Conditions: Myelodysplastic Syndrome
Keywords: high risk myelodysplastic syndrome natural killer cells
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 9
Healthy volunteers: no

Brief summary:
This is a Phase II therapeutic trial combining Decitabine days 1-5 with oral Vorinostat twice daily days 6-15 followed by a single infusion of CD3-/CD19- enriched donor natural killer (NK) cells on day 17 and a short course of Interleukin-2 (IL-2) to facilitate NK cell survival and expansion. Two courses of treatment will be given separated by 6-8 weeks. The intent is to administer all treatment in the outpatient setting.

Detailed description:
A single donor apheresis will be collected on day 15 of cycle 1, enriched for NK cells with the large scale CliniMacs device (Miltenyi) and activated by overnight incubation with IL-2. After washing, the final NK cell product will be divided in two, with half given fresh on day 17 of course #1 and half stored frozen until day 17 of course #2.

Clinical response will be formally assessed 4-6 weeks after the start of 2nd course based on International Working Group (IWG) criteria; however, bone marrow evaluations will be completed to assess for any sign of significant disease progression between cycle 1 and 2.

Arms:
arm 1: Patients who received treatment for high risk myelodysplastic syndromes (MDS). Treatment Received: Decitabine 10 mg/m\^2/day intravenous (IV) over 1 hour days 1-5; Vorinostat 200 mg by mouth (PO) twice a day days 6-15; Il-2 activated donor natural killer cells (NK) infusion IV over 15 to 60 minutes day 17; Interleukin-2 6 million units subcutaneous (SQ) 3 times a week for 3 doses beginning day 17. Repeat treatment course 6 to 8 weeks after cycle 1 start date.

Interventions: intervention 1: Decitabine intervention 2: Vorinostat intervention 3: Interleukin-2 intervention 4: Natural killer (NK) cells
Intervention descriptions: intervention 1: administered intravenous (IV), 10 mg/m\^2/day over 1 hour on days 1-5. intervention 2: 200 mg by mouth (PO) twice a day on days 6-15 intervention 3: 6 million Units subcutaneous (SQ) 3 times a week for 3 doses beginning day 17 intervention 4: infusion intravenously (IV) over 15 to 60 minutes day 17

Protocol document:
Prot_SAP_000.pdf: 
Masonic Cancer Center  
University of Minnesota 
Cancer Experimental Therapeutics Initiative (CETI) 
 
 
Decitabine and Vorinostat with CD3/CD19 Depleted Haploidentical 
Donor Natural Killer (NK) Cells for the Treatment of High Risk 
Myelodysplastic Syndromes (MDS)  
 
MT2012-04 
CPRC #2011LS124 
IND 8847  
 
 
 
Principal Investigator: 
Erica Warlick, MD 
Hematology, Oncology and Transplantation  
University of Minnesota 
 
 
 
Co-Investigators: 
 
University Of Minnesota 
Jeffrey S. Miller, MD (IND Sponsor) 
David H. McKenna, Jr., MD 
Daniel J. Weisdorf, MD 
 
Mayo Clinic 
Mark Litzow, MD (Institutional PI) 
Mrinal Patnaik, MD 
Aref AlKali, MD 
 
 
 
Biostatistician: 
Qing Cao, MS 
Masonic Cancer Center 
University of Minnesota 
 
 
 
Version Date: 
October 28, 2014 
 
Confidential 
 
 


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Contact Information – Key Study Personnel 
 
 
Site 
Contact Information 
Role 
Masonic Cancer Center, 
University of Minnesota 
Erica Warlick, MD 
Division of Hematology/Oncology/Transplantation 
420 Delaware Street SE MMC 480 
Minneapolis, MN 55455 
Phone: (612) 624-0123 
Fax: (612) 625-6919  
Email: ewarlick@umn.edu 
 
Study PI 
Jeff Miller, MD 
Division of Hematology/Oncology/Transplantation 
420 Delaware Street SE  MMC 806 
Minneapolis, MN 55455 
Phone: 612-625-7409 
Email: mille011@umn.edu 
Fax : 612-626-4915 
 
IND Sponsor 
Mayo Clinic 
Mark Litzow, MD 
Division of Hematology 
200 First Street SW 
Rochester, MN 55905 
Phone : 507-284 5362 
Fax : 507-266 4972 
Email : Litzow.Mark@mayo.edu 
Institutional PI 
 
 
 
 


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REVISION HISTORY 
 
Revision 
# 
Version 
Date 
Revision summary 
Consent 
Revised 
 
03/31/12 
Original to CPRC 
n/a 
 
04/12/12 
Original to IRB – In response to CPRC stipulations with additional edits 
n/a 
1 
06/25/12 
Revise treatment schedule to accommodate product processing at U of MN for 
both sites and to avoid weekends; 
Update statistical section.  Original to FDA. 
Yes 
2 
10/03/12 
In response to IRB ancillary committee review: 
Revise donor eligibility to adults only (18 – 75 years of age)  
In response to study initiation meeting: 
Synopsis, Sections 7.3 and 10.3:  Clarify that the NK cell product will be divided 
in half prior to IL-2 activation and that the IDS will prepare the IL-2 used in the 
overnight incubation for all patients (U of MN and Mayo Clinic), for course #2 
product MCT will send a post-thaw and post IL-2 cell sample to TTL; 
Sections 13.2 and 11.3:   Revise early study stopping rule to include any non-
hematologic, non-infectious grade 4-5 event, regardless of attribution and re-
calculate patient number thresholds; 
Section 4.11 (new) and Checklist:  Exclude patient who have received 7+3 or 
other AML-type induction chemotherapy; 
Section 11.2:  adjust post-IL-2 targeted toxicity assessments to coincide with 
clinic visits; 
Other minor clarifications and corrections throughout 
Yes 
3 
01/04/13 
Sections 7.3 and 7.4: update lot release information in that the final product must 
contain at least 20% NK cells (previously at least 30%) as permitted by the FDA 
and to match the current CMC; 
additional edits – Section 7.5 re-write IL-2 dose modification guidelines for clarity;  
Section 8.1.1:  clarify follow-up for survival only for the purpose of calendar 
creation (at Day 90, 180, 270, 360), Section 8.2:  delete donor repeat type and 
screen at day 15; other minor edits 
no 
4 
06/17/13 
Section 7.3 and 7.4:  change the %NK cells required for lot release to 30% 
reversing the January 2013 change to 20%; clarify course #2 cell preparation 
procedures 
no 
5 
5/19/14 
Study synopsis, section 4.2 - expand eligibility to include previously treated 
patients with refractory disease; 
Section 4.10 – delete prior therapy exclusion criteria – no longer applicable; 
Synopsis, sections 3, 7 - delete bone marrow biopsy between course 1 and 2 to 
minimize procedures but add off study marrow if patient discontinues treatment 
before completing two courses; 
Section 7.3 – delete the sentence “Final product must contain at least 30% NK 
cells.” as this is no longer correct based on the current CMC; 
Section 7.4 – update language to reflect current lot release criteria of > 3-fold NK 
cell enrichment between apheresis and final product; 
section 7.10 – redefine the definition of rapidly progressing disease based on 
peripheral blood since BM examination will not be routinely done between 
courses 1 and 2; 
section 10.2.9 – add that Vorinostat may be paid for by research funds; 
other edits and clarifications – all tracked 
 
 
yes 


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Revision 
# 
Version 
Date 
Revision summary 
Consent 
Revised 
6 
09/05/14 
Study synopsis, section 4.1, checklist - expand eligibility to include the following 
classifications of MDS: 
 International Prognostic Scoring System- Revised (IPSS-R) Category: High or 
Very High (Score of 5 or above) 
 WHO Classification: CMML that is not highly proliferative. WBC < 15k 
 Therapy related MDS 
 Severe cytopenias: Severe neutropenia (ANC < 0.8), platelet or PRBC 
transfusion dependent 
Update appendices IV (IPSS) to include IPSS-R  
Section 7.6 and section 8.1 – add a bone marrow biopsy between course 1 and 2 
for patients who failed prior treatment  (prior to revision #5 all patients had a bm 
bx mid-treatment, with this revision it is reinstated for a sub-set of patients) 
other edits and clarifications – all tracked 
yes 
7 
10/28/14 
Section 6 – clarify study enrollment/registration is on-study 
Section 8 – increase the window that pre-treatment evaluations may be done (28 
days unless otherwise stated, but 14 days for CBC, plt, CMP, chemistries), 
previously had been 14 days unless otherwise stated – clarify window is from 
start of treatment not study enrollment 
Section 11.4 – update event reporting to IRB to new requirements (UMN only) 
no 
 
 


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INDEX 
 
Contact Information – Key Study Personnel .............................................................................................. 2 
Study Synopsis .......................................................................................................................................... 7 
Study Schema ............................................................................................................................................ 8 
1.0 
Objectives ....................................................................................................................................... 9 
1.1 
Primary Objective .......................................................................................................................... 9 
1.2 
Secondary Objectives ................................................................................................................... 9 
1.3 
Correlative Laboratory Objectives ................................................................................................. 9 
2.0 
Background and Scientific Significance ......................................................................................... 9 
2.1 
Conventional Therapy for High Risk MDS .................................................................................. 11 
2.2 
History of Adoptive NK Cell Therapy for Refractory/Relapsed AML at the U of MN .................. 13 
2.3 
Rationale for Proposed Study ..................................................................................................... 14 
3.0 
Study Design ................................................................................................................................ 14 
4.0 
Selection of Patients .................................................................................................................... 15 
5.0 
Donor Selection ............................................................................................................................ 17 
6.0 
Patient/Donor Enrollment (On Study) .......................................................................................... 17 
7.0 
Treatment Plan ............................................................................................................................. 18 
7.1 
Decitabine (Days 1-5) ................................................................................................................. 19 
7.2 
Vorinostat Administration (Days 6-15) ........................................................................................ 19 
7.3 
Donor Apheresis (Day 15 Course 1 Only) and Cell Product Manufacturing ............................... 19 
7.4 
Allogeneic CD3- CD19- Selected NK Cell Product Infusion (Day 17) .......................................... 21 
7.5 
IL-2 (begin day 17) ...................................................................................................................... 21 
7.6 
Second Treatment Course .......................................................................................................... 22 
7.7 
Dose Modifications ...................................................................................................................... 23 
7.8 
Management of Selected Toxicities Associated with NK Cell Infusion ....................................... 23 
7.9 
Supportive Care Guidelines/Concomitant Medication Use ......................................................... 24 
7.10 
Duration of Therapy .................................................................................................................... 24 
7.11 
Follow-up ..................................................................................................................................... 25 
8.0 
Study Calendar ............................................................................................................................ 25 
8.1 
Patient ......................................................................................................................................... 26 
8.1.2 
Patient – Research Related ........................................................................................................ 27 
8.2 
Donor – Research Related .......................................................................................................... 28 
8.3 
Sample Shipping Information ...................................................................................................... 28 
9.0 
Study Endpoints ........................................................................................................................... 28 
10.0 
Drug Formulation And Procurement ............................................................................................ 29 
10.1 
Decitabine ................................................................................................................................... 29 
10.2 
Vorinostat (SAHA) ....................................................................................................................... 31 
10.3 
Interleukin-2 (IL-2) ....................................................................................................................... 32 
11.0 
Adverse Event Reporting ............................................................................................................. 35 
11.1 
Definitions .................................................................................................................................... 36 
11.2 
Adverse Event Documentation .................................................................................................... 37 
11.3 
Required Reporting:  Mayo Clinic to the Masonic Cancer Center .............................................. 38 
11.4 
MCC Required Reporting: FDA, IRB, Miltenyi, and MCC’s SAE Coordinator ............................ 39 
11.5 
Reporting of Device/Processing Malfunction .............................................................................. 40 
12.0 
Study Data Collection and Monitoring .......................................................................................... 40 
12.1 
Data Management ....................................................................................................................... 40 
12.2 
Case Report Forms ..................................................................................................................... 40 


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12.3 
Data and Safety Monitoring Plan (DSMP) .................................................................................. 41 
12.4 
Monitoring .................................................................................................................................... 41 
12.5 
Record Retention ........................................................................................................................ 42 
13.0 
Statistical Considerations ............................................................................................................. 42 
14.0 
Conduct Of The Study .................................................................................................................. 43 
14.1 
Good Clinical Practice ................................................................................................................. 43 
14.2 
Ethical Considerations ................................................................................................................ 44 
14.3 
Informed Consent ........................................................................................................................ 44 
15.0 
References ................................................................................................................................... 44 
Appendix I – Eligibility Checklist – Patient ............................................................................................... 47 
Appendix II - Eligibility Checklist - Donor ................................................................................................. 49 
Appendix III – ECOG Performance Status Criteria .................................................................................. 50 
Appendix IV – International Prognostic Scoring System (IPSS) Category and IPSS-R41 ....................... 51 
Appendix V – WHO Based Prognostic Scoring System42 ........................................................................ 53 
Appendix VI – MDS Response Criteria .................................................................................................... 54 
Appendix VII – Expected Toxicities of Study Treatment .......................................................................... 55 
Appendix VIII – Vorinostat Drug Log ........................................................................................................ 57 
Appendix IX – Targeted Toxicity Form NK Cells/IL-2 .............................................................................. 58 
 
 
 
 
 


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Study Synopsis 
Study Design: 
This is a Phase II therapeutic trial combining Decitabine days 1-5 with oral Vorinostat twice daily days 6-
15 followed by a single infusion of CD3-/CD19- enriched donor NK cells on day 17.  Subcutaneous 
Interleukin-2 (IL-2) will be given 2 hours after the NK cell infusion with a 2nd and 3rd dose given on day 19 
and day 22.  Two courses of treatment will be given separated by 6 - 8 weeks.  The intent is to administer 
all treatment in the outpatient setting. 
 
A single donor apheresis will be collected on day 15 of course 1.  Centralized product manufacturing will 
be done at the U of MN Molecular and Cellular Therapeutics (MCT) laboratory (utilizing overnight courier 
for Mayo Clinic cells).  At MCT the cells will be enriched for NK cells with the large scale CliniMacs device 
(Miltenyi) then the NK cell product will be divided in two with half stored frozen until course #2.  The other 
half will be activated by incubation with IL-2.  On the morning of day 17 (upon arrival back at Mayo, if 
applicable), the cells will be washed and final lot release done.  For course #2, the stored cells will be 
thawed, IL-2 activated, and infused in a manner identical to course #1. 
 
Clinical response will be formally assessed 4 - 6 weeks after the start of 2nd course based on International 
Working Group (IWG) criteria.  
 
Primary Objective: 
 
Evaluate the objective response rate (CR + PR+ Hematologic Improvement (HI)) after 2 courses of 
Decitabine and Vorinostat with haploidentical NK cells in patients with high risk MDS 
 
Secondary Objectives: 
 
Assess the safety and tolerability of Decitabine and Vorinostat followed by an infusion of CD3-/CD19- 
donor NK cells and IL-2 when given in the outpatient setting in patients with high risk MDS 
 
Assess the proportion of patients who become transfusion independent at 4-6 months post  
 
Estimate the association of in vivo expansion with clinical response 
 
Estimate 1 year Overall Survival 
 
Patient Population: 
Diagnosis of high risk MDS requiring treatment that meets at least one of the following classifications: 
 International Prognostic Scoring System (IPSS) Category: INT-2 or High Risk 
 International Prognostic Scoring System- Revised (IPSS-R) Category: High or Very High (Score of 5 
or above) 
 WHO Classification: RAEB-1 or RAEB-2 
 WHO Classification: CMML that is not highly proliferative, WBC < 15k 
 High risk cytogenetic abnormality as defined by presence of Monosomy 7, complex karytope, or 
monosomal karyotype 
 Therapy related MDS 
 Severe cytopenias: Severe neutropenia (ANC < 0.8), platelet or PRBC transfusion dependent 
 WHO Based Prognostic Scoring System (WPSS): High or Very High Risk 
Prior treatment: 
 Untreated/Minimally Treated: May be untreated or have had a maximum of 2 previous cycles of 
hypomethylating agents (azacitidine or Decitabine) without evidence of treatment failure  
 Treatment Failure: Patients who have not responded to or whose disease has progressed on 
hypomethylating agents (azacitidine or decitabine), 7+3 type induction chemotherapy, or 
immunosuppressive therapy such as ATG+CSA 
Age ≥ 18 years of age, ECOG 0-2, adequate renal, hepatic and cardiac function as defined in section 4.6 
Available related HLA haploidentical NK cell donor age 18-75 years 
 
Accrual Objective: 
Stage 1 – 15 evaluable patients; Stage 2 activate if ≥ 6 of stage I patients achieve response. If so, then 
enroll an additional 31 patients for a total of 46 evaluable patients 
 


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Study Schema 
 
 
Treatment Plan:  
 
All treatment to be administered as an outpatient 
 
Days 1-5 
Days 6-15 
Day 15 
Day 17 
Days 17, 19, 22  
 
 
 
 
 
 
 
 
 
 
Decitabine IV 
Vorinostat PO bid 
Donor Apheresis 
treatment course 1 only* 
NK cell infusion 
IL-2  
for 3 doses 
 
 
Decitabine 10 mg/m2 IV over 1 hour days 1-5 
Vorinostat 200 mg PO twice a day days 6-15 
Il-2 activated donor NK cell infusion IV over 15 to 60 minutes day 17 
IL-2 6 MU SQ for 3 doses beginning on day 17 (2 hours after NK cell infusion), then day 19 and day 22 
 
 
Repeat treatment course 6 to 8 weeks later unless unacceptable toxicity, medically unsafe, or 
evidence of rapid disease progression as defined in section 7.10 
 
 
Assess for disease response 4 to 6 weeks after 2nd treatment course 
 
 
Follow for survival and progression to AML for 1 year from enrollment 
 
 
* A single donor apheresis will be collected on day 15 of course 1.  Centralized cell processing will occur at the 
University of Minnesota utilizing overnight shipping for Mayo products (U of MN products will be held an extra 24 
hours to match Mayo’s timing).  The NK cell product will be divided in two after processing, but before IL-2 activation. 
Half will be stored frozen until course 2. The remaining cells will be prepared for fresh administration on day 17 of 
course 1. 


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1.0 
Objectives 
1.1 Primary Objective 
Evaluate the objective response rate (CR + PR+ Hematologic 
Improvement (HI)) after 2 courses of Decitabine and Vorinostat with 
haploidentical NK cells in patients with high risk MDS 
1.2 Secondary Objectives 
 Assess the safety and tolerability of Decitabine and Vorinostat followed 
by an infusion of CD3-/CD19- donor NK cells and a short course of IL-
2 when given in the outpatient setting in patients with high risk MDS 
 Assess the proportion of patients who become transfusion independent 
(red blood cells and/or platelets) 
 Estimate the association of in vivo NK cell expansion with clinical 
response 
 Estimate 1 year Overall Survival (OS) 
1.3 Correlative Laboratory Objectives 
 Estimate the incidence of successful in vivo expansion of adoptively 
transferred haploidentical NK cells by NK cell persistence 2 weeks 
after infusion (Day 28) 
 Monitor phenotypic and functional characteristics of natural killer cells 
and regulatory T cells in vivo 
 
 
2.0 
Background and Scientific Significance 
 
Myelodysplastic syndromes (MDS) are a complex and heterogeneous group of 
clonal stem cell disorders manifested by diverse clinical and biologic paths with 
varying needs for transfusions, risk of infection, and risk of progression to acute 
leukemia. The FDA approval of three new therapeutic agents for MDS over the 
last few years (azacitidine, lenalidomide, and decitabine) as well as innumerable 
available clinical trials has changed the treatment paradigm for this spectrum of 
diseases; however, stem cell transplantation remains the only curative therapy 
for MDS.  
 
MDS pathophysiology is complex, diverse, and still not completely understood. 
Structural alterations in DNA, as evident by the cytogenetic abnormalities seen in 
a majority of patients, play a role in the pathogenesis of disease due to loss or 
alteration of genetic material involved in proliferation, differentiation, or apoptosis. 
Epigenetic changes in the form of modifications to the transcriptional capacity of 
the cell via processes such as DNA methylation or histone acetylation can also 
alter gene expression impacting disease biology. 1 As such, DNA 
hypermethylation of key cellular machinery involved in cell cycle regulation, 


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apoptosis, and tumor suppressor control is well documented in the pathogenesis 
of myelodysplastic syndromes as well as other cancers. 1-6  
 
In addition to the known epigenetic alterations, the data also support evidence of 
a range of immune dysregulation in MDS subtypes. It is clear from extensive 
studies with immunosupressive therapies (ATG+ CSA, etc) that there are a 
subset of MDS patients (younger age, HLA-DR15, possible hypocellular 
marrows, with low risk IPSS MDS, and shorter duration of disease) where 
autoimmunity is a primary pathophysiologic defect. 7-11 In these settings, 
immunosupressive therapy is likely the most appropriate treatment strategy. 
Additional work investigating NK cell and T regulatory cell function and 
signatures in MDS suggest a divergent pattern for more advanced states of 
MDS. The currently available data regarding NK cell dysfunction in MDS, though 
yet to be fully characterized, appears to be multifactorial due to presence of 
clonal cytogenetic abnormalities, 12decreased activating receptors in peripheral 
blood NK cells (NKp30, NKp46, NKG2D) with NKG2D the primary effector versus 
decreased expression of bone marrow NK cell activating receptor DNAM-1 
contributing to the NK cell dysfunction, 12-14 and a correlation between NK cell 
dysfunction and increased blasts and more advanced WHO MDS 
categorization13. The influence of T regulatory cells (Tregs), defined as CD4+, 
CD25high, Foxp3+, on immune surveillance and development of autoimmunity or 
suppression of host immune response has also been widely researched in 
cancer and more recently in MDS. The overarching theme of T regulatory cell 
characteristics in MDS describe increased Treg frequency with disease 
progression and subsequent decrease with response to therapy. Functionally, 
the Tregs retained their function in late stage MDS, theoretically consistent with 
their impact on suppressing immune attack on the underlying disease, but in 
early stage MDS were less efficient at suppression of polyclonal T cell 
proliferative responses again theoretically consistent with the higher degree of 
autoimmunity at that disease state. 15-18 Combining these data support the 
potential role of Tregs in leukemic progression in INT-2/High risk MDS and a 
more autoimmune milieu in the low/INT-1 patients.   
 
These data highlight the role the immune system may play in the diverse 
spectrum of MDS by allowing either the development of or promoting the 
progression of disease. Immune dysregulation is unlikely to account for the entire 
pathogenesis of these diseases; however, identifying immune abberencies in 
Treg and NK cells in MDS and developing therapies to abrogate these responses 
and combining immune focused therapies into standard regimens is a rational 
next step.  


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2.1 
Conventional Therapy for High Risk MDS  
2.1.1 Hypomethylating Agents: Azacitidine and Decitabine 
2.1.1.1 Azacitidine as a Single Agent for Myelodysplastic 
Syndromes 
Azacitidine (5-azacytidine; Vidaza; Celgene Corporation, Summit, NJ, 
United States) was the first drug approved for the treatment of 
myelodysplastic syndromes by the Food and Drug Administration 
(FDA) in 2002. Azacitidine is an analog of cytidine, a pyrimidine 
nucleoside that is a component of human RNA. Although azacitidine 
falls into the category of hypomethylating agents, its mechanism of 
action is likely multifactorial. 
  
Based on work by Silverman and colleagues and the outcomes of 
CALGB 8421, 8921, 9221, and AZA-001, using a standard dose of 75 
mg/m2 Days 1-7, azacitidine became a first line therapeutic option for 
higher risk MDS (INT-2/High by IPSS) requiring therapy. Initial study 
results revealed an average overall response rate (complete remission 
+ partial remission + hematologic improvements) of approximately 40% 
but more importantly demonstrated delayed time to leukemia 
progression, improved quality of life, and improved overall survival 
compared to conventional care. 19-22 While these study revealed 
important strides in caring for high risk MDS patients, the delayed time 
to transformation to AML from 11 months to approximately 18 months, 
and the 5+ month benefit on survival with azacitidine therapy is far 
from perfect.  
2.1.1.2 Decitabine as Single Agent in MDS 
Related to azacitidine, Decitabine (5-aza-2’-deoxycytidine) which is a 
cytosine analog that eventually incorporates into DNA through a series 
of metabolic steps differing from azacitidine has been noted to lead to 
hypomethylation at low doses and direct cytotoxicity at higher doses. 23 
Initial studies using a dosing schedule of 15 mg/m2 IV over three hours 
every 8 hours for a total of 3 days repeated every 6 weeks 
demonstrated overall response rates of 17% 24while subsequent 
studies using more outpatient-friendly regimens (20mg/m2 Day 1-5 
SQ, 20mg/m2 Day 1-5 IV, and 10mg/m2 IV Day 1-10) produced higher 
CR and overall response rates. The dosing schedule of 20mg/m2 
intravenously Day 1-5 yielded the highest CR rates (39%). 25 Given 
these good responses, the above dosing schedule is the one most 
frequently used in clinical practice.  
 
Independent meta analysis of both azacitidine and decitabine with 
respect to overall survival and time to AML/death has interestingly 
shown the advantage in favor of azacitidine [OS:  azacitidine (HR 0.56, 


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95% CI 0.44-0.73) versus Decitabine (HR 0.88, 95% CI, 0.66-1.17)]; 
time to AML/death: azacitidine (HR of 0.54,95% CI 0.42-0.71) vs. 
Decitabine (HR 0.85, 95% CI, 0.66-1.07). To identify the reason for this 
discrepancy, characterization of the study groups within the azacitidine 
and decitabine trials revealed a similar proportion of IPSS risk 
groups/FAB groups and median ages; however, the duration of 
Decitabine therapy was slightly shorter with a median of 3-4 cycles 
versus 9 with azacitidine. 22 The differing treatment exposure may 
explain the differing impact on overall survival benefit; however, only 
randomized studies comparing azacitidine and Decitabine will answer 
the question of equivalence or superiority.  Both agents produce 
desirable clinical responses and are reasonable therapeutic tools, but 
given the documented benefits of improved OS and delayed time to 
AML in the current literature, azacitidine has a mild advantage. 
However, the higher rates of CR seen in the newer dosing schedule of 
Decitabine make this an attractive agent when the goal of therapy is 
disease response in preparation for next steps, such as transplant, and 
not necessarily as the definitive therapy. 
2.1.2 Histone Deacetylase Inhibitor (HDACi) use in MDS 
Epigenetic modulation through histone acetylation is another area of 
intense interest in cancer therapy, and specifically in the myeloid 
malignancies. Numerous HDAC inhibitors (ex. MS-275, sodium 
phenylbutyrate, Valproic acid, and Vorinostat, MGCD0103) have been 
studied extensively in AML and MDS with proposed effects on 
proliferation, differentiation, and apoptosis. 26-32 Response rates with 
single agent use of HDAC inhibitors has generally been low at 10-20%. 32 
Dose limiting toxicities have been relatively common regardless of the 
HDAC inhibitor used and typically involve fatigue, nausea, vomiting, and 
diarrhea. Interestingly, while increases in histone acetylation have been 
documented in the majority of early phase studies, the clinical responses 
have not always correlated directly, indicating the possibly of additional 
mechanisms of action. Because of the relatively low single agent response 
rates as well as biologic rationale for combination with other drugs,  these 
agents have been subtantially investigated in the combination setting with 
DNA methyltransferase inhibitors in the AML/MDS and is reviewed 
extensively in recent publications. 32, 33  
2.1.3 Vorinostat Use in MDS 
Vorinostat has been shown to be a popular HDAC inhibitor used in studies 
with MDS and AML. In early, Phase I testing of single agent Vorinostat 
(SAHA) in MDS/AML patients evaluating the MTD and safety profile 
(200mg BID versus 250mg TID - dose divided for improved histone 
acetylation) yielded an overall response rate appoximating 17% across 
doses. 26  Subsequent studies combining Vorinostat at various dosing 
regiments with either azacitidine or Decitabine reported a wide range of 


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responses from 16-86%, as reviewed in a recent publication by Quintas-
Cardama et al. 33  The variable response highlights the uncertainty of best 
dosing combination and the need for continued work utilizing this 
promising platform.  
 
2.1.4 Vorinostat Use as an Immunosuppressant  
Vorinostat has also recently been cited as a possible immune modulating 
drug as evidence by elegant mouse work published by Reddy at al. In 
their mouse models of acute graft versus host disease of allogeneic stem 
cell transplnation,  they showed that administration of Vorinostat soon 
after infusion of allogeneic stem cells, diminished inflammatory cytokines 
and subsequent development of acute graft versus host disease, while not 
impairing T cell responses to host antigens after transplant. 34 
2.2 
History of Adoptive NK Cell Therapy for Refractory/Relapsed AML at 
the U of MN  
Using the platform of lymphodepletion with cyclophosphamide, fludarabine 
with subsequent infusion of CD3 depleted haploidentical natural killer cells 
and subsequent high dose IL-2 administration, we have treated total of 32 
high risk refractory AML patients with the exact same therapy and NK cell 
enriched products at the University of Minnesota.  A total of 10 of these 
patients achieved a complete remission.  Of the ten patients achieving a 
remission three went on to get a subsequent allogeneic transplant and all 
had 2-year disease free survival. 35Three patients died of toxicity.  Four 
patients who were ineligible to go on to allogeneic transplant ultimately 
relapsed four to eleven months after achieving remission under this 
protocol. Morbidity associated with this regimen included a very prolonged 
hospital stay, on average of 4-6 weeks, as well as high fevers, capillary 
leak with pulmonary edema and peripheral edema, renal toxicity, etc with 
the high doses of IL-2 used. However, important to note that prolonged 
hospital admissions with potential higher toxicity is not uncommon for AML 
patients undergoing salvage chemotherapy. Although the outcomes were 
relatively favorable for patients with refractory leukemia, the transient 
nature of response in the absence of definitive therapy such as stem cell 
transplant and the associated high morbidity indicates that this adoptive 
cell therapy in its current form was not curative, at least in AML, and would 
likely be too high risk for an older cohort of MDS patients.  
In Vivo Expansion Correlates With Increasing The Intensity Of 
The Preparative Regimen 
Data from prior studies described in the section above suggest that those 
patients who achieved a remission with were those who expanded NK 
cells in vivo. In the subsequent trial,  MT2003-23, total body irradiation 
(TBI, 400 cGy) was added to cyclophosphamide and fludarabine (Cy/Flu) 
and we compared the rates of in vivo NK cell expansion (defined as 100 
donor derived NK cells/µL blood) and leukemia clearance (defined as less 
Fig. 2 


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1% blasts in the bone marrow). 
Using this approach (n=13), 
successful in vivo expansion of 
adult donor NK cells was 
detected in 75% of patients 
with a mean of 606±184 
circulating donor derived NK 
cells/µL blood 14 days after the 
adult NK cell infusion 
compared to a rate of only 10% 
in patients receiving Cy/Flu 
alone under the predecessor of 
this protocol, MT2004-25 
(Figure 1). In vivo expansion correlated with leukemia clearance. 
2.3 
Rationale for Proposed Study 
Based on the high single agent efficacy of Decitabine as a standard initial 
MDS therapy, the numerous studies suggesting a synergistic anti-tumor 
effect in MDS with HDAC inhibitor Vorinostat, and the potential 
immunosuppressive impact of Vorinostat, we propose the following 
therapeutic platform. Sequential Decitabine and Vorinostat will provide the 
basis for both a disease specific therapeutic and immunosuppressive 
conditioning regimen to allow for transient host acceptance of donor NK 
cells for added anti-tumor effect. Dosing of sequential Decitabine (10 
mg/m2 Days 1-5) and Vorinostat therapy (200 mg twice daily Days 6-15) is 
based on Phase I studies of the combination detailing the best delivery 
and tolerance of the combination with the fewest treatment delays 36 and 
early phase studies identify responses in MDS and AML patients. 37,38 
After haploidentical NK infusion, subsequent lower dose IL-2 will be given 
to promote NK cell expansion and predicted anti-tumor effect. The less 
intense conditioning regimen and IL-2 cytokine therapy is predicted to be 
more tolerable in an older population of patients and feasible in the 
outpatient setting. However, given the diminished intensity of the regimen, 
and the need for subsequent cycles of hypomethylating agent therapy to 
observe consistent clinical responses in the general practice setting, the 
study will consist of 2 consecutive courses (cycles) of therapy.   
 
 
3.0 
Study Design 
This is a Phase II therapeutic trial combining Decitabine days 1-5 with oral 
Vorinostat twice daily days 6-15 followed by a single infusion of CD3-/CD19- 
enriched donor NK cells on day 17 and a short course of Interleukin-2 (IL-2) to 
facilitate NK cell survival and expansion.  Two courses of treatment will be given 
separated by 6 - 8 weeks.  Clinical response will be formally assessed 4 - 6 
weeks after the 2nd course based on International Working Group (IWG) criteria; 
Fig. 1 


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however, a bone marrow evaluation will be done if the patient is taken off 
treatment prior to study completion.  The intent is to administer all treatment 
in the outpatient setting. 
 
The trial will use Simon’s two-stage design.  Fifteen patients will be enrolled in 
stage 1.  If 6 or more of the patients achieve an objective clinical response (CR + 
PR + hematologic improvement (HI)), stage 2 will be activated and an additional 
31 patients enrolled for a total of 46 evaluable patients.  Considering a predicted 
dropout rate of 10% during the two courses of therapy, stage 1 will need a 
maximum of 17 patients or a maximum of 51 patients if the study proceeds to 2nd 
stage. 
 
Research and related correlative studies will be done at baseline, between 
courses 1 and 2, and after completion of course 2 as per section 8.1.2. 
 
 
4.0 
Selection of Patients 
Study entry is open to adults regardless of gender or ethnic background.  While 
there will be every effort to seek out and include females and minority patients, 
the patient population is expected to be no different than that of other studies of 
high risk myelodysplastic syndromes at the University of Minnesota and the 
Mayo Clinic. 
 
 
 
Inclusion Criteria: 
4.1 
Diagnosis of high risk MDS that meets one of the following disease 
classifications and is requiring treatment: 
4.1.1 International Prognostic Scoring System (IPSS) Category: INT-2 or 
High Risk (see Appendix IV) 
4.1.2 International Prognostic Scoring System- Revised (IPSS-R) 
Category: High or Very High (Score of 5 or above) (Appendix IV) 
4.1.3 WHO Classification: RAEB-1 or RAEB-2 (Appendix V) 
4.1.4 WHO Classification: CMML that is not highly proliferative; WBC < 
15k 
4.1.5 High risk cytogenetic abnormality as defined by presence of 
Monosomy 7, complex karytope, or monosomal karyotype 
4.1.6 Therapy related MDS 
4.1.7 Severe cytopenias: Neutropenia (ANC ≤ 0.8), platelet or PRBC 
transfusion dependent 
4.1.8 WHO Based Prognostic Scoring System (WPSS): High or Very 
High Risk (Appendix V) 
4.2 
Prior Treatment: 
4.2.1 Untreated/Minimally Treated:  maximum of 2 cycles of 
hypomethylating agents (azacitidine or decitabine) without evidence 
of treatment failure as defined by progression to more advanced 
MDS Who classification or AML.   


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4.2.2 Treatment Failure:  Patients who have not responded to or whose 
disease has progressed on hypomethylating agents (azacitidine or 
decitabine), 7+3 type induction chemotherapy, or 
immunosuppressive therapy such as ATG+CSA. 
4.2.3 Patients must not have received treatment for their MDS within 4 
weeks of beginning this study.  
4.3 
Age ≥ 18  years of age 
4.4 
ECOG Performance Status 0-2  (Appendix III) 
4.5 
Available related HLA-haploidentical NK cell donor by at least Class I 
serologic typing at the A&B locus  
4.6 
Have acceptable organ function as defined below within 14 days (28 days 
for cardiac) of enrollment: 
Renal:  Creatinine:  ≤ 2.0 mg/dL 
Hepatic: SGOT/SGPT < 5 x upper limit of institutional normal (ULN)   
Pulmonary:  oxygen saturation ≥ 90% on room air  
Cardiac: LVEF by ECHO or MUGA ≥ 40%, no uncontrolled angina, severe 
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of 
acute ischemia or active conduction system abnormalities. QTc < 500 
msec 
4.7 
Ability to be off prednisone and other immunosuppressive drugs for at 
least 3 days prior to the NK cell infusion (excluding pre-meds) 
4.8 
Women of child bearing potential must agree to use effective methods of 
contraception (diaphragm, birth control pills, injections, intrauterine device 
[IUD], surgical sterilization, subcutaneous implants, or abstinence, etc.) 
from the time of signing the consent form and for 2 months after the last 
dose of chemotherapy.   
4.9 
Voluntary written consent before performance of any study-related 
procedure not part of normal medical care, with the understanding that 
consent may be withdrawn at any time without prejudice to future medical 
care. 
Exclusion Criteria: 
4.10 Pregnant or lactating. The agents used in this study are known to be 
teratogenic to a fetus and there is no information on the excretion of 
agents into breast milk. Confirmation that the patient is not pregnant must 
be established by a negative pregnancy test result obtained during 
screening. Pregnancy testing is not required for surgically sterilized or 
post-menopausal women.  
4.11 New progressive pulmonary infiltrates on screening chest x-ray or chest 
CT scan that has not been evaluated with bronchoscopy (when feasible)  
4.12 Uncontrolled bacterial or viral infections - chronic asymptomatic viral 


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hepatitis is allowed 
4.13 Pleural effusion moderate to large in size that are detectable on chest x-
ray 
4.14 Known hypersensitivity to one or more of the study agents  
4.15 Prior hypomethylating treatment greater than 2 cycles or with documented 
treatment failure 
4.16 Prior use of histone deacetylase inhibitors  
4.17 Serious medical or psychiatric illness likely to interfere with participation in 
this clinical study in the opinion of the enrolling investigator 
4.18 Inability to swallow capsules 
4.19 Active HIV  
4.20 Other active and potentially life threatening malignancy excluding localized 
basal or squamous cell skin cancer, cervical carcinoma in situ, superficial 
bladder cancer, localized prostate cancer 
 
5.0 
Donor Selection 
5.1 
Related donor (sibling, parent, offspring, parent or offspring of an HLA 
identical sibling) 18-75 years of age  
5.2 
At least 40 kilograms body weight 
5.3 
In general good health as determined by the evaluating medical provider 
5.4 
HLA-haploidentical donor/recipient match by at least Class I serologic 
typing at the A&B locus 
5.5 
Able and willing to undergo apheresis  
5.6 
Not pregnant 
5.7 
Voluntary written consent 
 
6.0 
Patient/Donor Enrollment (On Study) 
Enrollment onto the study will occur after the patient has signed the patient 
consent and eligibility is confirmed, but before any treatment has been 
administered.  Any patient signing consent, but not registered in the study, will be 
recorded as a screen failure in the screening log as detailed in the study’s 
Affiliate Manual.   
 
To be eligible for enrollment to this study, the patient must meet each criteria 
listed on the eligibility checklist based on the eligibility assessment documented 
in the patient’s medical record.  The eligibility checklists (patient - Appendix I, 


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donor – Appendix - II) can be found under attachments within the study in 
OnCore. 
 
6.1 
Registration with Masonic Cancer Center Clinical Trials Office 
Upon completion of the screening evaluation, eligibility checklist and 
obtaining consent, the site study coordinator or designee will enroll the 
patient and donor into OnCore.  The patient will be considered “on study”.  
Complete registration information is found in the study’s Affiliate Manual. 
 
OnCore will automatically generate an email alerting key study personnel 
of the registration. 
 
6.2 
Patients Who Do Not Begin Study Treatment 
If a patient is registered on study, and is later found not able to begin the 
preparative regimen (beginning with the first dose of decitabine), for 
whatever reason, the patient will be removed from study and treated at the 
physician’s discretion.  The patient will be considered a screen/baseline 
failure and the reason for removal from study will be clearly indicated in 
OnCore as detailed in the study’s Affiliate Manual.  The patient will be 
replaced. 
 
If a patient begins treatment, and then is discontinued for whatever 
reason, the patient will be replaced as the clinical response (CR + PR + 
HI) is not evaluable for response. If the patient discontinues therapy due to 
toxicity, it will count towards the toxicity stopping rules.  The patient must 
be followed for any unresolved toxicity per section 7.10. 
 
 
7.0 
Treatment Plan 
Treatment is planned to be given in the outpatient setting and must begin on a 
Monday to avoid weekends.  The administration of the study drugs will follow 
institutional drug and supportive care guidelines.  There will be no dose 
escalation or de-escalation except for IL-2 where modifications are allowed for 
unacceptable toxicity.     
Study Day 
Days of Week 
Study Drug 
Section of protocol 
Days 1-5 
Monday-Friday 
Decitabine 10 mg/m2 IV 
Section 7.1 
Days 6-15 
Saturday through 
the 2nd Monday 
Vorinostat 200 mg PO twice a day
Section 7.2 
Day 15 
Monday 
Donor apheresis (course 1 only) 
Section 7.3 
Day 16 
Tuesday 
Patient – rest 
Section 7.2 
Day 17 
Wednesday 
NK cell infusion 
Section 7.4 
Days 17, 
19, 22 
Wednesday, 
Friday, Monday 
IL-2 6 MU SQ beginning 2 hours 
after the NK cell infusion for 3 
doses 
Section 7.5 


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Repeat the treatment course 6 to 8 weeks later unless medically unsafe. 
Requirements for proceeding to course 2 are defined in Section 7.6. 
 
Clinical response will be formally assessed 4 - 6 weeks after the 2nd course 
based on International Working Group (IWG) criteria (Appendix VI); however a 
bone marrow evaluation will be done if the patient is taken off treatment early.  
7.1 
Decitabine (Days 1-5) 
Decitabine 10 mg/m2 will be administered as a 1 hour intravenous infusion 
days 1 through 5.   
7.2 
Vorinostat Administration (Days 6-15) 
Vorinostat will be taken at a dose of 200 mg (daily dose of 400 mg) twice 
daily with food for 10 days.  The capsules must be swallowed whole.  If a 
Vorinostat capsule is accidentally opened or crushed, the capsule or the 
powder must not be touched.  Patients will be provided with a daily drug 
log (appendix VIII) to record their vorinostat dosing as well as any side 
effects. 
 
Day 16 is a rest day with no treatment. 
7.3 
Donor Apheresis (Day 15 Course 1 Only) and Cell Product 
Manufacturing 
Peripheral blood cells will be collected by a single apheresis from the 
haploidentical related donor on day 15 of course 1 only (Monday). 
Apheresis collections will be performed on the Amicus Apheresis system 
(Fenwal Inc., Lake Zurich IL, USA) and will use a fixed time of 5 hours with 
a flow rate of 65 ml/min.  The cycle volume of 1400 ml (manufacturer 
recommendation) will be used.  Anticoagulant will consist of either ACD-A 
or heparin/ACD-A. 
 
Cell product manufacturing will be performed at the University of 
Minnesota Molecular and Cellular Therapeutics (MCT) laboratory.  Mayo 
Clinic will utilize overnight courier services.39  The apheresis product and a 
tube of donor blood (2ml EDTA) will be sent from Mayo Clinic by overnight 
courier the day of collection (day 15).  Refer to the Affiliate Laboratory 
Manual regarding shipping specifics. 
 
At MCT, the apheresis product will be enriched for NK cells with the large-
scale CliniMacs device (Miltenyi) by depletion of CD3+ cells to remove T-
lymphocytes and depletion of CD19+ cells to remove B-lymphocytes.  The 
NK cell product will then be divided in two with half stored frozen at MCT 
until day 17 of course #2. 
  


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The remaining NK cell enriched product will be activated by incubation 
with 1000 U/ml IL-2.   
 
For U of MN patient products, the cells with IL-2 will be processed with lot 
release testing per the CMC but held for infusion until the morning of day 
17. 
 
For Mayo patient products, the cells with IL-2 will be shipped to Mayo’s 
cell product lab on day 16 by overnight courier for arrival the morning of 
day 17.  Partial lot release testing on the pre-IL-2 product including sterility 
testing (Gram stain, endotoxin), cell viability, flow cytometry analysis will 
be performed prior to shipping the cells to Mayo.  Results will be 
confirmed with Mayo prior to the NK cell product infusion. 
 
At Mayo, the cells will be washed and final lot release performed.   
 
Samples for TTL in association with original cell production/infusion 
#1: 
A sample of the cell product will be sent from MCT to the Masonic Cancer 
Center’s Translational Therapy Lab (TTL) for cell function and phenotype 
studies from the following samples: 
1)  the apheresis unit before processing (100 x 106 cells)  
2)  the post-column pre IL-2 incubation sample (10 x 106 cells) 
3)  the final IL-2 product (10 x 106 cells) 
 
Course #2 
The frozen NK cells will be thawed by MCT on day 16 and incubated with 
IL-2.  For Mayo patients, the cells with IL-2 will be shipped to Mayo’s cell 
product lab by overnight courier for arrival the morning of day 17. On day 
17, the institutional cell product laboratory will wash and release for 
infusion according to the CMC for infusion on day 17 of the 2nd treatment 
course.   
 
Samples for TTL in association with infusion #2: 
A sample of the cell product will be sent to the Masonic Cancer Center’s 
Translational Therapy Lab (TTL) at the following time points:    
1)  the post thaw, pre IL-2 incubation sample (10 x 106 cells) 
2)  the final IL-2 product (10 x 106 cells) 
 
 
Refer to the chemistry, manufacturing and control (CMC) section of the 
Investigational New Drug (IND) application for additional preparation 
information and lot release criteria.   


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7.4 Allogeneic CD3- CD19- Selected NK Cell Product Infusion (Day 17) 
Pre-medication:  Patients should be pre-medicated with acetaminophen 
650 mg PO and/or diphenhydramine 25 mg PO/IV within 1 hour before 
and 4 hours after the NK cell infusion.  Demerol 25-50 mg IV may be given 
for chills/rigors during the NK cell infusion. Corticosteroids must not be 
used. 
 
Infusion guidelines:  The NK cells will be infused without a filter or pump, 
slowly by gravity over at least 15 minutes but no longer than 1 hour.  The 
targeted infused cell dose of CD3- CD19- selected NK cell product is within 
the range of 2-3 x 107 cells/kg. However, cell infusion will proceed 
regardless of cell dose if prior defined product collection parameter of > 3-
fold NK cell enrichment between the apheresis and final products is met. 
Flush tubing on completion of the NK cells with normal saline to ensure all 
of the cells are infused. 
 
Vitals:  Obtain vital signs before the NK cell infusion, every 15 minutes 
during the infusion, and then every 30 minutes x 2, then pre routine. 
Monitoring time will total at minimum 2 hours after NK cell infusion. 
 
Monitoring:  Patients will be monitored for adverse effects of the NK cell 
infusion such as rash, acute allergic reaction, bronchospasm, respiratory 
distress, and acute vascular leak syndrome.  If life threatening acute 
reactions occur (defined as CTCAE grade 4 - life-threatening 
consequences; urgent intervention indicated), the infusion will be stopped.  
If grade 4 infusion reaction occurs refer to section 8.1.3 regarding testing 
for HAMA. 
 
Hydration will be administered per institutional guidelines.  Any elevation 
of metabolic monitoring will be treated with more aggressive hydration, 
while being attentive to fluid overload.   
 
Corticosteroids are to be avoided from the time of NK cell infusion 
through day 25.  If essential, low doses of steroids (e.g. 25 mg 
hydrocortisone) may be given as clinically indicated during this window.    
7.5 
IL-2 (begin day 17) 
Start subcutaneous IL-2 approximately 2 hours, but no earlier than 2 
hours, after the NK cell infusion in the absence of grade 4 infusion related 
toxicity.   
 
If the patient has experienced grade 4 infusion related toxicity and it 
resolves to grade 2 or better, the IL-2 may be started up to 48 hours after 
the NK infusion.  If no IL-2 is given, the patient will be replaced for 
statistical analysis. 
 


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IL-2 administration:  IL-2 will be given at 6 million units on days 17, 19 
and 22.  For patients weighing less than 45 kilograms, the IL-2 will be 
given at a dose of 3 million units/m2 on days 17, 19 and 22.  For the 
purposes of outpatient scheduling and/or possible delay in treatment start, 
dosing may be altered to avoid weekends as long as IL-2 is not given on 
consecutive days and completed within a week. 
 
Pre-medication with acetaminophen 650 mg PO and diphenhydramine 
25 mg PO/IV before and 4 hours after each dose of IL-2 is recommended.  
 
Monitoring during IL-2 administration:  Patients are monitored for IL-2 
related toxicities on a daily basis in clinic until the day after the final IL-2 
administration with increased monitoring as clinically required.   
 
IL-2 dose-adjustment for individual patient intolerance:  Fevers, rash 
and flu-like symptoms are expected and should be treated supportively 
with acetaminophen and diphenhydramine as described above.  If a 
patient cannot tolerate full dose IL-2 due to fevers, rash or constitutional 
symptoms, a dose decrease to 4 million units is allowed (2 million units/m2 
if < 45 kg).  If the patient cannot tolerate the reduced dose, the IL-2 must 
be permanently discontinued.  
 
IL-2 dosing guidelines for non-hematologic grade 3-4 toxicity 
(CTCAE v4):   
Non-hematologic grade 3 toxicity persisting for > 24 hours:  Hold IL-2.  If 
the toxicity resolves to grade 2 or better within 48 hours, the IL-2 can be 
resumed at a reduced dose (4 million units or 2 million units/m2 if < 45 kg).  
If the same toxicity persists, worsens or recurs, the IL-2 must be 
permanently discontinued.  Missed doses are not made up. 
 
Non-hematologic grade 4 toxicity: Permanently discontinue IL-2 
7.6 
Second Treatment Course 
Any patient who failed prior treatment (i.e. met section 4.2.2 of the 
eligibility criteria at enrollment) will have a bone marrow biopsy and 
aspirate performed prior to the start of the 2nd treatment course. 
 
A second treatment course will be given 6 to 8 weeks after the start of 
course 1, identical to the first course substituting the frozen NK cell 
product for the fresh product, unless medically unsafe. 
 
The following criteria must be met before a new treatment course is 
started: 
 ANC recovery to baseline documented prior to course 1  
 Platelet transfusion that can be managed safely in the outpatient 
setting   


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 Treatment related non-hematologic toxicity, except fatigue, 
alopecia, resolved to ≤ grade 2   
 Absence of rapid disease progression as defined in Section 7.10 
 
If the above requirements are not met, delay and reassess weekly until 
recovery occurs.  If more than 2 weekly delays occur (>8 weeks from the 
start of course 1) without hematological recovery and/or non-hematologic 
treatment related toxicity resolution, the patient will be taken off study.  A 
bone marrow biopsy will be done to assess response to the therapy up to 
that point or to determine etiology for inadequate recovery of counts. 
7.7 
Dose Modifications 
There are no planned dose modifications or delays except as detailed in 
section 7.5 in association with the IL-2 administration. 
Note: If patients required dose modification of IL-2 during course 1 then the 
modified dose should be used for course 2. 
7.8 
Management of Selected Toxicities Associated with NK Cell Infusion  
See Appendix VII for expected toxicities of Decitabine, Vorinostat and 
Interleukin-2.  
7.8.1 Acute Allergic Reaction Secondary to the Infusion of 
Allogeneic NK Cells 
Although infusion of donor lymphocytes has not been associated 
with acute allergic reactions, patients will be closely watched for the 
occurrence of hypotension, dyspnea and angioedema during and 
immediately after the infusion.  
 
The NK cell infusion will be stopped if severe acute reactions 
occurs (defined as CTCAE grade 4 - life-threatening 
consequences; urgent intervention indicated).  A blood sample will 
be collected for HAMA testing per section 8.1.3.    
7.8.2 Vascular Leak Syndrome 
Neither administration of allogeneic NK cells nor autologous IL-2 
activated NK infusions have been associated with vascular leak 
syndrome in our previous experience.  Nevertheless, patients will 
be monitored for weight gain (by weights at least 3 times per week) 
and pulmonary edema during IL-2 administration. 
7.8.3 Tumor Lysis Syndrome 
Allopurinol will be initiated to according to standard medical 
practice when the risk of tumor lysis is high.   


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7.8.4 Prolonged Marrow Suppression 
Hematologic toxicity due to allogeneic NK cells may occur later, 
and therefore hematologic recovery will be assessed beyond the 
expected chemotherapy-induced nadir.   
 
Pancytopenia will occur with this regimen and should be treated as 
follows: 
 
Anemia and thrombocytopenia are expected in all patients, and 
they will receive standard supportive transfusion care according to 
transfusion committee guidelines or as modified based on clinical 
parameters. Prolonged anemia or thrombocytopenia are not 
unexpected and will not count towards toxicity.  
 
Neutropenia is expected in the majority of patients, and they will 
receive supportive care with prophylactic antibiotics as noted 
below. G-CSF and granulocytes should be avoided unless clinically 
indicated in the setting of severe, uncontrolled infection.  If the 
clinical situation warrants growth factor use, then any remaining IL-
2 administration will be stopped.  
7.9 
Supportive Care Guidelines/Concomitant Medication Use 
Patients will receive standard supportive care according to institutional 
guidelines or as modified based on clinical parameters.  
 
Antiemetics will be used according to standard medical practice. Given the 
modest incidence of nausea, diarrhea, and anorexia with the drug 
combination, scheduled prophylactic antiemetics will be given during Day 
1-15 of therapy. 
 
All patients will receive antibacterial prophylaxis and antifungal therapy 
while neutropenic (until ANC >1000 x 2 days).  Antibacterial options 
include but are not limited to levofloxacin, azithromycin, Pen V K and 
antifungal options include fluconazole, voriconazole, posaconazole as 
indicated. Choice of antibiotics is left to the discretion of the treating 
physician. Antiviral therapy and trimethoprim/sulfa for PCP prophylaxis are 
not required unless clinically indicated. 
7.10 Duration of Therapy 
Patients will receive two courses of study treatment unless one or more of 
the following occurs: 
 Patient withdraws consent or is non-compliant 
 Criteria in section 7.6 for a 2nd treatment course are not met 
 Medically unsafe, in the opinion of the treating investigator to continue 
with the treatment plan and based on development of grade 4 non-
hematologic toxicities 


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 Intercurrent illness that prevents further administration of treatment 
 Unacceptable toxicity 
 Evidence of rapid disease progression defined as ≥ 20% peripheral 
blood blast percentage suggesting progression to acute leukemia 
 
 
Any patient who discontinues therapy before the completion of 2 courses 
should have a bone marrow biopsy and aspirate performed at the time 
treatment is discontinued.  Those who are not evaluable per section 13 
will be followed only until the resolution or stabilization of treatment related 
toxicity.  No further follow-up for this study will be required, other than 
recording the date and cause of death upon knowledge in OnCore. 
7.11 Follow-up 
All evaluable patients will be followed for response and survival for 1 year 
from study enrollment unless the patient withdraws consent. 
 
Ongoing therapy with maintenance hypomethylating agents or proceeding 
to allogeneic stem cell transplantation will be at the discretion of the 
patient’s primary oncologist. 
 
For patients completing 1 year of follow-up no further data collection will 
be required for this study; however the date and cause of death will be 
entered in OnCore upon knowledge for IND annual reporting.  
 
An exception to this for all patients is the reporting upon knowledge of any 
serious, unexpected and at least possibly study treatment related event 
per sections 11.3 and 11.4.   
 
 
8.0 
Study Calendar 
The pre-treatment work-up must occur within 28 days (14 days for CBC, diff, 
CMP, and chemistries) of treatment start unless otherwise noted.  Scheduled 
evaluations (including research samples) up to day +22 may be performed +/-1 
day from the targeted date; evaluations and procedures (including research 
samples) performed after day +28 may be done +/-3 days of the targeted date.  
Follow-up for survival may be done +/- 4 weeks of the targeted date. In addition, 
targeted days may be altered as clinically appropriate. 
 
 


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8.1 Patient  
8.1.1 Standard of Care and Investigational Treatment 
 
Pre-
Treatment 
(within 28 
days of 
treatment 
start)* 
During each treatment course 
4- 6 
weeks 
after 2
nd 
treatment 
course 
Follow-up 
at Day 90, 
180, 270, 
360  
Day 
1
1 
Day 
5 
Day 
15 or 
17 
During IL-2 
administration 
(Day 17-22) 
Day 24, 
31, 38, 45 
EVALUATIONS 
Written consent 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Disease Characteristics  
X 
 
 
 
 
 
 
 
Pathology review of outside dx 
X 
 
 
 
 
 
 
 
Transfusion History  
X 
 
 
 
 
 
X 
 
Concomitant meds  
X 
X 
 
 
 
 
X 
 
Physical exam 
X 
X 
X
6
X
6 
X
6 
X
6 
X 
 
Vital signs 
X 
X 
 
X 
 
X 
 
 
Weight 
X 
X 
 
X 
3 x a week 
during IL-2 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
ECOG Performance Status  
X 
X 
 
 
 
 
X 
 
Survival Status 
 
 
 
 
 
 
 
X
7
LABORATORY 
CBC w/ diff
2 
X 
X 
X 
X 
daily during 
IL-2 
X 
X 
 
Na, K, Cl, CO2, BUN, creatinine, 
uric acid, phos, LDH, Mg 
X 
X 
X 
X 
X 
 
 
ALT/AST, bili, total protein, 
albumin, alk phos 
X 
X 
 
X 
 
X 
 
 
Chest X-ray  
X 
 
 
 
 
 
 
 
INR/PTT
 
X 
 
 
 
 
 
 
 
Pregnancy test
3 
X 
 
 
 
 
 
 
 
HLA typing (low resolution)* 
X 
 
 
 
 
 
 
 
Recipient Viral Serology 
X 
 
 
 
 
 
 
 
ECHO/MUGA* 
X 
 
 
 
 
 
 
Bone Marrow Bx/Asp
4 
X
4
 
 
 
X
5 
X
4 
 
Investigational TREATMENT 
Decitabine IV 
 
Day 
1-5 
 
 
 
 
 
 
Vorinostat PO 
 
 
Day 
6-15 
 
 
 
 
 
NK cell infusion (research) 
 
 
 
Day 
17 
 
 
 
 
IL-2 tiw for 3 doses (research) 
 
 
 
 
X  
(start Day 17) 
 
 
 
* CBC, dff, CMP, chemistries within 14 days of study treatment start, HLA typing may be done at any time 
1- 
Course 1 Day 1 evaluations need not be repeated if pre-study evaluations were done within 14 days of 1st 
treatment 
2- 
CBC with diff weekly throughout all treatment with increased frequency as clinically indicated 
3- 
Women of childbearing potential only; serum or urine 
4- 
Bone marrow aspirate and biopsy with standard flow cytometry, conventional cytogenetics, and MDS/AML 
FISH panel will be conducted at study initiation and at the completion of the 2nd cycle for standard disease 
assessment or at time of study withdrawal if early termination.  
5- 
Prior to course 2 ONLY in patients who enrolled in this study as a prior treatment failure per section 4.2.2 or 
any patient who is discontinuing study treatment after 1 course 
6- Clinical assessments will occur at a minimum of weekly up until the NK cell infusion on Day +17 after which 
clinical assessments will occur daily until the day after the final IL-2 administration. 
7- By record review, patient contact, etc.  
 


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8.1.2 Patient – Research Related 
 
 
Before 
start of 
each 
chemo 
course 
Before 
NK cell 
infusion 
 
After each treatment course 
Day 17 
Day 
24 
Day 
31 
Day 
38 
Day 
45
3 
Adverse Event Monitoring 
Per section 11 
Chimerism – PB 
(unseparated)* 
x 
 
x 
x
1 
x
1 
x
1 
60 ml of heparinized blood (green 
top tubes)* 
x 
x 
x 
x 
x 
x 
10 ml of serum (red top tube)* for 
HAMA
2 
 
x (post 
infusion) 
 
 
 
 
10 ml of serum (red top tube)* 
x 
x 
x 
x 
x 
x 
BM 30 ml
  (heparinized)* 
At the time of each bone marrow biopsy for clinical 
reasons 
1 – continue chimerism monitoring until they disappear 
2 –draw sample in the event of a grade 4 infusion related toxicity occurs – refer to section 8.1.3 
3 – the day 1 treatment course 2 sample may be eliminated if the patient is ready to start course 2 at 
day 45 
*For the Cancer Center’s Translational Therapy Lab (TTL) – refer to section 8.3 for shipping 
instructions. (U of MN chimerism samples to be sent directly to the Molecular Diagnostics) 
 
As recognized with novel therapies, as in this study, the timing of protocol 
directed research samples may miss important patient specific events.  
For this reason, up to 3 extra samples for a total of 180 ml of blood may 
be drawn at additional time points that are not specified above.   
8.1.3 Assessment for HAMA in the Event of a Grade 4 Infusion 
Reaction 
If a patient experiences a CTCAE v 4 grade 4 infusion related 
reaction (life-threatening consequences; urgent intervention 
indicated) serum will be drawn and be tested for the presence of 
HAMA.  If HAMA is detected, the results will be reported to the FDA 
in an expedited manner per section 11.4.  If not, it will be noted at 
the time of the IND annual report.     
 
 


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8.2 
Donor – Research Related 
 
Screen 
Day 15 
Consent 
X 
 
HLA Typing (class 1)  
SOC - not research 
X 
 
Type and Screen (ABO/RH 
/Indirect Antiglobulin) 
X 
X 
Donor Infectious Disease Panel 
X 
X1 
EBV IgG 
X 
 
BMT/DNA marker 
X 
 
Medical History 
X 
 
Physical Exam 
X 
X 
CBC, diff, platelet  
X 
X 
ALT, creatinine 
X 
 
Pregnancy test, if applicable 
X 
 
60 ml of heparinized blood (green 
top tubes)* 
 
X 
10 ml of serum (red top tube)* 
 
X 
Leukapheresis 
 
X 
1 -  repeat if more than 7 days since baseline testing 
*For the Cancer Center’s Translational Therapy Lab (TTL) – refer to section 8.3 for shipping 
instructions. 
8.3 
Sample Shipping Information 
Samples are shipped the day of collection to the Masonic Cancer Center’s 
Translational Therapy Lab (TTL) for overnight delivery in an insulated 
container with a frozen gel pack Monday-Thursday.  Refer to the Affiliate 
Laboratory Manual for additional details. 
 
Translational Therapy Core Facility 
University Of Minnesota 
420 Delaware St. SE 
Room A410 Mayo Building 
Minneapolis, MN 55455 
Phone: 612-625-6165 
Fax: 612-625-9631 
 
 
9.0 
Study Endpoints 
 
This study is designed as a two stage study of the combination of Decitabine and 
Vorinostat and haploidentical NK cell infusion. The primary endpoint is clinical 
response (CR + PR + HI) at the end of the required 2 cycles of therapy. An 
assessment of response differences between untreated/minimally treated and 
those with prior treatment failures will be conducted. 


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The secondary endpoints include evaluation of safety tolerability, the proportion 
of patients who become transfusion independent, the association of the in vivo 
NK cell expansion with clinical response, and 1 year Overall Survival.  
 
Clinical responses are defined in Appendix VI. 
 
Determination of toxicities will be important for this new combination. As per NCI 
CTCAE Version 4.0, the term toxicity is defined as adverse events that are 
classified as either possibly, probably, or definitely related to study treatment.  
The maximum grade for each type of toxicity will be recorded for each patient, 
and frequency tables will be reviewed to determine toxicity patterns.  In addition, 
we will review all adverse event data that is graded as 3, 4, or 5 and classified as 
either “unrelated or unlikely to be related” to study treatment in the event of an 
actual relationship developing.  
 
 
10.0 Drug Formulation And Procurement 
10.1 Decitabine 
 
10.1.1 Other Names 
Dacogen 
 
10.1.2 Classification   
Antineoplastic 
 
10.1.3 Mode of Action 
May cause hypomethylation of DNA and cellular differentiation or 
apoptosis by phosphorylation and direct incorporation into DNA. 
 
10.1.4 Metabolism 
Routes of decitabine metabolism and elimination are unknown. 
Elimination of decitabine is believed to occur through deamination 
by cytidine deaminase. The effects of renal or hepatic impairment 
on decitabine pharmacokinetic parameters have not been studied. 
 
10.1.5 Storage and Stability 
Store vials at 25°C (77°F); excursions permitted to 15 - 30°C (59 - 
86°F).   
 
Unless used within 15 minutes of reconstitution, the diluted solution 
must be prepared using cold (2°C - 8°C) infusion fluids and stored 
at 2°C - 8°C (36°F - 46°F) for up to a maximum of 7 hours until 
administration. 
 


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10.1.6 Dose Specifics 
For the purposes of this study, decitabine will be given at a dose of 
10 mg/m2 on days 1-5 of each treatment course. 
 
Decitabine for Injection is supplied as a sterile lyophilized white to 
almost white powder, in a single-dose vial, packaged in cartons of 1 
vial. Each vial contains 50 mg of decitabine. 
 
10.1.7 Preparation 
Decitabine is a cytotoxic drug and, as with other potentially toxic 
compounds, caution should be exercised when handling and 
preparing decitabine. 
 
Decitabine should be aseptically reconstituted with 10 mL of Sterile 
Water for Injection (USP); upon reconstitution, each mL contains 
approximately 5.0 mg of decitabine at pH 6.7-7.3. Immediately after 
reconstitution, the solution should be further diluted with 0.9% 
Sodium Chloride Injection, 5% Dextrose Injection, or Lactated 
Ringer’s Injection to a final drug concentration of 0.1 - 1.0 mg/mL.  
 
Unless used within 15 minutes of reconstitution, the diluted solution 
must be prepared using cold (2°C - 8°C) infusion fluids and stored 
at 2°C - 8°C (36°F - 46°F) for up to a maximum of 7 hours until 
administration. 
 
10.1.8 Administration 
Patients may be pre-medicated with standard anti-emetic therapy 
per institutional guidelines. 
 
10.1.9 Availability 
Commercially available 
 
10.1.10 Side Effects 
Pregnancy category D 
Decitabine may cause fetal harm when administered to a pregnant 
woman. Women of childbearing potential should be advised to 
avoid becoming pregnant while using Decitabine. Men should be 
advised not to father a child while receiving treatment with 
Decitabine, and for 2 months afterwards. 
 
The most commonly occurring adverse reactions include 
neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, 
cough, petechiae, constipation, diarrhea, and hyperglycemia. 
 


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10.2 Vorinostat (SAHA) 
 
10.2.1 Other Names 
Suberoylanilide hydroxamic acid, zolinza 
 
10.2.2 Classification   
Histone deacetylase (HDAC) inhibitor 
 
10.2.3 Mode of Action 
Inhibits the enzyme histone deacetylase (HDAC), induces 
differentiation in some cell types, and has been shown to induce 
p53-independent apoptosis 
 
10.2.4 Metabolism 
The major pathways of Vorinostat metabolism involve 
glucuronidation and hydrolysis followed by β-oxidation.  In vitro 
studies using human liver microsomes indicate negligible 
biotransformation by cytochromes P450 (CYP). 
 
10.2.5 Elimination 
Vorinostat is eliminated predominantly through metabolism with 
less than 1% of the dose recovered as unchanged drug in urine, 
indicating that renal excretion does not play a role in the elimination 
of Vorinostat. 
 
10.2.6 Storage and Stability 
Store it at room temperature and away from excess heat and 
moisture. 
 
10.2.7 Dose Specifics 
For the purposes of this study, the Vorinostat dose will be 200 mg 
twice a day days 6-15 of each treatment course. 
 
10.2.8 Administration 
Swallow the capsules whole; do not open, chew, or crush them.  
Take with food same times each day.   
 
10.2.9 Availability 
Commercially available; however study funds may cover the cost of 
the drug if not paid for by the patient’s 3rd party payer. 
 
10.2.10 Drug Interactions 
Coumarin-derivative anticoagulants: Prolongation of prothrombin 
time and International Normalized Ratio have been observed with 
concomitant use. 
 


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10.2.11 Side Effects 
   Pregnancy category D 
Vorinostat can cause fetal harm when administered to a pregnant 
woman.  There are no adequate and well controlled studies of 
Vorinostat in pregnant women.  Results of animal studies indicate 
that Vorinostat crosses the placenta and is found in fetal plasma at 
levels up to 50% of maternal concentrations.  Doses up to 50 and 
100 mg/kg/day were tested in rats and rabbits, respectively (~0.5 
times the human exposure based on AUC 0-24 hours).  Treatment 
related developmental defects included decreased mean live fetal 
weights, incomplete ossification of the skull, thoracic vertebra, 
sternum, and skeletal variations (cervical ribs, supernumerary ribs, 
vertebral count and sacral arch variations) in rats at the highest 
dose of Vorinostat tested.  Reductions in mean live fetal weight and 
an elevated incidence of incomplete ossification of the metacarpals 
were seen in rabbits dosed at 150 mg/kg/day.  The no observed 
effect levels for these findings were 15 and 50 mg/kg/day (<0.1 
times the human exposure based on AUC) in rats and rabbits, 
respectively.   
Common (Occurring in > 20%) : weight decrease, anorexia, 
diarrhea, nausea, altered taste sensation, fatigue, 
thrombocytopenia, muscle spasms 
Uncommon (in 5-19%):  peripheral edema, alopecia, pruritus, 
dizziness or headache, shivering, raised serum creatinine, cough, 
upper respiratory infection, anemia 
Rare: prolonged QT (3.5 – 6%), DVT/PE 
 
10.3 Interleukin-2 (IL-2) 
10.3.1 Other Names 
Aldesleukin (modified human recombinant interleukin-2) 
 
10.3.2 Classification   
Antineoplastic agent, Immunotherapy, Cytokine 
 
10.3.3 Category   
Biologic Response Modifier Agent 
 
10.3.4 Mechanism of Action 
• Systemic: Aldesleukin has been shown to possess the biological 
activity of human native interleukin-2. In vitro studies performed 
on human cell lines demonstrate the immunoregulatory 
properties of aldesleukin, including:  


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 Enhancement of lymphocyte mitogenesis and stimulation 
of long-term growth of human interleukin-2 dependent 
cell lines;  
 Enhancement of lymphocyte toxicity;  
 Induction of killer cell (lymphokine-activated killer [LAK] 
cells and natural killer [NK] cells) activity; and  
 Induction of interferon-gamma production.  
• The in vivo administration of aldesleukin in select murine tumor 
models and in the clinic produces multiple immunological effects 
in a dose-dependent manner. These effects include activation of 
cellular immunity with profound lymphocytosis, eosinophilia, and 
thrombocytopenia, and the production of cytokines, including 
tumor necrosis factor, interleukin-1 and gamma interferon. In vivo 
experiments in murine tumor models have shown inhibition of 
tumor growth. However, the exact mechanism by which 
aldesleukin mediates its antitumor activity in animals and 
humans is unknown.  
• Aldesleukin causes a capillary leak syndrome (CLS) as a result 
of increased capillary permeability, leading to extravasation of 
plasma proteins and fluid into the extravascular space and 
contributing to loss of vascular resistance. Interleukin-2 has been 
reported to reversibly decrease serum cholesterol 
concentrations. Interleukin-2 has been reported to transiently 
decrease serum testosterone and dihydroepiandrosterone 
concentrations and to transiently increase plasma estradiol 
concentrations. It has also been reported to transiently increase 
adrenal secretion of ACTH and cortisol. 
 
10.3.5 
Metabolism 
Systemic: 85 min. 
 
10.3.6 
Dose Specifics 
For the purposes of this study, subcutaneous IL-2 6 million units 
per dose will be given on days 17, 19 and 22 of each treatment 
course.  Dose for patients weighing less than 45 kg:  3 million 
units/m2 per dose using the same schedule and route 
 
10.3.7 
Dose Forms and Strengths   
Lyophilized vials containing 22 million units of IL-2 
 
10.3.8 
Reconstitution and Syringe Preparation  
U of MN patients only (IL-2 for product activation plus 3 injections 
at 6 million units/dose):  
Reconstitute IL-2 vial with 1.2ml sterile water for injection 
Add 1.2ml 0.1% albumin in 5% dextrose to IL-2 vial 
Yield: 9 million units/ml solution.  


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Repeat with 2nd vial 
 
Using a 1ml syringe and 18 gauge needle, withdraw 0.56 ml IL-2 
from one vial.  
Add to an empty, sterile, 10ml vial 
Add 3.44ml 0.1% albumin in 5% dextrose. 
Yield 5 million units/4ml vial for pheresis product. 
 
Withdraw the remaining contents from the two IL-2 vials into a 
10ml syringe, using an 18 gauge needle. Pull the contents from 
the needle into the syringe. 
 
Attach a syringe tip connector to the 10ml syringe.  
Withdraw 0.72 ml dose into a 1ml syringe. Attach luer tip to 
syringe. Syringe contains a 0.05ml overfill to fill the needle when 
attached. 
 
Repeat for a total of 3 doses.   
 
Mayo Clinic patients only (IL-2 for pheresis product): 
To be prepared by University of Minnesota Medical Center, 
Fairview IDS 
 
IL-2 will be reconstituted and prepared by Using a 1ml syringe 
and 18 gauge needle, withdraw 0.56 ml IL-2 from one vial.  
Add to an empty, sterile, 10ml vial 
Add 3.44ml 0.1% albumin in 5% dextrose. 
Yield 5 million units/4ml vial for pheresis product. 
 
Mayo Clinic patients only (IL-2 preparation for patient use):  
To be prepared at the Mayo Clinic 
 
Reconstitute IL-2 vial with 1.2ml sterile water for injection 
Add 1.2ml 0.1% albumin in 5% dextrose to IL-2 vial 
Yield: 9 million units/ml solution 
 
Withdraw the contents from the IL-2 vial into a 10ml syringe, 
using an 18 gauge needle. Pull the contents from the needle into 
the syringe. 
 
Attach a syringe tip connector to the 10ml syringe.  
Withdraw 0.72 ml dose into a 1ml syringe. Attach luer tip to 
syringe. Syringe contains a 0.05ml overfill to fill the needle when 
attached. 
 


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Repeat for a total of 3 doses.  Label the last filled syringe with 
the actual dose and as dose #3, in the event this dose is short. 
 
10.3.9 Administration 
IL-2 will be administered as an outpatient for three doses no 
sooner than 2 hours after the NK cell infusion on day 17, and 
again on days 19 and 22.  Pre-medication with acetaminophen 
650 mg PO and diphenhydramine 25 mg PO/IV before and 4 
hours after each dose of IL-2 is recommended. 
 
10.3.10 Availability 
IL-2 will be provided for the purposes of this study. 
 
10.3.11 Warnings and Precautions 
 
patients with a history of cardiac disease exhibiting a normal 
thallium stress test 
 
patients with a history of pulmonary disease exhibiting 
normal pulmonary function tests 
 
severe hypotension (due to capillary leak syndrome) 
 
impaired neutrophil function (reduced chemotaxis) 
 
increased risk of disseminated infection 
 
kidney and liver function impairment (avoid concurrent 
administration with nephrotoxic or hepatotoxic drugs) 
 
mental status changes 
 
exacerbation of preexisting autoimmune diseases or initial 
presentation of autoimmune and inflammatory disorders 
 
may increase the risk of allograft rejection in transplant 
patients (due to enhancement of cellular immune function) 
 
cardiac, pulmonary, renal, hepatic, or central nervous 
system impairment 
 
patients with a history of seizures 
 
Pregnancy Category C 
 
 
11.0 Adverse Event Reporting 
Toxicity and adverse events will be classified according to NCI's Common 
Terminology Criteria for Adverse Events V 4.0 (CTCAE) and reported on the 
schedule below.   A copy of the CTCAE can be downloaded from the CTEP 
home page 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_
40).   
 
Note:  throughout this section the generic term “study drug” refers to the study 
related treatment (Vorinostat/Decitabine, NK cell infusions and IL-2 injections). 


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11.1 Definitions 
The following definitions are based on the Code of Federal Regulations 
Title 21 Part 312.32 (21CFR312.32(a)). 
  
 
Adverse Event:  Any untoward medical occurrence associated with the 
use of a drug in humans, whether or not considered drug related.  
 
Suspected Adverse Reaction:  Any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event.  
 
Life-Threatening Adverse Event Or Life-Threatening Suspected 
Adverse Reaction: An adverse event or suspected adverse reaction is 
considered “life-threatening” if, in the view of either the investigator or 
sponsor, its occurrence places the patient or subject at immediate risk of 
death. 
   
Serious Adverse Event Or Serious Suspected Adverse Reaction:  An 
adverse event or suspected adverse reaction is considered “serious” if, in 
the view of either the investigator or sponsor, it results in any of the 
following outcomes:  
 Death 
 A life-threatening adverse event 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions 
 A congenital anomaly/birth defect.  
 
Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  
 
If either the IND sponsor or the investigator believes the event is life-
threatening or serious, the event must be evaluated by the sponsor for 
expedited reporting (21CRF 312.32(a)).  
 
Unexpected adverse event or unexpected suspected adverse 
reaction: An adverse event or suspected adverse reaction is considered 
“unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or, if an investigator 
brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in 
the current application, as amended.  Thus, adverse events that occur as 
part of the disease process (including relapse/progress and death from 


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such) or underlying medical conditions are considered unexpected; 
however, they will not be reportable per section 11.4. 
 
Unanticipated (unexpected) problems/events as defined by the 
University Of Minnesota IRB are those that are not already described as 
potential risks in the consent form, not listed in the Investigator’s Brochure 
or not part of an underlying disease. 
 
Expedited (Rapid) Reporting: Certain events may require rapid 
notification to entities providing patient safety oversight (e.g. IRB, FDA) as 
detailed in section 11.4.  
11.2  Adverse Event Documentation 
Adverse events occurring after the initiation of any study treatment must 
be documented.  Adverse events attributed to a study-related procedure 
which occur prior to the initiation of study treatment must be documented 
as well.  Refer to appendix VII for a list of expected toxicities. 
 
For the purposes of this study, adverse event documentation requirements 
will be determined based on grade, expectedness and relationship to 
study therapy as follows: 
 
 
Grade 1 
Grade 2
Grade 3
Grade 4 and 5
Expected or 
Unexpected 
Expected 
Unexpected
Expected 
Unexpected 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not 
required 
Not required 
Not required 
Required 
Required 
Possible 
Probable 
Definite 
Not required 
Not 
required 
Required 
Required 
non-
hematological 
Required 
Required 
Not required - 
hematologic 
events  
 
All patients will be monitored from the initiation of any study treatment 
through day 45 after the last dose of study treatment or the start of a new 
treatment, whichever occurs earlier, as it is expected that most treatment 
related adverse events will occur during this period.  However, the 
investigator is obligated, upon knowledge of, to report any adverse event 
considered to be related to study treatment meeting the expedited 
reporting criteria in section 11.4. 
 
In addition, adverse event collection will include targeted adverse events 
and unexpected adverse events at specific time points in relation to the 
NK cell infusion and post NK cell infusion IL-2 injections.    
 


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Targeted adverse events (Appendix IX) and unexpected events will be 
collected at the following time points.  Adjust the day to match the time 
point description.  All time points are 24 hours +/- 2 hours.   
 Post-Chemo/Pre-NK cell infusion (day 17) 
 A single assessment 1-2 hours post NK cell infusion/pre IL-2 
injection (day 17) 
 pre IL-2 dose 2  
 pre IL-2 dose 3 
 48 hours post IL-2 dose 3 (or to coincide with day 24 clinic visit) 
 1 week after last IL-2 dose (or to coincide with day 31 clinic visit) 
 
At each time point, the worst grade of the targeted toxicity since the last 
assessment or the previous 24 hours (whichever is shorter) will be 
recorded in addition to any unexpected toxicities felt at least possibly 
related to the NK cells and/or the IL-2. 
 
In addition, although not always a reportable event, deaths will be 
recorded in OnCore upon knowledge in the follow-up tab. 
 
11.3 Required Reporting:  Mayo Clinic to the Masonic Cancer Center 
Serious events:  Beginning with the first dose of decitabine and continue 
through day 45 of the last treatment course, as an affiliate, Mayo will 
report all events meeting the definition of serious, regardless of attribution 
or expectedness, within 24 hours of knowledge of the event.  After day 45 
of the last treatment course, the investigator must report upon knowledge 
any event that is serious, unexpected and felt to be at least possibly 
related to study therapy.  
 
Reports are to be submitted to the Study Coordinator at the University of 
Minnesota Masonic Cancer Center (MCC) using the SAE reporting form 
found in OnCore.  The MCC Study Coordinator will facilitate reporting to 
the University Of Minnesota IRB and the FDA as required. 
 
 
 
Stopping rule events:  Any grade 4 or 5 non-hematologic, non-infectious 
toxicity occurring through day 45 of the last treatment course will count 
toward the early study stopping rule per section 13 and must be reported 
to the MCC Study Coordinator using the Early Stopping Rule Report Form 
found OnCore under the reports tab.   
 
No more than one excess toxicity event will be accumulated per patient 
within in the same episode of toxicity (i.e. a grade 4 event worsening to a 
grade 5 is a single event) or when multiple events occur concurrently.  
 
Events that count toward an early stopping rule do not necessarily 
constitute a serious adverse event requiring expedited reporting and 


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should be reported as such only if they meet the criteria for expedited 
reporting as defined in section 11.1. 
 
Lot release issues:  Any safety issues associated with the final lot release 
at the treating institution must be reported immediately to either Dr. Miller 
or Dr. Warlick at the University of Minnesota (contact information on page 
2) with follow-up reporting to MCC Study Coordinator using the Deviation 
Report found in OnCore. 
 
 
 
Affiliate institutions will be responsible for submitting reportable events to 
their institutional IRB and any other required local regulatory entities. 
 
11.4 Masonic Cancer Center Required Reporting: FDA, IRB, Miltenyi, and 
MCC’s SAE Coordinator 
The reporting period for this study is from initiation of any study treatment 
through day 45 of the last treatment course; however after day 45, the 
investigator must report upon knowledge any study treatment related 
event meeting the expedited reporting criteria below. 
 
Agency 
Criteria for reporting 
Timeframe 
Form to Use 
Submission address/ fax 
numbers 
Copy to: 
U of MN 
IRB 
Unanticipated death of a 
locally enrolled subject(s);  
New or increased risk; Any 
adverse event  that require a 
change to the protocol or 
consent form – refer to the 
IRB website for complete 
details 
 
5 Business 
Days 
IRB’s Report 
Form 
 
irb@umn.edu 
 
With copy to the Mayo Clinic PI 
or designee 
 
MCC SAE 
Coordinator 
MMC 6 
mcc-
saes@umn.edu 
FDA 
Unexpected and fatal or life 
threatening suspected 
adverse reaction  
As soon as 
possible but no 
later than 7 
Calendar-Day 
UMCC SAE 
form  
Submit as an amendment to 
IND 
 
With copy to the Mayo Clinic PI 
or designee 
 
1) Serious and unexpected 
suspected adverse reaction 
or 
2)  increased occurrence of 
serious suspected adverse 
reactions over that listed in 
the protocol or investigator 
brochure or 
3) findings from other 
sources (other studies, 
animal or in vitro testing) 
4) positive HAMA in 
association with a grade 4 
infusion reaction 
As soon as 
possible but no 
later than 15 
Calendar-Day 
Note:  Events due to the disease under treatment or an underlying medical condition will not require reporting 
to the FDA for the purposes of this study 
Miltenyi 
Any safety issues associated 
with cell processing failure or 
device malfunction 
Refer to section 11.5 
Not applicable 
Masonic 
Cancer 
Center SAE 
Coordinator 
Any event that counts toward 
a study stopping rule (see 
section 13) 
Upon reporting 
Study 
stopping rule 
form 
SAE Coordinator 
mcc-saes@umn.edu 
Not applicable 


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In each IND safety report, the sponsor must identify all IND safety reports 
previously submitted to the FDA concerning a similar suspected adverse 
reaction and must analyze the significance of the suspected adverse 
reaction in light of the previous, similar reports. 
 
The SAE Coordinator will provide the Cancer Center’s Data and Safety 
Monitoring Council (DSMC) with the SAE in an appropriate format 
depending on the individual SAE (as reported or in a summary format). 
 
11.5 Reporting of Device/Processing Malfunction  
Any clinically significant safety issues associated with cell processing 
failure or device malfunction regarding the CliniMACS® system must be 
reported to immediately to either Dr. Miller or Dr. Warlick at the University 
of Minnesota (contact information on page 2) with follow-up reporting 
(copy U of MN study coordinator on any correspondence) to: 
 Miltenyi Biotec, Inc. 
Attn: Regulatory Affairs 
120 Presidential Parkway 
Suite 305 
Woburn, MA 01801 
There is no specific reporting form, and at a minimum a deviation report 
must be completed in OnCore. 
 
12.0 Study Data Collection and Monitoring 
12.1 Data Management 
This study will report clinical data using The Online Enterprise Research 
Management Environment (OnCoreTM), a web based Oracle® database 
utilizing study specific electronic case report forms.  Key study personnel 
are trained on the use of OnCore and will comply with protocol specific 
instructions embedded within the OnCore forms.  Patient demographics, 
patient specific study treatment calendars, targeted adverse events, 
reporting of deaths, and other information required for IND annual 
reporting will be placed in OnCore and other research databases 
maintained by MCC IT. 
12.2 Case Report Forms 
Participant data will be collected using protocol specific electronic case 
report forms (e-CRFs) developed within OnCore based on its library of 
standardized forms.  The e-CRF will be approved by the study’s Principal 
Investigator and the Biostatistician prior to release for use.  The Study 
Coordinator or designee will be responsible for registering the patient into 
OnCore at time of study entry, completing e-CRFs based on the patient 


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specific calendar, and updating the patient record until patient death or 
end of required study participation.   
12.3 Data and Safety Monitoring Plan (DSMP) 
The study’s Data and Safety Monitoring Plan will be in compliance with the 
University of Minnesota Masonic Cancer Center's Data & Safety 
Monitoring Plan (DSMP), which can be accessed at 
http://www.cancer.umn.edu/exfiles/research/dandsmplan.pdf. 
 
For the purposes of data and safety monitoring, this study is classified as 
high risk (under a locally held IND).  Therefore the following requirements 
will be fulfilled: 
 
 The PI (Dr. Warlick) will complete and submit a quarterly Trial Progress 
Report to the Masonic Cancer Center Data and Safety Monitoring 
Council (DSMC) with the understanding the Cancer Protocol Review 
Committee (CPRC) may require more frequent reporting. 
 The PI will comply with at least twice yearly monitoring of the project by 
the Masonic Cancer Center monitoring services. 
 The PI will oversee the submission of all reportable events per the 
definition of reportable in section 11.4 to the Masonic Cancer Center’s 
SAE Coordinator, the University of Minnesota IRB, and the FDA.   
 
In addition, at the time of the continuing review with the University of 
Minnesota IRB, a copy of the report with any attachments will be 
submitted to the Cancer Protocol Review Committee (CPRC). 
 
IND Annual Reports 
In accordance with regulation 21 CFR § 312.33, the IND sponsor (Dr. 
Miller) will submit a progress report annually.  The report will be submitted 
within 60 days of the anniversary date that the IND went into effect.    
12.4 Monitoring 
The PI with the CTO has oversight responsibility for trial monitoring at 
affiliate sites.  Affiliate sites must self-monitor following the University of 
Minnesota Masonic Cancer Center Data and Safety Monitoring Plan 
(DSMP - http://www.cancer.umn.edu/exfiles/research/dandsmplan.pdf) 
and the CTO Affiliate and Satellite Site Monitoring SOPs.   
 
The investigator will permit study-related monitoring, audits, and 
inspections by the study’s Principal Investigator and/or IND sponsor 
and/or any designees, the local IRB, government regulatory bodies, and 
University of Minnesota compliance groups.  The investigator will make 
available all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data, etc.).  The investigator 
will ensure the capability for inspections of applicable study-related 


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facilities (e.g. pharmacy, diagnostic laboratory, etc.) will be available for 
trial related monitoring, audits, or regulatory inspections. 
 
12.5 Record Retention 
The investigator will retain study records including source data, copies of 
case report forms, consent forms, HIPAA authorizations, and all study 
correspondence in a secured facility for at least 6 years after the study file 
is closed with the IRB and FDA.   
 
In addition, the Clinical Trials Office (CTO) will keep a master log of all 
patients participating in the study with sufficient information to allow 
retrieval of the medical records for that patient.  Please contact the CTO 
before destroying any study related records. 
 
 
13.0 Statistical Considerations 
13.1 Simon’s Two-Stage Design and Sample Size 
This is a single clinic Simon’s optimum two-stage phase II clinical trial 
designed to determine the objective response rate (CR+PR+HI) after two 
courses of Decitabine and Vorinostat with haploidentical NK cell s in 
patients with high risk MDS.  The null hypothesis of the study is PR0 ≤ 0.30 
and alternative hypothesis is PR1 ≥ 0.50. Based on this design and the 
assumption that the majority of patients will complete both cycles of 
therapy, a maximum of 46 evaluable patients will be used which is 
sufficient to maintain an overall type I error 5% while providing 80% 
statistical power.  
 
In the first stage 15 patients will be enrolled, the trial will be terminated if 5 
or fewer respond. If 6 patients respond, then the trial goes on to the 
second stage, and 31 more patients will be studied. If the total number 
responding is less than or equal to 18, then this approach will be deemed 
unworthy of further study.  
 
Considering a predicted dropout rate of 10% during the two courses of 
therapy, in order to have 15 or 46 patients evaluable for the response rate, 
we will need a maximum of 17 patients (if the study is stopped by 1st 
stage) or 51 patients (if the study proceeds to 2nd stage).  
 
Only patients completing both course 1 and 2 of planned therapy will be 
evaluable for response. However, all the patients with complete or partial 
treatment will be included in the evaluation for toxicities. 
 
13.2 Early Stopping Rule for Toxicities 


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The complications and adverse events will be closely monitored in this 
study. The hypothesized rate of having grade 4 or 5 non-hematologic, 
non-infectious toxicities for the approach is 5%. Enrollment will be stopped 
and the trial re-evaluated if the grade 4 or 5 toxicity rate shows signs to 
exceed 15%. This means enrollment will be stopped and the study re-
evaluated if there are 3 patients with a non-hematologic, non-infectious 
grade 4-5 toxic event occurring through day 45 of the last treatment 
course out of the first 7 patients, 4 out of 18, 5 out of 29, 6 out of 40, and 7 
patients at any time.  Toxicities such as infections, including but not limited 
to pneumonia, bacteremia, cellulitis, and neutropenic fever, etc are known 
results of high risk MDS and will not be included as toxicities attributed to 
the study therapy. Assessment for toxicities will begin upon initiation of 
trial therapy and will conclude 2 weeks after last dose of study related 
treatment.  These stopping rules of a statistical sequential probability ratio 
test designed for no more than 5% the probability of type I error and at 
least 80% statistical power.  
 
13.3 Statistical Analysis Methods 
Ninety-five percent confidence intervals for the response probability were 
calculated using methodology reported by Duffy and Santner.40 
The summary statistics including 95% confidence intervals for toxicity rate 
and proportion of patients who become transfusion independent will be 
calculated. The association of in vivo NK cell expansion, as defined as 
persistence of donor NK cell chimerism at day +8, (yes or no) with clinical 
response will be estimated by chi-square test. Kaplan- Meier method will 
be used to estimate 1- year survival from the date of treatment. Given that 
the majority of patients will go on to receive additional therapy with either 
ongoing hypomethylating agents versus stem cell transplant, the 
estimates of 1 year overall survival from the point of study enrollment, will 
only be partially attributable to the study therapy and thus a minor focus of 
our statistical analysis.  
 
SAS 9.2 (Cary, NC, USA) will be used for statistical analyses.  
 
 
14.0 Conduct Of The Study 
14.1 Good Clinical Practice 
The study will be conducted in accordance with the appropriate regulatory 
requirement(s).  The investigator will be thoroughly familiar with the 
appropriate use of the drug as described in the protocol and Investigator’s 
Brochure.  Essential clinical documents will be maintained to demonstrate 
the validity of the study and the integrity of the data collected.  Master files 
should be established at the beginning of the study, maintained for the 


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duration of the study and retained according to the appropriate 
regulations.   
14.2 Ethical Considerations 
The study will be conducted in accordance with ethical principles founded 
in the Declaration of Helsinki.  The IRB will review all appropriate study 
documentation in order to safeguard the rights, safety and well-being of 
the patients.  The study will only be conducted at sites where IRB approval 
has been obtained.  The protocol, informed consent, written information 
given to the patients, safety updates, annual progress reports, and any 
revisions to these documents will be provided to the IRB by the 
investigator.   
14.3 Informed Consent 
All potential study participants will be given a copy of the IRB-approved 
consent to review. The investigator or designee will explain all aspects of 
the study in lay language and answer all questions regarding the study. If 
the participant decides to participate in the study, he/she will be asked to 
sign and date the consent document. Patients who refuse to participate or 
who withdraw from the study will be treated without prejudice. 
 
 
15.0 References 
 
1. Warlick ED and Smith BD. Myelodysplastic syndromes: review of pathophysiology and 
current novel treatment approaches. Curr Cancer Drug Targets. 2007;7:541-558. 
2. Herman JG, Civin CI, Issa JP, Collector MI, Sharkis SJ, Baylin SB. Distinct patterns of 
inactivation of p15INK4B and p16INK4A characterize the major types of hematological 
malignancies. Cancer Res. 1997;57:837-841. 
3. Leone G, Teofili L, Voso MT, Lubbert M. DNA methylation and demethylating drugs in 
myelodysplastic syndromes and secondary leukemias. Haematologica. 2002;87:1324-1341. 
4. Quesnel B, Guillerm G, Vereecque R, et al. Methylation of the p15(INK4b) gene in 
myelodysplastic syndromes is frequent and acquired during disease progression. Blood. 
1998;91:2985-2990. 
5. Aggerholm A, Holm MS, Guldberg P, Olesen LH, Hokland P. Promoter hypermethylation of 
p15INK4B, HIC1, CDH1, and ER is frequent in myelodysplastic syndrome and predicts poor 
prognosis in early-stage patients. Eur J Haematol. 2006;76:23-32. 
6. Christiansen DH, Andersen MK, Pedersen-Bjergaard J. Methylation of p15INK4B is 
common, is associated with deletion of genes on chromosome arm 7q and predicts a poor 
prognosis in therapy-related myelodysplasia and acute myeloid leukemia. Leukemia. 
2003;17:1813-1819. 
7. Molldrem JJ, Caples M, Mavroudis D, Plante M, Young NS, Barrett AJ. Antithymocyte 
globulin for patients with myelodysplastic syndrome. Br J Haematol. 1997;99:699-705. 
8. Jonasova A, Neuwirtova R, Cermak J, et al. Cyclosporin A therapy in hypoplastic MDS 
patients and certain refractory anaemias without hypoplastic bone marrow. Br J Haematol. 
1998;100:304-309. 


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9. Sloand EM, Wu CO, Greenberg P, Young N, Barrett J. Factors affecting response and 
survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin 
Oncol. 2008;26:2505-2511. 
10. Passweg JR, Giagounidis AA, Simcock M, et al. Immunosuppressive therapy for patients 
with myelodysplastic syndrome: a prospective randomized multicenter phase III trial 
comparing antithymocyte globulin plus cyclosporine with best supportive care--SAKK 33/99. 
J Clin Oncol. 2011;29:303-309. 
11. Olnes MJ and Sloand EM. Targeting immune dysregulation in myelodysplastic syndromes. 
JAMA. 2011;305:814-819. 
12. Kiladjian JJ, Bourgeois E, Lobe I, et al. Cytolytic function and survival of natural killer cells 
are severely altered in myelodysplastic syndromes. Leukemia. 2006;20:463-470. 
13. Epling-Burnette PK, Bai F, Painter JS, et al. Reduced natural killer (NK) function associated 
with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK 
receptors. Blood. 2007;109:4816-4824. 
14. Carlsten M, Baumann BC, Simonsson M, et al. Reduced DNAM-1 expression on bone 
marrow NK cells associated with impaired killing of CD34(+) blasts in myelodysplastic 
syndrome. Leukemia. 2010;24:1607-1616. 
15. Kordasti SY, Ingram W, Hayden J, et al. CD4+CD25high Foxp3+ regulatory T cells in 
myelodysplastic syndrome (MDS). Blood. 2007;110:847-850. 
16. Hamdi W, Ogawara H, Handa H, Tsukamoto N, Nojima Y, Murakami H. Clinical significance 
of regulatory T cells in patients with myelodysplastic syndrome. Eur J Haematol. 
2009;82:201-207. 
17. Kotsianidis I, Bouchliou I, Nakou E, et al. Kinetics, function and bone marrow trafficking of 
CD4+CD25+FOXP3+ regulatory T cells in myelodysplastic syndromes (MDS). Leukemia. 
2009;23:510-518. 
18. Alfinito F, Sica M, Luciano L, et al. Immune dysregulation and dyserythropoiesis in the 
myelodysplastic syndromes. Br J Haematol. 2010;148:90-98. 
19. Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in 
patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J 
Clin Oncol. 2002;20:2429-2440. 
20. Silverman LR, McKenzie DR, Peterson BL, et al. Further analysis of trials with azacitidine in 
patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and 
Leukemia Group B. J Clin Oncol. 2006;24:3895-3903. 
21. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that 
of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a 
randomised, open-label, phase III study. Lancet Oncol. 2009;10:223-232. 
22. Gurion R, Vidal L, Gafter-Gvili A, et al. 5-Azacitidine Prolongs overall Survival in Patients 
with Myelodysplastic Syndrome - Systematic Review and Meta-Analysis. Haematologica. 
2009. 
23. Issa JP and Kantarjian HM. Targeting DNA methylation. Clin Cancer Res. 2009;15:3938-
3946. 
24. Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in 
myelodysplastic syndromes: results of a phase III randomized study. Cancer. 
2006;106:1794-1803. 
25. Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of 3 schedules 
of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic 
leukemia. Blood. 2007;109:52-57. 
26. Garcia-Manero G, Yang H, Bueso-Ramos C, et al. Phase I study of the histone deacetylase 
inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced 
leukemias and myelodysplastic syndromes. Blood. 2007. 


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27. Kuendgen A, Schmid M, Schlenk R, et al. The histone deacetylase (HDAC) inhibitor valproic 
acid as monotherapy or in combination with all-trans retinoic acid in patients with acute 
myeloid leukemia. Cancer. 2006;106:112-119. 
28. Gore SD, Weng LJ, Figg WD, et al. Impact of prolonged infusions of the putative 
differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute 
myeloid leukemia. Clin Cancer Res. 2002;8:963-970. 
29. Gojo I, Jiemjit A, Trepel JB, et al. Phase 1 and pharmacologic study of MS-275, a histone 
deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. Blood. 
2007;109:2781-2790. 
30. Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and 
cancer: causes and therapies. Nat Rev Cancer. 2001;1:194-202. 
31. Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitors: inducers of differentiation 
or apoptosis of transformed cells. J Natl Cancer Inst. 2000;92:1210-1216. 
32. Prince HM, Bishton MJ, Harrison SJ. Clinical studies of histone deacetylase inhibitors. Clin 
Cancer Res. 2009;15:3958-3969. 
33. Quintas-Cardama A, Santos FP, Garcia-Manero G. Histone deacetylase inhibitors for the 
treatment of myelodysplastic syndrome and acute myeloid leukemia. Leukemia. 
2011;25:226-235. 
34. Reddy P, Maeda Y, Hotary K, et al. Histone deacetylase inhibitor suberoylanilide 
hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-
leukemia effect. Proc Natl Acad Sci U S A. 2004;101:3921-3926. 
35. Miller JS, Soignier Y, Panoskaltsis-Mortari A, et al. Successful adoptive transfer and in vivo 
expansion of human haploidentical NK cells in patients with cancer. Blood. 2005;105:3051-
3057. 
36. Stathis A, Hotte SJ, Chen EX, et al. Phase I study of decitabine in combination with 
vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas. Clin 
Cancer Res. 2011;17:1582-1590. 
37. Ravandi F, Faderl S, Thomas D, et al. Phase I Study of Suberoylanilide Hydroxamic Acid 
(SAHA) and Decitabine in Patients with Relapsed, Refractory or Poor Prognosis Leukemia 
[abstract]. Blood. 2007. 
38. Kirschbaum M, Gojo I, Goldberg S, et al. Phase I Study of Vorinostat in Combination with 
Decitabine in Patients with Relapsed or Newly Diagnosed Acute Myelogenous Leukemia or 
Myelodysplastic Syndrome [abstract]. Blood. 2008. 
39. Kadidlo D, Bostrom N, Adams S, Fautsch S, McCullough J, Wagner J, Miller J, McKenna D. 
Validation of Natural Killer Cell Activation During Long-Distance Shipping. Transfusion 
(2006); 46(9S): 59A-60A. 
40. Duffy DE, Santner TJ. Confidence intervals for a binomial para parameterbased on 
multistage tests. Biometrics 1987; 43: 81–93. 
41. Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating 
prognosis in myelodysplastic syndromes. Blood. 1997;89:2079-2088. 
42. Malcovati L, Germing U, Kuendgen A, et al. Time-dependent prognostic scoring system for 
predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol. 
2007;25:3503-3510. 


Appendix I – Eligibility Checklist – Patient 
Decitabine and Vorinostat with CD3/CD19 Depleted Haploidentical Donor Natural 
Killer (NK) Cells for the Treatment of High Risk Myelodysplastic Syndromes 
(MDS) - MT2012-04 
Eligibility Checklist – page 1 of 2 
Patient initials   
     
 
 
Patient ID
-
  
 
 
1
st 2 initials of first name + 1
st 2 initials of last name 
        3 letter site code – Seq # (i.e. 01, 02, 03, etc.) 
 
INCLUSION CRITERIA  
A "NO" response to any of the following disqualifies the patient from study entry. 
 
 
 
 
Yes      No 
1. 
Diagnosis of high risk MDS that meets at least one of the following disease classifications and is 
requiring treatment: 
  International Prognostic Scoring System (IPSS) Category: INT-2 or High Risk (Appendix IV) 
  International Prognostic Scoring System- Revised (IPSS-R) Category: High or Very High (Score of 
5 or above) (Appendix IV) 
  WHO Classification: RAEB-1 or RAEB-2 
  WHO Classification:  CMML that is not highly proliferative.  WBC < 15K 
  High risk cytogenetic abnormality as defined by presence of Monosomy 7, complex karytope, or 
monosomal karyotype 
  Therapy related MDS 
   Severe cytopenias: Severe neutropenia (ANC < 0.8), platelet or PRBC transfusion dependent 
  WHO Based Prognostic Scoring System (WPSS): High or Very High Risk (Appendix V) 
 
 
2. 
  Untreated/Minimally Treated:  maximum of 2 cycles of hypomethylating agents (azacitidine or 
decitabine) without evidence of treatment failure as defined by progression to more advanced MDS 
Who classification or AML.   
  Treatment Failure:  Patients who have not responded to or whose disease has progressed on 
hypomethylating agents (azacitidine or decitabine), 7+3 type induction chemotherapy, or 
immunosuppressive therapy such as ATG+CSA. 
Patients must not have received treatment for their MDS within 4 weeks of beginning the trial.  
 
3. Age ≥ 18  years of age 
 
4. ECOG Performance Status 0-2                                                                PS - 
 
 
5. Available related HLA-haploidentical NK cell donor by at least Class I serologic typing at the A&B 
locus 
 
6. 
Acceptable organ function within 14 days of study enrollment defined as: 
Creatinine 
≤ 2.0 mg/dL 
.
 
/
/
 
SGOT 
< 5 x institutional ULN 
 
/
/
 
SGPT 
< 5 x institutional ULN 
 
/
/
 
oxygen saturation 
≥ 90% on room air    
% 
/
/
 
Ejection Fraction 
≥ 40% and no 
uncontrolled angina,  
% 
/
/
 
severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active 
conduction system abnormalities. QTc < 500 msec    
 
 
7. Able to be off prednisone or other immunosuppressive medications for at least 3 days prior to NK cell 
(excluding pre-meds) 
 
8. 
Women of child bearing potential must agree to use effective methods of contraception (diaphragm, 
birth control pills, injections, intrauterine device [IUD], surgical sterilization, subcutaneous implants, or 
abstinence, etc.) from the time of signing the consent form and for 2 months after the last dose of 
chemotherapy 
 
9. Voluntary written consent 
 


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Decitabine and Vorinostat with CD3/CD19 Depleted Haploidentical Donor Natural 
Killer (NK) Cells for the Treatment of High Risk Myelodysplastic Syndromes 
(MDS) - MT2012-04 
 
 
Eligibility Checklist – page 2 of 2 
Patient initials   
     
 
 
EXCLUSION CRITERIA 
A "YES" response to any of the following disqualifies the patient from study entry. 
 
 
Yes      No 
10.  Pregnant or lactating 
 
 
11.  New progressive pulmonary infiltrates on screening chest x-ray or chest CT scan that has 
not been evaluated with bronchoscopy (when feasible) 
 
 
12.  Uncontrolled bacterial or viral infections - chronic asymptomatic viral hepatitis is allowed 
 
 
13.  Pleural effusion moderate to large in size that are detectable on chest x-ray 
 
 
14.  Known hypersensitivity to one or more of the study agents 
 
 
15.  Prior hypomethylating treatment greater than 2 cycles or with documented treatment 
failure 
 
 
16.  Prior use of histone deacetylase inhibitors 
 
 
17.  Serious medical or psychiatric illness likely to interfere with participation in this clinical 
study in the opinion of the enrolling investigator 
 
 
18.  Inability to swallow capsules 
 
 
19.  Active HIV 
 
 
20.  
Other active and potentially life threatening malignancy excluding localized basal or 
squamous cell skin cancer, cervical carcinoma in situ, superficial bladder cancer, localized 
prostate cancer 
 
 
 
Date consent form signed: 
 
 
 
 
Having obtained consent and reviewed each of the inclusion/exclusion criteria, I verify that this patient is:  
 
  Eligible 
  Ineligible    Date registered  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of person verifying eligibility 
 
 
 
 
Date 
 
 


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Appendix II - Eligibility Checklist - Donor 
 
Decitabine and Vorinostat with CD3/CD19 Depleted Haploidentical Donor Natural 
Killer (NK) Cells for the Treatment of High Risk Myelodysplastic Syndromes 
(MDS) - MT2012-04 
 
Eligibility Checklist – page 1 of 1 
Donor initials   
     
 
 
 
Donor ID 
-
-D 
 
 
 
1
st 2 initials of first name + 1
st 2 initials of last name 
 3 letter site code – Pt seq # (i.e. 01, 02, 03, etc.)  
 
 
INCLUSION CRITERIA  
A "NO" response to any of the following disqualifies the donor from study entry. 
 
 
Yes      No 
1. 
Related donor (sibling, parent, offspring, parent or offspring of an HLA identical sibling) 18 to 
75 years of age 
 
 
2. 
At least 40 kilogram body weight 
 
3. 
In general good health as determined by the evaluating medical provider 
 
4. 
HLA-haploidentical donor/recipient match by at least Class I serologic typing at the A&B locus 
 
5. 
Able and willing to undergo apheresis 
 
6. 
Not pregnant  
 
7. 
Voluntary written consent 
 
 
Date consent form signed: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of person verifying eligibility  
 
 
 
 
Date 
 
 


Appendix III – ECOG Performance Status Criteria 
 
 
ECOG 
Score 
Performance Status 
Karnofsky 
Equivalent 
0 
Asymptomatic 
100 
1 
Symptomatic, fully ambulatory 
80-90 
2 
Symptomatic, in bed < 50% of the day 
60-70 
3 
Symptomatic, in bed > 50% of the day but not bedridden 
40-50 
4 
Bedridden 
20-30 
5 
Dead 
 
 
 
 
  


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CPRC # 2011LS124 
Appendix IV – International Prognostic Scoring System (IPSS) 
Category and IPSS-R41 
 
 
 
 
 


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CPRC # 2011LS124 
 
IPSS-R Cytogenetic risk groups*,**  
Cytogenetic prognostic 
subgroups 
Cytogenetic abnormalities 
Very good 
-Y, del(11q) 
Good 
Normal, del(5q), del(12p), del(20q), double including del(5q) 
Intermediate 
del(7q), +8, +19, i(17q), any other single or double independent clones
Poor 
-7, inv(3)/t(3q)/del(3q), double including -7/del(7q), Complex: 3 
abnormalities 
Very poor 
Complex: >3 abnormalities 
 
 
IPSS-R Prognostic Score Values*  
Prognostic variable 
0 
0.5 
1 
1.5 
2 
3 
4 
Cytogenetics 
Very Good
 
Good 
 
Intermediate 
Poor 
Very 
Poor 
BM Blast % 
≤2 
 
>2-<5%
 
5-10% 
>10% 
 
Hemoglobin 
≥10 
 
8-<10 
<8 
 
 
 
Platelets 
≥100 
50-<100
<50 
 
 
 
 
ANC 
≥0.8 
<0.8 
 
 
 
 
 
 
 
IPSS-R Prognostic Risk Categories/Scores*  
RISK CATEGORY 
RISK SCORE 
Very Low 
≤1.5 
Low 
>1.5 - 3 
Intermediate 
>3 - 4.5 
High 
>4.5 - 6 
Very High 
>6 
 
*Greenberg, Tuechler, Schanz et al, Revised International Prognostic Scoring System (IPSS-R) for 
Myelodysplastic Syndrome, Blood 120: 2454, 2012. 
**Schanz J et al, J Clin Oncology 2012; 30:820  
 
 
Source:  http://ipss-r.com/ (accessed September 5, 2014) 
 
 
 


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Appendix V – WHO Based Prognostic Scoring System42 
 
 
 
 
 


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Appendix VI – MDS Response Criteria 
 
Based on International Working Group 2006 Modified Criteria 
 
 Complete Remission (CR): < 5% myeloblasts with normal maturation of all cell 
lines 
o Persistent dysplasia will be noted 
o Peripheral Blood: 
 Hgb > 11g/dl 
 Platelets > 100 X 109 /L 
 Neutrophils > 1000 
 Blasts = 0% 
 Partial Remission (PR): all CR criteria if abnormal before except: 
o BM blasts decreased by > 50% over pre-treatment but still >5% 
 Marrow CR: Bone marrow with < 5% myeloblasts and decrease by >50% over 
pretreatment with incomplete peripheral blood count normalization 
 Hematologic Improvement (HI): 
o Hgb: Increase by > 1.5g/dl or decreased PRBC transfusions by at least 
4/8 week period (only PRBC given for Hgb<9.0g/dl) 
o Platelet Response: Absolute increase of > 30 X 109/L for those starting at 
>20 X 109/L For those < 20 X 109/L at baseline increase by 100%. 
o Neutrophil Response: at least 100% increase and an absolute increase of 
>0.5 X 109/L 
 Stable Disease:  Failure to achieve at least a PR but no evidence of disease 
progression for >8 weeks 
 Failure: Death during treatment or disease progression characterized by 
worsening cytopenias, increase percentage of marrow blasts, or progression to a 
more advanced MDS FAB subtype 
 Cytogenetic Response:  
o Complete: Disappearance of any pre-treatment chromosomal 
abnormalities without the appearance of new ones 
o Partial: At least 50% reduction of chromosomal abnormality 
 Disease Progression: Compared to pre-treatment values 
o Less than 5% blasts: greater than 50% increase to >5% blasts 
o 5-10% blasts: greater than 50% increase to >10% blasts 
o 10-20% blasts: greater than 50% increase to >20% blasts 


MT2012-04: Decitabine and Vorinostat with CD3-/CD19- Donor NK Cells for High Risk MDS 
 
 
 
 
 
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Appendix VII – Expected Toxicities of Study Treatment 
Decitabine 
Common 
Less Common 
Rare 
 low platelet count with increased risk 
of bruising/bleeding* 
 low white blood cell count with 
increased risk of infection* 
 low red blood cell count (anemia) 
with symptoms like tiredness, low 
energy, or shortness of breath* 
 nausea  
 vomiting  
 diarrhea 
 constipation 
 tiredness 
 fever 
 pain or swelling in the arms or legs 
 blurred vision 
 pain  
 high blood sugar* 
 headache 
 bruises or bleeding 
 swollen lymph nodes 
("glands") 
 sores in mouth, on tongue, 
or on lips* 
 infection 
 indigestion or sour 
stomach 
 abnormal blood tests which 
suggest that the drug is 
affecting the liver  
 confusion 
 trouble sleeping 
 fluid in the lungs* 
 severe allergic reaction, 
with symptoms like 
flushing, hives, trouble 
breathing or swallowing, 
dizziness, swelling of 
mouth or throat (while drug 
is being infused) 
 serious infections  
 death from infection, 
bleeding, or other cause 
 
 
Vorinostat 
Common 
Less Common 
Rare 
 feeling tired 
 nausea/vomiting* 
 diarrhea 
 loss of appetite 
 changes in how foods taste 
 weight loss 
 muscle aches  
 low blood platelet count with 
increased risk of bleeding 
 high blood sugar levels  
 abnormal blood or urine tests which 
suggest that the drug is affecting the 
kidneys  
 muscle spasms 
 hair loss (including face 
and body hair) 
 dry mouth 
 constipation  
 fever, chills 
 feeling dizzy 
 swelling in the hands, feet, 
legs, or ankles 
 headache 
 itching 
 low red blood cell count 
(anemia)  
 cough 
 upper respiratory infection 
 blood clots in the lungs or 
legs 
 changes in electric 
impulses of the heart, 
abnormal heart rhythm  
 slow or fast heart rate 
 death due to infection or 
other cause 
 
 
 


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CPRC # 2011LS124 
 
 
 
 
Refer to section 7.8 for NK cell expected toxicity 
Interleukin-2 (IL-2) 
Common 
Less Common 
Rare 
 flu-like syndrome (may 
include fever, chills, 
tiredness, headache, 
muscle and joint pain)  
 low blood pressure 
 nausea/vomiting 
 diarrhea 
 feeling weak 
 confusion 
 shortness of breath 
 flushing of the face 
 rash or dry, itchy skin 
 low urine output  
 abnormal blood tests which 
suggest that the drug is 
affecting the liver or 
kidneys  
 feeling dizzy  
 feeling drowsy 
 sores in the mouth or on the lips  
 loss of appetite  
 abdominal pain 
 increased heart rate or change in 
heart rhythm 
 swelling in the face, hands, or feet 
 trouble sleeping 
 trouble concentrating 
 runny nose 
 low platelet count with increased 
risk of bleeding* 
 low red blood cell count (anemia) 
with symptoms like tiredness, 
weakness, shortness of breath 
 low white blood cell count with 
increased risk of infection 
 allergic reaction* 
 cough 
 confusion  
 psychosis (loss of touch 
with reality) 
 depression 
 seizures 
 coma 
 damage to bowel, ruptured 
or bleeding bowel 
 serious infection 
 kidney failure 
 heart attack 
 stroke 
 breathing problems 
 death from low blood 
pressure, capillary leak 
syndrome, heart problems, 
or other complications 


Appendix VIII – Vorinostat Drug Log 
 
Patient Number:  __________  Course Number: 
 
Record the date and time each dose of vorinostat is taken.  If not taken, record dose as 0 for that day and indicate reason 
not taken.   
 
Contact the study doctor or research nurse with any questions or concerns. 
 
Day # 
Date 
Dose 1 
Time taken 
Dose 2 
Time taken
Notes (side effects, reason not taken, etc) 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
 
Return this form with any leftover tablets and drug containers  
at the time of your next treatment appointment. 
  
 


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Appendix IX – Targeted Toxicity Form NK Cells/IL-2 
 Patient Initials:  _______ Date of Assessment:  _________     Assessment Time point:  _________ 
ADL = activities of daily living      
Toxicity 
Grade 0 
Grade 1 
Grade 2
Grade 3
Grade 4
Infusion related 
reaction 
None 
Mild transient reaction; 
infusion interruption not 
indicated; intervention 
not indicated 
Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment; 
prophylactic medications 
indicated for ≤ 24 hrs 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion);  
Life-threatening 
consequences; urgent 
intervention indicated (collect 
sample for HAMA) 
Dyspnea 
None or 
 no change 
Shortness of breath 
with moderate exertion 
Shortness of breath with minimal 
exertion; limiting instrumental ADL 
Shortness of breath at rest; 
limiting self care ADL 
Life-threatening 
consequences; urgent 
intervention indicated 
Hypoxia 
None 
……………… 
Decreased O2 saturation with 
exercise (e.g., pulse oximeter < 
88%) intermittent supplemental 
oxygen 
Decreased oxygen saturation 
at rest (e.g., pulse oximeter < 
88% or PaO2 ≤ 55 mm Hg) 
Life-threatening airway 
compromise; urgent 
intervention indicated (e.g., 
tracheotomy or intubation) 
Fever  
None 
38.0 - 39.0 degrees C 
(100.4 -102.2 F) 
> 39.0 - 40.0 degrees C (102.3 - 
104.0 degrees F) 
> 40.0 degrees C (>104.0 
degrees F) for ≤ 24 hrs 
> 40.0 degrees C (>104.0 
degrees F) for > 24 hrs 
Febrile neutropenia 
 
……………… 
……………… 
temperature of >38.3 degrees 
C (101 degrees F) or a temp 
of ≥38 degrees C (100.4 
degrees F) for > 1hour 
Life-threatening 
consequences; urgent 
intervention indicated 
Chills 
None 
Mild sensation of cold; 
shivering; chattering of 
teeth 
Moderate tremor of the entire body; 
narcotics indicated 
Severe or prolonged, not 
responsive to narcotics 
……………………… 
Hypertension 
None 
Pre-hypertension 
(systolic BP 120 - 139 
mm Hg or diastolic BP 
80 - 89 mm Hg) 
Stage 1 hypertension (systolic BP 
140 - 159 mm Hg or diastolic BP 
90 - 99 mm Hg); medical 
intervention indicated; recurrent or 
persistent  ≥ 24 hrs); symptomatic 
increase by >20 mm Hg (diastolic) 
or to >140/90 mm Hg if previously 
WNL; monotherapy indicated 
Pediatric: recurrent or 
persistent (≥ 24 hrs) BP 
>ULN; monotherapy indicated 
Stage 2 hypertension 
(systolic BP ≥ 160 mm Hg or 
diastolic BP ≥ 100 mm Hg); 
medical intervention 
indicated; more than one 
drug or more intensive 
therapy than previously used 
indicated.   
Pediatric: Same as adult 
Life-threatening 
consequences (e.g., 
malignant hypertension, 
transient or permanent 
neurologic deficit, 
hypertensive crisis); urgent 
intervention indicated.  
Pediatric: Same as adult 
Hypotension 
None 
Asymptomatic, 
intervention 
not indicated 
Non-urgent medical 
intervention indicated 
Medical intervention or 
hospitalization indicated 
Life-threatening and urgent 
intervention indicated 
Edema 
None 
Localized to dependent 
areas, no disability or 
functional impairment 
Moderate localized edema 
and intervention indicated; 
limiting instrumental ADL 
Severe localized edema and 
intervention indicated; limiting 
self care ADL 
……………………… 
Pneumonitis 
 
None 
Asymptomatic; clinical 
or diagnostic 
observations only;  
Symptomatic; medical 
intervention indicated; limiting 
instrumental ADL 
Severe symptoms; limiting 
self care ADL; oxygen 
indicated 
Life-threatening respiratory 
compromise; urgent 
intervention indicated (e.g. 
intubation or tracheotomy) 
Injection Site 
Reaction 
None 
Tenderness with or 
without associated 
symptoms  
Pain; lipodystrophy; edema; 
phlebitis 
Ulceration or necrosis; severe 
tissue damage; operative 
intervention indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Rash 
None 
Covering < 10% body 
surface area (BSA) 
Covering 10-30% body surface 
area (BSA) 
>30% body surface area 
(BSA) 
Generalized exfoliative, 
ulcerative, or bullous dermatitis
Creatinine 
Increased 
None 
>1 - 1.5 x baseline; 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x baseline; >1.5 -3.0 x 
ULN 
>3.0 baseline; >3.0 - 6.0 x 
ULN 
>6.0 x ULN 
Weight Gain 
None 
5 - <10% from baseline  10 - <20% from baseline  
≥20% from baseline 
……………………… 
Other- Specify 
_______________ 
  
Mild 
Moderate 
Severe 
Life- threatening 
 Person Completing Form:  
 
 
 
 
 
PI Signature:  
 
 
 
 
  
All Events are Expected and Attributable Except: