 
mild to moderate nausea and vomiting occurred in 92% and 95% of patients, 
respectively, during high-dose clinical trials; nausea was severe in 7% of patients. Severe 
stomatitis (26%), esophagitis (2%), diarrhea (75%, severe 5%), constipation (38%), 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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dyspepsia (44%), hematemesis (2%), pancreatitis (2%), rectal discomfort (24%), and 
anorexia (mild/moderate 64%, severe 21%) Hepatic veno-occlusive disease (VOD) has 
been reported in patients receiving busulfan, usually in combination with 
cyclophosphamide or other agents prior to bone marrow transplantation. Busulfan-
induced hepatic VOD has been associated with high AUC values (> 1500 micro-
mol•min/L) of busulfan.  VOD 8-12% incidence with iv Busulfan .   A reduced incidence 
of hepatic VOD and other regimen-related toxicities have been observed in patients 
treated with high-dose oral busulfan and cyclophosphamide when the first dose of 
cyclophosphamide has been delayed for > 24 hours after the last dose of busulfan. 
 Hyperbilirubinemia occurred in 49% with grade 3/4 hyperbilirubinemia occurred 
in 30% of patients within 28 days of transplantation and was considered life-threatening 
in 5% of these patients. Hyperbilirubinemia was associated with graft-versus-host disease 
in 6 patients and the hepatic veno-occlusive disease in 5 patients. Elevated hepatic 
enzymes including grade 3/4 SGPT elevations (7%), mild to moderate alkaline 
phosphatase increases (15%), and mild to moderate jaundice (12%) were also reported in 
patients following high-dose therapy.  
 Pulmonary: Interstitial pulmonary fibrosis is rare but potentially fatal complication.  
Symptoms have been reported to occur within 8 months to 10 years after the initiation of 
therapy; the average onset is within 4 years of busulfan therapy. Most patients die within 
6 months of diagnosis.  Mild or moderate dyspnea in 25% (severe 2%) of patients and 
hyperventilation in 5% of patients. Alveolar hemorrhage (5%), rhinitis (44%), cough 
(28%), epistaxis (25%), pharyngitis (18%), hiccups (18%), asthma (8%), atelectasis (2%), 
pleural effusion (3%), hypoxia (2%), hemoptysis (3%), and sinusitis (3%). 
 Skin hyperpigmentation (5—10%), nail discoloration, urticaria, erythema multiforme, 
alopecia, porphyria cutanea tarda, excessive dry skin (xerosis) and skin fragility with 
anhidrosis, rash (unspecified) (57%), pruritus (28%), alopecia (17%), vesicular rash 
(10%), maculopapular rash (8%), vesicular-bullous rash (10%), exfoliative dermatitis 
(5%), erythema nodosum (2%), acne/acneiform rash (7%),  
 Cataracts, corneal thinning and lens changes 
 Cardiac: mild to moderate sinus tachycardia (44%), arrhythmias (unspecified) (5%), atrial 
fibrillation (2%), ventricular extrasystoles (2%), third degree heart block (2%), 
hypertension (36%, grade 3/4 7%), hypotension (11%, grade 3/4 3%), flushing/hot 
flashes (25%), cardiomegaly (5%), mild ECG abnormalities (2%), and grade 3/4 left-
sided heart failure in one patient (2%).  
 Gonadal suppression, atrophy of the testis, azoospermia, and gynecomastia has been 
reported in male patients receiving busulfan. Amenorrhea, anovulation, ovarian 
suppression, and ovarian failure including failure to reach puberty may occur in 
premenopausal women treated with busulfan. Fertility and normal menses may return; 
however, infertility may be permanent following busulfan therapy.   Teratogenesis and 
fetal death may occur, which may occur even after busulfan therapy is completed.  
Busulfan-induced fetal malformations and anomalies include significant alterations in the 
musculoskeletal system, body weight gain, and size. In animals, busulfan produced 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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sterility in both male and female offspring due to the absence of germinal cells in the 
testes and ovaries; germinal cell aplasia or sterility in offspring of mothers receiving 
busulfan during pregnancy has not been reported in humans. 
 Secondary malignancy, including acute myeloid leukemia and malignant tumors, within 
5—8 years of chronic oral busulfan therapy. Busulfan may cause cellular dysplasia in many 
organs including lymph nodes, pancreas, thyroid, adrenal glands, liver, lungs and bone 
marrow. This cytologic dysplasia may be severe enough to interfere with interpretation of 
exfoliative cytologic examinations of the lungs, bladder, breast, and uterine cervix. In 
addition, chromosomal aberrations have been reported in cells from patients receiving 
busulfan. 
 Generalized complaints: headache (64%, severe 5%), abdominal pain (69%, 
severe 3%), asthenia/weakness (49%, severe 2%), unspecified pain (43%, 
severe 2%), injection site reaction (inflammation 25%, pain 15%), allergic 
reactions including anaphylactoid reactions (26%), chest pain (unspecified) 
(26%), arthralgia (13%), and ear disorder (3%). 
 Seizures may occur during high-dose busulfan therapy. Prophylactic anticonvulsant 
therapy, usually with phenytoin, is recommended. Patients with a history of seizures, 
head trauma or who are taking medication which may decrease the seizure threshold may 
be at increased risk. Insomnia (84%), anxiety (75%), dizziness (30%), depression (23%), 
confusion (11%), hallucinations (5%), lethargy (7%), delirium (2%), agitation (2%), and 
encephalopathy (2%).  
 The solvent used in the busulfan intravenous formulation, dimethylacetamide (DMA), 
has been associated with neurologic effects, including hallucinations, and hepatic 
toxicity.  
 
Mycophenolate Mofetil: 
 Side effects include: pancytopenia, nausea, vomiting, diarrhea, hypertension, 
headache, dizziness, insomnia, hyperglycemia, electrolyte imbalances, rash, and 
leg cramps/bone pain. 
 
Tacrolimus: 
 Side effects include: reversible renal insufficiency, hypertension, hyperglycemia, 
hypomagnesemia, hypokalemia, and neurologic toxicity. 
 
 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
______________________________________________________________________________ 
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Graft Failure: 
 Based on historical data, there is a 5-15% chance of graft failure with the NMA 
regimens.  Recovery of autologous hematopoiesis occurred in 14 out of 16 
patients experiencing graft failure in the original Johns Hopkins/Seattle trial. In 
the more recent BMT CTN 0603 trial, primary graft failure occurred in 1/50 
patients. In that patient, no second transplant was done and the patient died at day 
+67. No cases of secondary graft failure were reported.  There were no cases of 
graft failure reported with the MA preparative regimen and peripheral blood stem 
cell transplant.  The risk of graft failure is known to be higher after bone marrow 
grafts as opposed to stem cells grafts.  In the experience so far at UCSD, of the 3 
patients transplanted one patient had primary engraftment failure following a 
NMA bone marrow graft.  This was felt to be related by the low total nucleated 
cells infused due to a collection that was limited by the donor size.  This patient 
was subsequently able to undergo salvage with the same donor using peripheral 
blood stem cells.   
 
2.10 
Growth Factor Support 
 
G-CSF will be given beginning on Day 5 at a dose of 5 mcg/kg/day (rounding to the nearest vial 
dose is allowed), until absolute neutrophil count (ANC) is ≥ 1,000/mm3 for three consecutive 
days.  G-CSF may be given by IV or subcutaneously. 
 
2.11 
Management of Slow Engraftment and Graft Failure 
 
Slow engraftment or graft failure shall be managed according per physician preference, and may 
include the administration of colony stimulating factors and prophylactic antibiotics. 
If the recipient is eligible for both an ablative and a nonmyeloablative transplant the treating 
physician will ultimately make a decision regarding using the ablative versus nonmyeloablative 
preparative regimens as described above.  This decision is generally based upon the underlying 
diagnosis , the age of the patient, and the comorbidities.  If the stem cell donor is able to donate 
either stem cells or bone marrow the decision to use peripheral blood stem cells versus bone 
marrow collection will be based upon the logistics of coordinating the bone marrow collection 
(avoiding extended delays in treatment) , the preference of the treating physician, and the donor 
preference.  At UCSD there are frequently logistical constraints that result in delay of adequate 
operating room time which can result in delay of transplant.   
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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3. STUDY ENDPOINTS 
 
3.1 
Primary Endpoint 
 
The primary endpoint is overall survival at 180 days from the time of transplantation. 
 
3.2 
Secondary Endpoints 
 
 Neutrophil Recovery 
 
Neutrophil recovery is defined as achieving an ANC ≥ 500/mm3 for three consecutive 
measurements on different days.  The first of the three days will be designated the day of 
neutrophil recovery.  The only competing event for neutrophil recovery is death without 
neutrophil recovery. 
 
 Primary graft failure 
 
Primary graft failure is defined as < 5% donor chimerism on all measurements. 
 
 Secondary graft failure 
 
Secondary graft failure is defined as initial recovery followed by neutropenia with < 5% donor 
chimerism. If no chimerism assays were performed and ANC is < 500/mm3, then it will be 
counted as a secondary graft failure. 
 
 Platelet recovery 
 
Platelet recovery is defined by two different metrics.  It will be counted as the first day of a 
sustained platelet count >20,000/mm3 or >50,000/mm3 with no platelet transfusions in the 
preceding seven days.  The first day of the sustained platelet count will be designated the day of 
platelet engraftment. 
 
 Donor Cell Engraftment 
 
Donor cell engraftment is defined as donor chimerism  5% on Day  56 after transplantation.  
Chimerism should be evaluated on Days ~28, ~56, ~180, and ~365 after transplantation.  
Chimerism may be evaluated in whole blood or mononuclear fraction. 
 
 Acute Graft-versus-Host Disease 
 
The cumulative incidences of grade II – IV and III – IV acute GVHD will be determined.  Acute 
GVHD will be graded as shown below.  This is already standard practice for patients at UCSD. 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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The time to onset of acute grades II-IV GVHD and grades III-IV GVHD will be recorded, as 
well as the maximum grade achieved. 
 
 
Stages of Acute GVHD: Individual Organ 
----------------------------------------------------------------------------------------------------- 
Stage Skin % BSA  
Liver (bilirubin) 
Gut (stool volume, mL) 
    
(rules of 9s) 
----------------------------------------------------------------------------------------------------- 
0 
0 
 
 
<2 
 
 
≤500 
1 
<25 
 
 
2-3 
 
 
>500*  
2 
25-50  
 
3.1-6  
 
>1000 
3 
>50 
 
 
6.1-15  
 
>1500 
4 
Bullae  
 
≥15 
 
 
>2000(**) 
----------------------------------------------------------------------------------------------------- 
*or persistent anorexia, nausea, vomiting 
**or severe abdominal pain with or without ileus 
Glucksberg et al. Transplantation 1974; 18:295. 
 
Consensus Grading (modified Glucksberg) 
Grade  
Skin Stage 
Liver Stage 
 
Gut Stage 
I 
 
1-2 
 
none 
 
 
none 
II 
 
3 
 
1 
 
 
1 
III 
 
-- 
 
2-3 
 
 
2-4 
IV 
 
4 
 
4 
 
 
4 
-------------------------------------------------------------------------------------------------------- 
 
 
 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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 Chronic Graft-versus-Host Disease 
 
Chronic GVHD will be scored in the historical manner.  This is already standard for all UCSD 
transplant patients.  The time to onset of limited and extensive chronic GVHD will be recorded.  
Given the short duration of this study, cGVHD data is being documented for purposes of our 
participation in CIBMTR/NMDP. 
 
Chronic GVHD Grading 
-------------------------------------------------------------------------------------------------------------------- 
Limited: localized skin involvement and/or evidence of hepatic dysfunction 
 
Extensive:  
-generalized skin involvement or  
-localized skin involvement or hepatic dysfunction plus at least one of the following: 
 liver histology showing chronic progressive hepatitis, bridging necrosis, cirrhosis 
 eye involvement (Schirmer’s test with <5 mm wetting) 
 minor salivary gland or oral mucosa involvement (on labial or mucosal biopsy specimen) 
 involvement of any other target system 
--------------------------------------------------------------------------------------------------------------------- 
 
 Progression-free Survival 
 
Progression-free survival is defined as the minimum time interval of the time to relapse, 
recurrence, death, or last follow-up. 
 
 Treatment-Related Mortality (TRM) 
 
The cumulative incidence of TRM will be estimated at Day 100, 180, and at 1 year.  An event for 
this endpoint is death without evidence of disease progression.  Documented disease progression 
is a competing risk. 
 
 Infections 
 
Infections will be reported by anatomic site, date of onset, organism and resolution, if any.  
Patients will be followed for infection for 1 year post-transplant. 
 
 Time from initiation of unrelated donor search to Day 0. 
 
 Relapse and Residual Disease 
 
Relapse of Malignancy – Testing for recurrent malignancy in the blood, marrow or other sites 
will be used to assess relapse after transplantation.  For the purpose of this study, relapse is 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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defined by either morphological or cytogenetic evidence of acute leukemia consistent with pre-
transplant features, or radiologic evidence (including the recurrence of fluoro-deoxyglucose 
[FDG]-avid lesions on PET scan) of progressive lymphoma.  When in doubt, the diagnosis of 
recurrent or progressive lymphoma should be documented by tissue biopsy. 
 
Minimal Residual Disease – Minimal residual disease is defined by the sole evidence of 
malignant cells by flow cytometry, or fluorescent in situ hybridization (FISH), or Southern blot, 
or Western blot, or polymerase chain reaction (PCR), or other techniques, in absence of 
morphological or cytogenetic evidence of disease in blood or marrow.  Since the frequency of 
testing for minimal residual disease is highly variable among centers, and the sensitivity is highly 
variable among laboratory techniques, evidence of minimal residual disease will not be sufficient 
to meet the definition of relapse in the context of this study.  Data on tapering 
immunosuppression, administering chemotherapy or biological agents to in response to detection 
of minimal residual disease will be captured in the case report forms. 
 
Acute Leukemia – Relapse will be diagnosed when there is: 
1. The reappearance of leukemia blast cells in the peripheral blood; or, 
2. > 5% blasts in the marrow, not attributable to another cause (e.g., bone marrow 
regeneration); or 
3. The appearance of new dysplastic changes within the bone marrow; or, 
4. The development of extramedullary leukemia or leukemic cells in the cerebral spinal 
fluid. 
 
Lymphoma – Relapse will be diagnosed when there is: 
1. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size.  Increased FDG uptake in a 
previously unaffected site should only be considered relapsed or progressive disease after 
confirmation with other modalities.  In patients with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are mostly benign. Thus, a therapeutic 
decision should not be made solely on the basis of the PET without histologic 
confirmation. 
2. At least a 50% increase from nadir in the sum of the product diameters (SPD) of any 
previously involved nodes, or in a single involved node, or the size of other lesions (e.g., 
splenic or hepatic nodules).  To be considered progressive disease, a lymph node with a 
diameter of the short axis of less than 1.0 cm must increase by  50% and to a size of 1.5 
x 1.5 cm or more than 1.5 cm in the long axis. 
3. At least a 50% increase in the longest diameter of any single previously identified node 
more than 1 cm in its short axis. 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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4. Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be detected with 
current PET systems (<.1.5 cm in its long axis by CT). 
 
TABLE 3.2 RESPONSE CRITERIA FOR LYMPHOMA 
From Cheson, B.D. et al.  Revised response criteria for malignant lymphoma.  J Clin 
Oncol 5:579-586, 2007. 
 
 
Acute Leukemia - Remission is defined as < 5% blasts with no morphological characteristics of 
acute leukemia (e.g., Auer Rods) in a bone marrow with > 20% cellularity, peripheral blood 
counts showing ANC >1000/l, including patients in CRp.  
 
 
4. PATIENT ENROLLMENT AND EVALUATION 
 
Enrollment Procedures 
 
Screening and Eligibility Procedures 
 
Patients who have an indication for an allogeneic transplant but no suitable unrelated donor, 
matched related donor or cord blood option will be screened for this study. Review for eligibility 
will be done by treating physician (all transplant physicians at UCSD will be sub-investigators). 
If treating physician unavailable, then review will be performed by the PI.  
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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Patients will be registered using the standard procedures currently used for all patients 
transplanted at UCSD.  This includes pre-registration with CIBMTR/NMDP/NMDP, 
documentation of disease status and classification, comorbidities, prior treatment, and donor 
characteristics. 
 
Study Monitoring 
 
Follow-up Schedule: 
Currently at UCSD Medical Center patients are hospitalized from the beginning of the 
preparative regimen through neutrophil engraftment.  After discharge patients will be seen 
weekly by a medical provider until day 60 post transplant then as dictated by physician 
preference and institutional practices.  Data will be collected from clinical assessments around 
day 30, day 100, day 180, and 1 year post transplant.  This is standard institutional practice. 
 
Reporting Patient Deaths:  
Patient deaths will be reported to CIBMTR/NMDP per our standard reporting procedures for 
allogeneic and autologous transplant. This is not for the purpose of the study.  Otherwise, deaths 
are already automatically reported to our group. 
 
 
CIBMTR/NMDP Data Reporting:  
As a Center for International Blood and Marrow Transplant Research/National Marrow Donor 
Program (CIBMTR/NMDP) participating transplant center, we are required to pre-register all 
transplant recipients with the CIBMTR/NMDP.   This is done with patient consent through a 
different consent form. In addition, we will complete the CIBMTR/NMDP Day 100 Report Form 
(including the Core Form and Graft Inserts) and Core Follow-up Forms at 6 months then at one 
year   CIBMTR/NMDP forms will be submitted directly to the CIBMTR/NMDP at the times 
specified on the Form Submission Schedule; The endpoints of this study are already being 
collected for CIBMTR/NMDP and automatically entered into our own CIBMTR/NMDP 
database registry. We will be creating a separate file within the standing secured database to 
group these patients together. The only additional piece of data is time to transplant. This will be 
added to the UCSD portion of the registry for these patients. 
 
Weekly GVHD Monitoring:   
GVHD will be monitored in accordance with CIBMTR/NMDP guidelines. .  Patients should be 
assessed weekly until Day 100 post-transplant for GVHD.  After Day 100 patients will be 
assessed at each follow-up visit (Day 180, 365) for the presence of GVHD. 
 
Adverse Event Reporting 
 
Toxicity and adverse events will be classified according to NCI's Common Terminology Criteria 
for Adverse Events V 4.0 (CTCAE). A copy of the CTCAE can be downloaded from the CTEP 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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home page (http://ctep.cancer.gov). The occurrence of an adverse event will be based on changes 
in the patient’s physical examination, laboratory results, and/or signs and symptoms.  
  
Definitions  
An adverse event (AE) is any symptom, sign, illness or experience, regardless of causality, that 
develops or worsens in severity during the course of the study.  
 
Attribution:  
 Not related - The adverse event is most likely related to other factors such as the patient's 
clinical state, environmental factors, or other modes of therapy or concomitant drugs 
administered to the patient.  
 
 Related – There is a reasonable possibility that the study drug caused or exacerbated the 
adverse event, ie, there is evidence to suggest a causal relationship between the study 
treatment and the adverse event.  
 
An unexpected adverse event is defined as any adverse experience that is neither identified in 
nature, severity, or frequency of risk in the information provided for IRB review (typically the 
protocol, investigator’s brochure and prescribing information) nor mentioned in the consent form.  
 
Adverse Event Documentation  
Adverse events as specified above occurring after the initiation of the study treatment (day -5) 
through day 30 must be documented and reported on patient CRFs.  Given the high volume of 
transplant-related adverse events and laboratory abnormalities expected in this population, 
hematologic and other non-clinically significant laboratory abnormalities and expected grade 1-3 
adverse events assessed by the investigator as related to the transplant procedure will not be 
captured.  Organ toxicity reporting required by the NMDP/CIBMTR will be reported on the 
NMDP/CIBMTR report forms.  
 
It is expected that all patients who undergo the transplant procedure experience depression of their 
blood counts. Therefore, hematological lab results of this nature will not be reported as adverse 
events. Further to this, abnormal laboratory results deemed not to be clinically significant but for 
which the patient is receiving treatment will not be reported as adverse events, per investigator 
judgment.  
 
Thus, given the high number of transplant-related adverse events in the patient population being 
studied, adverse events will be reported on patient CRFs using the following guidelines:  
 
 
All grades 4-5 AEs through day 30, excluding hematologic lab abnormalities and other laboratory 
results deemed by the investigator not to be clinically significant, will be reported on the case 
report forms.  
All documented infections through day 100 will be reported  
All GVHD through day 100 will be reported  

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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All UPRs through day 100 will be reported  
 
UPR Reporting and Follow-up  
Federal regulations [45CFR46.103(b)(5) and 21CFR56.108(b)(1)] require the IRB to ensure that 
researchers promptly report “any unanticipated problems involving risk to subjects or others” 
(UPIRTSOs).   http://irb.ucsd.edu/Factsheet_UPR_120208.pdf 
 
As soon as an investigator or study personnel becomes aware of an adverse event which meets the 
definition of a UPR this should be reported by phone, fax or email to the extent that information 
is available to the BMT Clinical Trials Office at 858-822-6387/6397/6396/6382.  And reported 
per UCSD IRB SOPs. 
 
PI Responsibilities  
The PI is required to review all unanticipated problems, serious adverse events, and all deaths 
associated with the protocol and provide an unbiased written report of the event.  
At the minimum the PI should comment on the outcomes of the event or problem and in the case 
of a serious adverse event or death, comment on the relationship  
to participation in the study. UPRs should be promptly reported to the UCSD IRB. 
 
Patient Assessments 
 
Table 4.2.3 summarizes patient clinical assessments over the course of the study. 
 
Pre-transplant evaluations 
 
The following observations are considered standard evaluations for transplant eligibility and 
should be determined < 4 weeks before initiation of conditioning therapy, unless otherwise 
noted. This evaluation is standard practice for potential transplant patients. 
1. History, physical examination, height and weight. 
2. Karnofsky performance status. 
3. CBC with differential and platelet count, serum creatinine, bilirubin, alkaline 
phosphatase, ALT, and AST. Urine for 24 hour creatinine clearance. Serum beta HCG 
test for females of child bearing potential. 
4. CMV antibody test, hepatitis panel (HepA Ab, HepB sAb, HepB SAg, HepB Core Ab, 
HepC Ab), syphilis, herpes simplex virus, varicella zoster virus, HIV and HTLV1 I/II 
antibody. 
5. HLA typing, if not already performed. 
6. EKG, < 6 weeks before initiation of conditioning therapy. 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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7. Transthoracic echocardiogram to evaluate left ventricular ejection fraction or shortening 
fraction, < 6 weeks before initiation of conditioning therapy. 
8. Pulmonary function testing to evaluate DLCO, FEV1, and FVC or O2 saturation. < 6 
weeks before initiation of conditioning therapy. 
9. Bone marrow aspirates for pathology and cytogenetics and/or biopsy. 
10. β-HCG serum pregnancy test for females of childbearing potential. 
11. Chest imaging (Chest X-Ray or Chest CT) as clinically indicated. 
12. Lymphomas (large/aggressive cell, B- cell, and Hodgkin): Whole Body PET/CT as 
clinically indicated. 
 
Post-transplant evaluations 
 
The following evaluations are considered standard evaluations for transplant recipients: 
1. History and physical exam to assess GVHD and other morbidity weekly until Day 100 
post-transplant, then at six months, one year.  GVHD evaluation and grading to be in 
keeping with CIBMTR/NMDP reporting.   
2. CBC at least three times a week from Day 0 until ANC > 500 mm3 for 3 days after nadir 
reached.  Thereafter CBC at a minimum of twice per week until Day 28, then weekly 
until 12 weeks, then at six months, one year post-transplant. 
3. Creatinine, bilirubin, alkaline phosphatase, ALT, AST, at least twice a week until Day 28 
(or four weeks) and then weekly until 12 weeks, and then at six months, one year years 
post-transplant. 
4. Heparinized blood on Day ~28, ~56, ~180, and ~365 for post-transplant chimerism assay. 
5. Immunizations will be given per institutional guidelines.  
6. Toxicity assessments at Days ~ 28, ~56, ~180 s, and ~365. 
7. Disease status evaluation required within 100 days of transplant (may be done from day 
80-120) and at ~1 year.  Testing to determine disease status should follow pre-transplant 
evaluation process.  
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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TABLE 4.2.3:  SUMMARY OF PATIENT CLINICAL ASSESSMENTS 
 
Study Assessments/ 
Testing 
Baseline 
 
Days after Transplantation 
7
14
21
28
35
42
49 
56 
100 
180
365
History, physical exam, weight, height, 
and Karnofsky/Lansky performance 
status 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
CBC1, differential, platelet count, and 
blood chemistries2 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Infectious disease titers3 
X 
 
 
 
 
 
 
 
 
 
 
 
EKG, LVEF, or shortening fraction 
X 
 
 
 
 
 
 
 
 
 
 
 
DLCO, FEV1 and FEV or O2 saturation 
X 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow aspirate for pathology and 
cytogenetics and/or biopsy4 
X4 
 
 
 
 
 
 
 
 
X4 
X4 
X4 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
 
 
 
ß-HCG serum pregnancy test (females 
only) 
X 
 
 
 
 
 
 
 
 
 
 
 
GVHD and other morbidity assessments5 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Toxicity assessments 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
Chimerism6 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
Notes: 
1  CBC performed at least twice a week from Day 0 until ANC >500 mcL for two days after nadir.  CBC 
performed twice weekly until Day 28. CBC performed weekly after Day 28 until 12 weeks post-transplant. 
2  Blood chemistries include: serum creatinine, bilirubin, alkaline phosphatase, AST, and ALT, LDH, sodium, 
magnesium, potassium, chloride, and thyroid function tests (where standard of care should be according to 
institutional guidelines).  Blood chemistries performed twice weekly until Day 28.  Blood chemistries 
performed weekly after Day 28 until 12 weeks post-transplant. 
3  Infectious disease titers include: CMV, Hepatitis panel (HepA Ab, HepB SAb, HepB SAg, HepB Core Ab, 
HepC Ab), herpes simplex virus, varicella zoster virus, syphilis, HIV and HTLV I/II antibody. 
4  LEUKEMIA PATIENTS ONLY.  Bone marrow biopsy and aspirates to pathology and aspirate for 
cytogenetics.  Flow cytometry required on aspirate.  Day 21 bone marrow aspirate only if WBC < 500. 
5  GVHD and other morbidity assessments performed weekly until Day 100 post-transplant, and then at Day 
180 and 365. 
6 Chimerism will be measured by RFLP or microsatellite analysis of a peripheral whole blood sample.. 
 
 
5. STATISTICAL CONSIDERATIONS 
 
5.1 Study Design 
 
The study is a Phase 2 single center study designed to assess our outcomes in the context of 
previously published outcomes in haplo-identical transplant. It is designed to assess overall 
survival 180 days after peripheral blood stem cell  or bone marrow transplantation using a 
myeloablative or  nonmyeloablative preparative regimen and post-transplantation Cy using a 
partially HLA-mismatched first-degree relative (parent, sibling, or child) as a donor.  Patients 
with acute lymphoblastic leukemia/lymphoma, acute myelogenous leukemia, marginal zone B-
cell lymphoma, follicular lymphoma, and chemotherapy-sensitive Burkitt, large-cell/aggressive 
lymphoma, and Hodgkin lymphoma are eligible. 
 

 
 
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5.2 Accrual 
 
It is estimated that three years of accrual will be necessary to enroll the targeted sample size.  
Accrual will be reported by race, ethnicity, gender, and age. 
 
5.3 Study Duration 
 
Patients will be followed by UCSD as per CIBMTR/NMDP guidelines for transplant patients. 
Patient data and monitoring for the purposes of this study will continue for 1 year. 
 
5.4 Randomization 
 
There is no randomization in this trial. 
 
5.5 Primary Objective 
 
The primary endpoint is the proportion of patients who survive for 180 days after transplantation, 
the same primary endpoint as in the BMT CTN 0603 trial as well as in a larger published study 
for reduced intensity transplant (RIC) of unrelated donors.13 The primary analysis will include all 
transplanted patients.  
 
5.6 Sample Size and Power Considerations 
 
15 patients will be enrolled in total. We determined the sample size based on a Simon’s two-stage 
design14. In the BMT CTN 0603 trial overall survival at 180 days was 84% with 95% CI 70% - 
92%11.  We hypothesize that the proportion of OS at day +180 in this study would be similar to 
that. We will test the null hypothesis H0: p≤60% against the alternative hypothesis H1: p>60%, 
where p is the overall survival proportion at day +180.   Of note, 60% was the survival rate at 180-
day reported after RIC adult unrelated donor transplantation13.  The proposed two stage design will 
have 80% power to reject the null and conclude that the true rate is above 60%, if the true rate is 
≥85%, at 10% significance level. (The calculation was carried out using PASS 2008.) 
 
The study design can be described in detail as follows: 
 
Stage 1: Seven patients will be accrued; accrual will be held up until the overall survival at day 
+180 for all 7 patients are known. The trial will be terminated at Stage 1 if ≤4 of the 7 patients 
have survived at day +180; otherwise it continues to Stage 2.  
 
Stage 2: Eight more patients will be accrued. We will reject the therapy if the number of total 15 
(=7+8) patients who have survived at day +180 is ≤11.  
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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Interim analysis and early stopping: The interim analysis will be conducted as soon as the first 7 
patients have been accrued and are evaluable for the primary endpoint. If ≤4 subjects have survived 
at day +180, the trial will be stopped early for lack of efficacy. Under this design, if the null 
hypothesis is true, the probability of stopping the trial early will be 58%.  
 
Final analysis: If the study continues, after all 15 subjects are evaluable the study data set will be 
locked.  Out of the total of 15 subjects, if the number of subjects who have survived at day +180 
is 12 or more, the conclusion will be that the trial has demonstrated a statistically significant 
improvement in survival against 60% at 6 months.  The point estimation and 95% confidence 
interval for the OS proportion at 6 months will be estimated based on the method described in 
Koyama T., Chen H. Proper inference from Simon’s two-stage designs. Statistics in Medicine 
2008; 27: 3145-54.15 
 
 
5.7 Demographic and Baseline Characteristics 
 
Demographics and baseline characteristics will be summarized for all patients.  Characteristics to 
be examined are: age, gender, race/ethnicity, performance status, HLA match, disease type and 
stage, remission status and number, number of prior treatments, prior autologous transplantation 
(yes or no), serum bilirubin level, serum creatinine level, donor age, donor gender, and donor 
ethnicity. 
 
5.8 Analysis of Primary Endpoint 
 
The primary analysis will consist of estimating the 180 day overall survival probability based on 
the Kaplan-Meier product limit estimator.  The 180 day overall survival probability and 
confidence interval will be calculated.  All registered patients will be considered for this analysis. 
 
5.9 Analysis of Secondary Endpoints 
1. Overall survival: The overall survival distribution at one year after transplantation will 
be estimated by the Kaplan-Meier curve.  All patients will be followed for one year post-
transplant for mortality. 
2. Neutrophil recovery: To assess the incidence of neutrophil recovery from day of 
transplant, a cumulative incidence curve will be computed along with a 95% confidence 
interval. Death prior to neutrophil recovery will be considered a competing risk. 
3. Platelet recovery: To assess the incidence of platelet recovery from day of transplant, a 
cumulative incidence curve will be computed along with a 95% confidence interval. 
Death prior to platelet recovery will be considered a competing risk. 
4. Chimerism: The degree of donor chimerism will be assessed on Days 28, 56, 180, and 
365 after transplantation. 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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Haplo Orig. Protocol 8-2-12 
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5. Graft failure: To assess the incidence of primary and secondary graft failure a 
cumulative incidence curve will be computed along with a 95% confidence interval. 
Death prior to graft failure will be considered as a competing risk. 
6. Acute GVHD:  To assess the incidence of grades II-IV and grade III-IV acute GVHD 
from day of transplant.  The first day of acute GVHD onset at a certain grade will be used 
to calculate a cumulative incidence curve for that acute GVHD grade.  An overall 
cumulative incidence curve will be computed along with a 95% confidence interval at 
100 days post-transplant with graft failure, disease progression, and death considered a 
competing risk. 
7. Chronic GVHD: To assess the incidence and severity of extensive chronic GVHD from 
day of transplant, a cumulative incidence curve will be computed along with a 95% 
confidence interval at one and two years post-transplant.  The first day of clinical onset of 
extensive chronic GVHD will be used. Death, disease progression, or graft failure prior to 
occurrence of chronic GVHD will be considered competing risks. 
8. Treatment-related mortality: Treatment-related mortality at 100 days, six months, and 
one year will be estimated.  Disease progression is considered a competing risk. 
9. Relapse/progression: To assess the incidence of relapse/progression from day of 
transplant, a cumulative incidence curve will be computed along with a 95% confidence 
interval.  Death prior to relapse or progression will be considered a competing risk. 
10. Progression-free survival: To assess current progression-free survival, the one and two 
year progression-free survival probability after transplantation and 95% confidence 
interval will be calculated based on the Kaplan-Meier product limit estimator. 
 
 
 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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Haplo Orig. Protocol 8-2-12 
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Proprietary and Confidential 
APPPENDIX A 
 
HUMAN SUBJECTS 
 
 
1. 
Subject Consent 
 
A conference will be held with the patient, donor, and family to discuss this study and 
alternative treatments available for the treatment of the underlying disease.  The conference will 
be conducted by the principal investigator or other designated physician in a private setting. 
 
 
2. 
Confidentiality 
 
Confidentiality of a subject's protected health information will be maintained by the following 
methods: study-specific records containing protected health information and copies of study-
related medical records will be kept in locked filing cabinets and on computers with password-
access.  Access to such information will be limited to those study personnel who need to use it to 
accomplish the purpose of the research.  When protected health information is sent outside of the 
University of California, it will be disclosed only to those parties listed in the subject's 
authorization, and an audit trail log will be maintained of what information was sent and to whom 
it was sent.  
Study patients are assigned a study number which is entered on all case report forms.  No direct 
identifiers will be recorded on the study records.  Study staff members will keep a confidential log 
of all patients enrolled on the study. 
The medical record number is included in the consent form in order for it to be filed in the patient 
medical record.  No study related documents other than the consent form will be filed in the 
medical records. 
Only data directly related to the study will be shared amongst the study team members. 
 
 
 
3. 
Participation of Women and Minorities 
 
Women and ethnic minorities and other populations will be included in this study. 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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APPENDIX B 
 
LABORATORY PROCEDURES 
 
 
1. 
HLA TYPING 
 
HLA typing will be performed for all patients and donors in an American Society of 
Histocompatibility and Immunogenetics (ASHI)-approved laboratories.  HLA typing must be 
performed by DNA methods for HLA-A, -B, -Cw, DRB1, and DQB1 at high resolution (allele 
level). 
 
 
2. 
CHIMERISM 
 
Prior to transplantation, a sample of peripheral blood from the patient and from the donor is 
collected for chimerism studies according to institutional standards.  Patient samples are also 
collected on Day ~28, ~56, ~180 and ~365 after transplantation.  Chimerism will be measured by 
RFLP or microsatellite. Donor chimerism after transplantation shall be measured on samples of 
whole blood or mononuclear fraction. 
 
 
 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
______________________________________________________________________________ 
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Haplo Orig. Protocol 8-2-12 
Am1 8-7-13; Am 2 11-8-13; Am3 2-3-14; Am4 06-12-2014 
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APPENDIX C 
 
GUIDELINES FOR DONOR TYPING AND SELECTION 
 
 
An HLA-haploidentical donor is defined as a family member who shares one complete HLA 
haplotype with the recipient, and is variably HLA mismatched on the non-shared haplotype. A 
transplant recipient is HLA-haploidentical to each parent, to each child, and each sibling has a 
50% chance of being HLA-haploidentical to the recipient. Typing all siblings, parents, and 
children is neither practical nor economically feasible.  Siblings are always typed first in the 
attempt to find an HLA-matched donor. 
 
If an HLA-matched donor is unavailable (Section 2.4), the following sequence is recommended: 
1. Review HLA-typing of siblings and perform extended family typing, as appropriate, to 
ascertain parental haplotypes.  If an HLA-haploidentical donor is identified, then proceed 
with criteria for “preferred donor” below.  If no HLA-haploidentical donor is identified 
and there are additional siblings or half-siblings willing to be typed for potential 
donation, then perform HLA and ABO typing and determine CMV serologic status of the 
remaining siblings or half-siblings. 
2. If a preferred donor (defined below) is not identified from the siblings or half-siblings, 
then consider performing HLA and ABO typing and determining CMV serologic status 
of parents that are ≤ 60 years of age and children  18 years of age.  If typing of parents 
and children is not performed, and no HLA-haploidentical sibling meets the criteria for a 
preferred donor, then choose a suitable donor, defined as the HLA-haploidentical sibling 
who meets most of the criteria for preferred donor, in the order listed.  If typing of 
parents and children is performed but no preferred donor is identified, then choose the 
most suitable donor. 
3. If a preferred or suitable donor is still not identified, perform HLA and ABO typing and 
determine CMV serologic status of parents 60 years old. 
 
A preferred donor is defined as one who meets all the following criteria: 
1. Medically and psychologically fit and willing to donate. 
2. If the patient is CMV seronegative, then the donor should be CMV seronegative. 
3. No major ABO incompatibility: 
a. If the patient is blood type “O”, then the donor should be type “O”. 
b. If the patient is blood type “A”, then the donor should be type “A” or “O” 
c. If the patient is blood type “B”, then the donor should be type “B” or “O” 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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If more than one preferred donor or more than one suitable donor is identified and there is no 
medical reason to prefer one of them, then the following guidelines are recommended: 
1. If the patient and family express a strong preference for a particular donor, use that one 
2. If the donor is a sibling, choose the youngest sibling 
3. If the donor is not a sibling, choose a parent over a child (for psychological reasons) 
If the recipient is eligible for both an ablative and a nonmyeloablative transplant the treating 
physician will ultimately make a decision regarding using the ablative versus nonmyeloablative 
preparative regimens as described above.  This decision is generally based upon the underlying 
diagnosis , the age of the patient, and the comorbidities.  If the stem cell donor is able to donate 
either stem cells or bone marrow the decision to use peripheral blood stem cells versus bone 
marrow collection will be based upon the logistics of coorrdinating the bone marrow collection 
(avoiding extended delays in treatment) , the preference of the treating physician, and the donor 
preference.  At UCSD there are frequently logistical constraints that result in delay of adequate 
operating room time which can result in delay of transplant.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
______________________________________________________________________________ 
40 
Haplo Orig. Protocol 8-2-12 
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APPENDIX D 
 
REFERENCES 
 
1 Weiden PL, Flournoy N, Thomas ED, et al.: Antileukemic effect of graft-versus-host disease in 
human recipients of allogeneic-marrow grafts. N Engl J Med 300:1068-1073, 1979. 
2 Weiden PL, Sullivan KM, Fournoy M, et al.: Antileukemic effect of chronic graft-versus-host 
disease: contribution to improved survival after allogeneic marrow transplantation. N Engl J 
Med 304:1529-1533, 1981. 
3 Beatty PG, Mori M, Milford E. Impact of racial genetic polymorphism on the probability of 
finding an HLA-matched donor. Transplantation 60:778-783, 1995. 
4 Barker JN, Krepski TP, Defor TE, et al.: Searching for unrelated donor hematopoietic stem cells: 
Availability and speed of umbilical cord blood versus bone marrow. Biology of Blood and 
Marrow Transplantation 8:257-260, 2002. 
5 Anasetti C, Amos D, Beatty PG, et al.: Effect of HLA compatibility on engraftment of bone 
marrow transplants in patients with leukemia or lymphoma. N Engl J Med 320:197-204, 1989. 
6 Anasetti C, Beatty PG, Storb R, et al.: Effect of HLA incompatibility on graft-versus-host disease, 
relapse, and survival after marrow transplantation for patients with leukemia or lymphoma. 
Hum Immunol 29:79-91, 1990. 
7 Luznik L, Jalla S, Engstrom LW, et al.: Durable engraftment of major histocompatibility 
complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose 
total body irradiation, and posttransplantation cyclophosphamide. Blood 98:3456-3464, 2001. 
8 Luznik L, Engstrom LW, Iannone R, et al.: Posttransplantation cyclophosphamide facilitates 
engraftment of major histocompatibility complex-identical allogeneic marrow in mice 
conditioned with low-dose total body irradiation. Biol Blood Marrow Transplant 8:131-138, 
2002. 
9 O'Donnell PV, Luznik L, Jones RJ, et al.: Nonmyeloablative bone marrow transplantation from 
partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biol 
Blood Marrow Transplant 8:377-386, 2002. 
10 Mayumi H, Umesue M, Nomoto K: Cyclophosphamide-induced immunological tolerance: an 
overview. [Review] [74 refs]. Immunobiology 195:129-139, 1996. 
11 Brunstein CG, Fuchs EJ, Carter SL, et al. Alternative donor transplantation after reduced 
intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related 
bone marrow or unrelated double cord blood grafts. Blood 118:282-288, 2011. 
12 Maris MB, Niederwieser D, Sandmaier BM, et al.: HLA-matched unrelated donor hematopoietic 
cell transplantation after nonmyeloablative conditioning for patients with hematologic 
malignancies. Blood 102:2021-2030, 2003. 
                                                 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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13 Giralt S, Logan B, Rizzo D, et al. Reduced-intensity conditioning for unrelated donor progenitor 
cell transplantation: long-term follow-up of the first 285 reported to the national marrow donor 
program. Biol Blood Marrow Transplant. 2007; 13(7): 844-852. 
 
14 Simon R. Optimal Two-Stage Designs for Phase II Clinical Trials. Controlled Clinical Trials 
1989; 10: 1-10. 
 
15 Koyama T., Chen H. Proper inference from Simon’s two-stage designs. Statistics in Medicine 
2008; 27: 3145-54. 
 
16  Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK, Morris LE, Bashey 
A.  Haploidentical Transplantation Using T cell Replete Peripheral Blood stem cells and 
Myeloablative Conditioning in Patients with High-Risk Hematologic Malignancies Who Lack 
Conventional Donors is Well Tolerated and Produeces Excellent Relapse-Free Survival: Results 
of a Prospective Phase II Trial.  Biol Blood Marrow Transplant.  2012; 18: 1859-1866 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX E. 
 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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Data Safety Monitoring and Verification:   
 
Overview:  The Moores UCSD Cancer Center has established DSMB Policies and Procedures for 
cancer clinical trials in order to insure the safety of participants; the validity of data; and the 
appropriate, early termination for findings of unjustifiable risk, of likely futility due to inadequate 
accrual or data acquisition, or if interim analysis shows the emergence of a significant benefit 
among intervention alternatives.  DSMB Policies and Procedures specifically address the 
integration of ongoing protocol review and clinical trials monitoring functions into a 
comprehensive DSM program; the DSMB requirements for clinical trials; procedures for DSMB 
review and confidential reporting of decisions to investigators, the IRB, FDA, and supporting NIH 
Institutes and Centers; and procedures for assuring compliance by investigators with DSM 
requirements for study conduct, monitoring, and adverse event reporting.  The complete UCSD 
Cancer Center DSM policies and procedures are available on the UCSD website in a publication 
entitled “UCSD Cancer Center:  Policies And Procedures” at the following website:  
 
https://ccweb2.ucsd.edu/ONcLINE/documents/DSM_PP_2012_Final_062912.pdf 
 
Specific elements of DSM for this trial will include:   
1. 
 Review and approval by the Cancer Center PRMC:  The purpose of the PRMC is to 
promote the conduct of scientifically meritorious clinical cancer research under the 
authority of the Cancer Center. This goal is accomplished through systematic 
research protocol review, interim monitoring of progress, and oversight of protocol 
prioritization, as required by NCI. 
2. 
Data collection by Study Staff: Data is collected by the trained study coordinator 
(SC) who is assigned to the trial.  SC will enter the data into the study specific case 
report forms and also the CIBMTR/NMDP data collection forms used for transplant 
patients.  Audits of the data will be performed by the Cancer Center DSMB and its 
auditing coordinator.  
Data review and analysis by the PI:  Patient eligibility and outcome data is 
reviewed by the PI, including severity of signs, symptoms, and adverse reactions 
associated with the transplant procedures and during follow-up and also relevant 
outcome events during the 1 year follow-up for progression-free survival . 
Data audit by the UCSD Cancer Center CTO:  The CTO is a Shared Resource 
of the UCSD Cancer Center, and its purpose is to provide a supportive 
environment for the successful conduct of clinical trials within the center in 
order to enhance the excellence of clinical cancer research at UCSD. To fulfill 
this mission, the CTO provides centralized administrative and management 
support for all UCSD cancer clinical trials at every stage of development. The 
CTO has the responsibility of providing monitoring support as part of the Cancer 
Center DSM Policies and Procedures. The CTO Administrative Coordinator 
conducts regularly scheduled monitoring of UCSD Clinical Trials data.  Data 

 
 
PI: Grace Ku, MD 
________________________________________________________________HRPP#: 120931 
 
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that is monitored for this study will be extracted from the completed case report 
forms.  
3. 
 DSMB reports will be provided by the PI to the DSMB every 3 months.  In-Depth 
Audits are conducted annually and at least 25% of the subject records (minimum of 
5) are reviewed. The audit includes informed consent, eligibility criteria, protocol 
compliance, dose modifications, toxicity and adverse event reporting, drug 
accountability, record keeping, drug inventory, quality of data and timeliness of data 
submission. Individual aspects of study conduct are assessed for compliance with 
protocol-specified procedures and with Good Clinical Practice guidelines. Audit 
findings are detailed in a Level 3 Audit Report, prepared by the Auditing 
Coordinator for presentation at a quarterly meeting of the Cancer Center DSMB. 
4. 
Review of data by the Data Safety Monitoring Board (DSMB):  The DSMB exists 
to assure that all cancer clinical trials conducted with the support of the Moores 
UCSD Cancer Center receive monitoring for issues of protocol compliance, adverse 
events, and data quality. The purpose of the Center DSMB activity is to insure the 
safety of participants, the validity of data, and the appropriate closure of studies 
when interim data analysis indicates futility, unanticipated risks, or early 
accomplishment of study objectives.  The DSMB provides review of the conduct 
and outcomes of clinical trials through scrutiny of data collection and adverse event 
summary reports, and interim data analysis.  This study will be monitored and 
audited by the Moores UCSD Cancer Center Data Safety and Monitoring Board 
(DSMB). The UCSD Cancer Center DSMB will also review serious adverse effects 
(SAEs). The DSMB will also review the conclusions of this Phase2 trial, including 
the 1 year survival data.