Clinical trial NCT04055844
Conditions: Acute Myeloid Leukemia Myeloid and Monocytic Leukemia Myelodysplastic Syndromes
Keywords: AML MDS
Sponsor: Masonic Cancer Center, University of Minnesota
Start date: 2020-02-17; Completion date: 2022-09-06
Enrollment: 14 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This is a multi-center, single-arm, open-label, phase II trial for the frontline treatment of relapsed AML or MDS following allo-HCT. Eligible subjects will receive up to 4 cycles of combined modality treatment. The number of cycles depends on response, toxicity, and the remaining cell dose.

Detailed description:

Arms: arm 1: Eligible subjects will receive up to 4 cycles of combined modality treatment. The number of cycles depends on response, toxicity, and the remaining cell dose.
Interventions: intervention 1: Decitabine intervention 2: Ruxolitinib intervention 3: Donor Lymphocyte Infusion (DLI)
Intervention descriptions: intervention 1: 10 days of decitabine 20 mg/m2 IV daily; or, alternatively, per institution, physician, or patient preference on a 5-2-5 schedule with no weekend infusion. If a CR is achieved after 2 cycles using the 10-day schedule, subsequent cycles will change to a 5-day schedule. intervention 2: Starting with day 1 of cycle 1 and continuing for up to 6 months after the end of the last cycle, patients will receive ruxolitinib 5 mg twice daily orally. Dose may be increased to 10 mg twice daily in cycles 2 through 4 if platelets improve to \>100 x 10\^9/L. intervention 3: DLI from the original donor will be infused within 10 days after the last dose of decitabine in each cycle.

Protocol documents:
Prot_SAP_000.pdf: 
MT2018-07: ruxolitinib, decitabine, and DLI for post-transplant relapse of AML or MDS 
 
 
 
 
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CPRC #2018LS066 
 
 
 
Masonic Cancer Center 
University of Minnesota 
Cancer Experimental Therapeutics Initiative (CETI) and Bone Marrow Transplant Program 
 
 
A Multi-Center Phase 2 Study of Combined Modality Treatment with Ruxolitinib, 
Decitabine, and Donor Lymphocyte Infusion for Post-Transplant Relapse of AML or MDS 
 
MT2018-07  
CPRC #2018LS066 
IND# 18863 
 
 
University Of Minnesota 
Principal Investigator: 
Mark Juckett, MD 
 
Collaborator: 
Jeffrey S. Miller, M.D. 
 
Biostatistician: 
Ryan Shanley, MS 
 
Affiliate Institutions: 
Washington University, St. Louis, MO: 
Mark A. Schroeder, M.D., PI 
John F. DiPersio, M.D., Ph.D., Co-PI 
Jaebok Choi, Ph.D.* 
Matthew J. Christopher, M.D., Ph.D. 
 
*will not consent patients 
 
University of Rochester, Rochester, NY: 
Eric Huselton, M.D., PI 
 
 
Version Date: 
February 25, 2022 
Confidential 


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CPRC #2018LS066 
 
 
Key Study Personnel Contact Information 
Site 
Contact Information 
Role 
Masonic Cancer 
Center, University of 
Minnesota 
Mark Juckett, MD 
Division of Hematology/Oncology/Transplantation 
Masonic Cancer Center 
University of Minnesota 
420 Delaware Street SE MMC 480 
Minneapolis, MN 55455 
Phone: 612-624-6104  
Email: juck0001@umn.edu 
IND 
sponsor/ 
Study PI 
Affiliate Manager 
Clinical Trials Office 
MMC 498 
420 Delaware Street SE 
Minneapolis, MN 55455 
Phone: 612 626-5174 
Email:  affiliates@umn.edu 
Fax: 612 625-6145 
Affiliate 
Sites 
Manager 
Washington 
University 
Mark Schroeder, M.D. 
Assistant Professor of Medicine, Division of Oncology, 
Section of Bone Marrow Transplantation and Leukemia 
Division of Oncology  
Washington University Medical School  
660 South Euclid Avenue  
Campus Box 8007  
Saint Louis, MO 63110 
314-454-8323 (office) 
314-454-7551 (fax) 
markschroeder@wustl.edu 
Site PI 
University of 
Rochester 
Eric Huselton, M.D. 
Wilmot Cancer Center 
University of Rochester Medical Center 
601 Elmwood Ave. 
Rochester, NY 14642 
Site PI 
 
Refer to the Procedures Manual for Affiliate Sites for a complete list of study personnel and contact 
information.  
 
 


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CPRC #2018LS066 
 
 
Revision History 
 
 
Revision 
# 
Version 
Date 
Detail of Changes 
Consent 
change 
 
12/03/2018 
Original to CPRC 
 
 
1/16/2019 
Updated study committee 
Section 15: Statistical clarifications and minor edits (error 
corrections and clarifications) per UMN and University of 
Rochester CPRC stipulations 
Section 11.2: Added optional research bone marrow biopsy prior 
to cycle one 
Section 12.5: Clarified institutional SAE reporting table based on 
current MCC SOPs 
 
1 
03/18/2019 
Title Page: Added IND # 
Per FDA request – Section 5.2: Eligibility- Patients with Active 
GVHD will be excluded from the study 
Per FDA request - Section 15.4 Stopping Rules and section 12.3, 
Event Reporting – the FDA will be notified if stopping rule is 
triggered 
No 
2 
03/27/2019 
Clarifications to Section 11: after clinical care planning meeting 
and IRB initial review: 
• Updated timing of windows around clinical care evaluations and 
research samples 
• Added recipient type and screening to clinical care evaluations 
• Clarified bone marrow biopsy timing 
• Removed specification of sample tube color 
Section 12.3, Section 12.4, and Section 12.5 Updated sponsor 
reporting criteria 
Corrected typographical errors 
Yes 
3 
05/01/2019 
Administrative change: 
Section 11.1 and Section 11.2 Clarified standard of care and 
research bone marrow in order to synchronize timing. 
No 
3A 
09/03/2019 
Administrative change: 
Section 11.1 and Section 11.2  Reorganized calendars for clarity 
No 
4 
11/25/2019 
Administrative Changes: 
• Section 5.1: Clarified that minors will either assent or be given 
an information sheet, per institutional IRB requirements 
• Removed eligibility checklists – these documents will now be 
stored in Oncore 
• Correction of typographical errors 
Yes 
4A 
01/03/2020 
Section 8.5 removed karnofsky from re-screening procedures 
No 


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Revision 
# 
Version 
Date 
Detail of Changes 
Consent 
change 
5 
09/18/2020 
Synopsis, Section 5.1 Clarifications to Inclusion criteria 
Section 6, Section 11.3 Clarified that related / unrelated donors 
will be screened and consented per individual institutional and/or 
NMDP SOPs  
Section 8.8 – Clarified that patients discontinuing DLI treatments, 
may continue to receive Ruxolitinib 
Section 11.1 Clarified timing of clinical screening labs 
Section 11.2 Removed screening research labs 
Section 12.3, Section 13.3 and Section 13.5 Minor clarification to 
institutional monitoring 
Yes; also 
removed 
study 
specific 
donor 
consents 
6 
12/30/2020 
Section 11.1 and Section 11.2 Clarifications to timing of procedures 
Section 12.2 and Section 15.4 Clarification to timing period of AE 
documentation and stopping rules 
No 
7 
06/23/2021 
Section 9.1 updated expected adverse events based on new 
Ruxolitinib IB 
Section 8.8 Minor edit to Duration of Study. Rationale clarification 
and consistency 
Yes 
8 
02/25/2022 
Updated study PI and biostatistician 
Yes 


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Table of Contents 
Key Study Personnel Contact Information ............................................................................................................. 2 
Revision History ...................................................................................................................................................... 3 
Table of Contents ................................................................................................................................................... 5 
Abbreviations ......................................................................................................................................................... 7 
Synopsis .................................................................................................................................................................. 9 
Schema ................................................................................................................................................................. 12 
1 
Objectives .................................................................................................................................................... 13 
1.1 
Primary Objective................................................................................................................................ 13 
1.2 
Secondary Objectives .......................................................................................................................... 13 
1.3 
Correlative Objectives ......................................................................................................................... 13 
2 
Background .................................................................................................................................................. 13 
2.1 
DLI ....................................................................................................................................................... 13 
2.2 
HMAs ................................................................................................................................................... 14 
3 
Study Rationale ............................................................................................................................................ 14 
4 
Study Design ................................................................................................................................................ 15 
5 
Patient Selection .......................................................................................................................................... 16 
5.1 
Inclusion Criteria: ................................................................................................................................ 16 
5.2 
Exclusion Criteria: ............................................................................................................................... 18 
6 
Donors ......................................................................................................................................................... 19 
7 
Study Registration ........................................................................................................................................ 19 
7.1 
Registration with the University of Minnesota Clinical Trials Office ................................................... 19 
7.2 
Patients Who Do Not Begin Study Treatment .................................................................................... 20 
8 
Treatment Plan ............................................................................................................................................ 21 
8.1 
Chemotherapy Regimen ..................................................................................................................... 23 
8.2 
DLI ....................................................................................................................................................... 23 
8.3 
Monitoring .......................................................................................................................................... 24 
8.4 
Ruxolitinib Dose modification ............................................................................................................. 24 
8.5 
Re-screening Eligibility for Cycles 2- 4 ................................................................................................. 24 
8.6 
Supportive Care .................................................................................................................................. 26 
8.7 
General Concomitant Medication Guidelines ..................................................................................... 26 
8.8 
Duration of Study Treatment .............................................................................................................. 26 
8.9 
Duration of Study Participation .......................................................................................................... 27 
9 
Expected Adverse Events and Potential Risks ............................................................................................. 27 
9.1 
Ruxolitinib ........................................................................................................................................... 27 
9.2 
Decitabine ........................................................................................................................................... 28 
9.3 
Risks Due to DLI ................................................................................................................................... 29 
10 
Study Agent Information ............................................................................................................................. 30 
10.1 
Ruxolitinib ........................................................................................................................................... 30 
10.2 
Decitabine ........................................................................................................................................... 31 
11 
Clinical Evaluations and Procedures ............................................................................................................ 33 
11.1 
Required Clinical Care Evaluations ...................................................................................................... 34 
11.2 
Patient – Research Related ................................................................................................................. 36 
11.3 
Donor – Recommended Standard of Care .......................................................................................... 37 
12 
Adverse Event Monitoring, Documentation, and Reporting ....................................................................... 37 
12.1 
Adverse Event Terminology ................................................................................................................ 37 
12.2 
AE Documentation .............................................................................................................................. 39 
12.3 
SAE Documentation and MCC Reporting Requirements .................................................................... 40 
12.4 
Early Stopping Rule Events Documentation and Reporting Requirements ........................................ 41 
12.5 
Institutional Event Reporting Table .................................................................................................... 41 
13 
Study Data Collection and Monitoring ........................................................................................................ 42 


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13.1 
Data Management .............................................................................................................................. 42 
13.2 
Case Report Forms .............................................................................................................................. 43 
13.3 
Data and Safety Monitoring Plan (DSMP) ........................................................................................... 43 
13.4 
Teleconferences – Lead Site and Affiliate Site .................................................................................... 44 
13.5 
Affiliate Site Monitoring ...................................................................................................................... 44 
13.6 
Record Retention ................................................................................................................................ 44 
14 
Study Endpoints ........................................................................................................................................... 45 
14.1 
Primary Endpoint ................................................................................................................................ 45 
14.2 
Secondary Endpoints .......................................................................................................................... 45 
14.3 
Correlative Endpoints.......................................................................................................................... 45 
15 
Statistical Considerations ............................................................................................................................. 45 
15.1 
Objectives and Study Design ............................................................................................................... 45 
15.2 
Statistical Analysis ............................................................................................................................... 45 
15.3 
Sample Size ......................................................................................................................................... 46 
15.4 
Stopping Rules .................................................................................................................................... 47 
16 
Ethical and Regulatory Considerations ........................................................................................................ 47 
16.1 
Good Clinical Practice ......................................................................................................................... 47 
16.2 
Ethical Considerations ......................................................................................................................... 47 
16.3 
Informed Consent ............................................................................................................................... 48 
17 
References ................................................................................................................................................... 49 
Appendix I – Karnofsky Performance Status Scale ............................................................................................... 51 
Appendix II –– GVHD Grading Scales .................................................................................................................... 52 
 
 
 


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Abbreviations 
ABBREVIATION 
DEFINITION 
ABO 
TYPE A, TYPE B, TYPE O, OR TYPE AB 
AE 
 
ADVERSE EVENT 
aGVHD 
ACUTE GRAFT VERSUS HOST DISEASE 
AHC 
ACADEMIC HEALTH CENTER 
ALT 
ALANINE AMINOTRANSFERASE 
AML 
ACUTE MYELOID LEUKEMIA 
AST 
ASPARTATE AMINOTRANSFERASE 
BMP 
BASIC METABOLIC PANEL 
BMT 
BONE MARROW TRANSPLANT 
CBC 
COMPLETE BLOOD COUNT 
CETI 
CANCER EXPERIMENTAL THERAPEUTICS INITIATIVE 
CFR 
CODE OF FEDERAL REGULATIONS 
CMP 
COMPREHENSIVE METABOLIC PROFILE 
CPRC 
CANCER PROTOCOL REVIEW COMMITTEE 
CMV 
CYTOMEGALOVIRUS 
CNS 
CENTRAL NERVOUS SYSTEM 
CR 
COMPLETE REMISSION 
CRCL 
CREATININE CLEARANCE 
CRF 
CASE REPORT FORM 
CTCAE 
COMMON TOXICITY CRITERIA ADVERSE EVENT 
CTEP  
CANCER THERAPY EVALUATION PROGRAM 
CTO 
CLINICAL TRIALS OFFICE 
CTSI 
CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE 
DLI 
DONOR LYMPHOCYTE INFUSION 
DMSO 
DIMETHYLSULFOXIDE 
DNA 
DEOXYRIBONUCLEIC ACID 
DSMP 
DATA AND SAFETY MONITORING PLAN 
ECG 
ELECTROCARDIOGRAM 
EBV 
 
EPSTEIN-BARR VIRUS 
FDA 
FOOD AND DRUG ADMINISTRATION 
G-CSF 
GRANULOCYTE-COLONY STIMULATING FACTOR 
GVHD 
GRAFT VERSUS HOST DISEASE 
GVL 
GRAFT-VERSUS-LEUKEMIA 
HBV 
HEPATITIS B VIRUS 
HCV 
HEPATITIS C VIRUS 
HIV 
HUMAN IMMUNODEFICIENCY VIRUS 
HLA 
HUMAN LEUKOCYTE ANTIGEN 
HMA 
HYPOMETHYLATING AGENTS 
HTLV1/2 
HUMAN T CELL LYMPHOTROPIC VIRUS 1/2 
IB 
INVESTIGATOR’S BROCHURE 
IGG 
IMMUNOGLOBULIN G 
IRB 
INSTITUTIONAL REVIEW BOARD 
IV 
INTRAVENOUS 


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ABBREVIATION 
DEFINITION 
JAK 
JANUS KINASE 
MCC 
MASONIC CANCER CENTER 
MCC-CISS 
MASONIC CANCER CENTER - CLINICAL INFORMATICS SHARES SERVICES 
MDS 
MYELODYSPLASTIC SYNDROME 
MPN 
MYELOPROLIFERATIVE NEOPLASMS 
MSD 
MATCHED SIBLING DONOR 
MUD 
MATCHED UNRELATED DONOR 
NAT 
NUCLEIC ACID TESTING 
NCI 
NATIONAL CANCER INSTITUTE 
NK 
NATURAL KILLER CELLS 
NRM 
NON-RELAPSE MORTALITY 
ONCORE 
ONLINE ENTERPRISE RESEARCH MANAGEMENT ENVIRONMENT 
OS 
OVERALL SURVIVAL 
PFS 
PROGRESSION FREE SURVIVAL 
PHI 
PROTECTED HEALTH INFORMATION 
RFLP 
RESTRICTION FRAGMENT LENGTH POLYMORPHISM 
RH 
RHESUS 
SAE 
SERIOUS ADVERSE EVENT 
SOP 
STANDARD OPERATING PROCEDURE 
STAT 
SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 
T. Cruzi 
TRYPANOSOMA CRUZI 
TTL 
TRANSLATIONAL THERAPY LAB 
ULN 
UPPER LIMIT OF NORMAL 
WBC 
WHITE BLOOD CELL 
WOCBP 
WOMEN OF CHILDBEARING POTENTIAL 
 
 


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Synopsis 
Study Design: 
This is a multi-center, single-arm, open-label, phase II trial for the frontline treatment 
of relapsed AML or MDS following allo-HCT.  
 
Eligible subjects will receive up to 4 cycles of combined modality treatment. The 
number of cycles depends on response, toxicity, and the remaining cell dose. 
 
Cycles include: 
• 
10 days of decitabine 20 mg/m2 IV daily, or, alternatively on a 5-2-5 schedule 
with no weekend infusion. If a CR is achieved after 2 cycles using the 10-day 
schedule, subsequent cycles will change to a 5-day schedule.  
• 
Starting with day 1 of cycle 1 and continuing for up to 6 months after the end 
of the last cycle, patients will receive ruxolitinib 5 mg twice daily orally. Dose 
may be increased to 10 mg twice daily in cycles 2 through 4 if platelets 
improve to >100 x 109/L. 
• 
DLI from the original donor will be infused within 10 days after the last dose 
of decitabine in each cycle.  
Patients will be screened for ongoing eligibility before each subsequent cycle of 
therapy. Patients with disease progression, new GVHD (except grade I acute 
GVHD), prolongation of the most recent cycle to more than 8 weeks (for any 
reason), or inadequate cell dose for further DLI will not receive further treatment 
on study. The DLI dose in each cycle will be determined according to a donor-
dependent dose-escalation algorithm (schema).  
 
The expected duration of treatment for each subject is 4 cycles of treatment, each 
lasting 4-8 weeks. Subjects will be followed on study for 12 months.  
 
Primary 
Objectives: 
Determine the efficacy of combined modality treatment (ruxolitinib, 10-day 
decitabine, and DLI) for relapsed AML or MDS post allo-HCT. 
Secondary  
Objectives: 
● 
Evaluate OS 
● 
Determine incidence of grade II-IV acute graft-versus-host disease (aGVHD II-IV)  
● 
Evaluate PFS  
● 
Determine incidence of relapse  
● 
Evaluate complete remission (CR)  
● 
Determine incidence of non-relapse mortality (NRM)  
● 
Best response  
Correlative 
Objectives: 
● Incidence and severity of adverse events (AEs) and serious AEs (SAEs) until 3 
months after day 1 of the last received cycle 
● Correlative studies: T cell and NK cell subset analysis by flow cytometry, 
correlation between TP53 mutation and response, clonal dynamics during and 
after the course of therapy 
Key 
Inclusion 
Criteria:  
● Age 12 years or older  
● Undergone first allo-HCT from a 6/6 matched sibling donor, 8/8 matched 
unrelated donor, or an HLA haploidentical donor.  


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● AML or MDS  
● Additional cells sufficient for the first DLI available from the same donor or the 
donor willing to donate 
● Partial (or better) engraftment from the bone marrow showing relapse: Defined 
as >50% donor chimerism on non-split RFLP.   Patients with chimerism of 25-50% 
may be enrolled with approval of the site PI and Sponsor/Investigator. 
● Karnofsky Performance Status  ≥ 50%  
● Adequate organ function: Total bilirubin < 1.5 x ULN; AST/ALT < 2.5 x ULN; 
Creatinine clearance ≥40 mL/minute 
● Peripheral white blood cell count <50 x 109/L   
● Subjects and spouse/partner who are of childbearing potential must be using 
highly effective contraception consisting of 2 forms of birth control starting at 
Screening and continuing through the entire study 
● Male subjects must not donate sperm during the Screening and Treatment 
Periods, and for at least 3 months after the last dose of ruxolitinib 
Key Exclusion 
Criteria: 
● Active uncontrolled infection.  
● History of infection with human immunodeficiency virus (HIV), unresolved 
hepatitis B, or hepatitis C  
● Untreated CNS leukemia  
● Untreated  or active GVHD (acute or chronic)  
● History of grade III-IV acute GVHD 
● Any form of iatrogenic immunosuppression except <0.5 mg/kg/day of 
prednisone or equivalent  
● Unresolved veno-occlusive disease of the liver 
● Subjects who are pregnant, breast feeding or sexually active and unwilling to use 
effective birth control for the duration of the study 
● Radiation therapy within 14 days prior to consent 
● Any prior therapy for relapse after allo-HCT   
● Prior DLI. CD34-selected boost is allowed 
● Exposure to any other investigational agent, device or procedure within 2 weeks 
prior to consent 
● Patients or donors with any medical or psychological condition that, in the 
opinion of the Investigator, might interfere with the subject’s participation in the 
trial, pose any additional risk for the patient/donor, or confounds the 
assessments of the subject 
● Subjects with known allergies, hypersensitivity or intolerance to ruxolitinib or 
similar compounds 
Key 
Rescreening 
Inclusion 
Criteria (before 
Cycle 2-4):  
● Additional cells available from the same donor used for the first DLI or the donor 
willing to donate  
● Karnofsky Performance Status ≥ 50%  
● Adequate organ function: Total bilirubin < 1.5 x ULN; AST/ALT < 2.5 x ULN; 
Creatinine clearance ≥40 mL/minute within 3 days prior to day 1 
● Peripheral white blood cell count <50 x 109/L within 3 days prior to day 1  
Key 
Rescreening 
● Active uncontrolled infection  
● Any new GVHD except grade I acute GVHD during the most recent cycle 


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Exclusion 
Criteria (before 
Cycle 2-4): 
● Any form of iatrogenic immunosuppression except <0.5 mg/kg/day of 
prednisone or equivalent  
● Unresolved veno-occlusive disease of the liver 
● Subjects who are pregnant, breast feeding or sexually active and unwilling to use 
effective birth control for the remaining duration of the study 
● Radiation therapy during the most recent cycle 
● Disease progression during the most recent cycle. Screening bone marrow biopsy 
is required only before cycles 1 and 3.   
● Exposure to any other investigational agent, device or procedure during the most 
recent cycle 
● Patients or donor with any medical or psychological condition that, in the opinion 
of the Investigator, might interfere with the subject’s continuation in the trial, 
pose any additional risk for the patient/donor, or confounds the assessments of 
the subject 
● Any condition resulting in prolongation of the most recent cycle beyond 8 weeks. 
If in the view of the investigator, postponing the next cycle is justified for any 
reason, this is allowed as long as the current cycle does not exceed 8 weeks. If 
longer than 8 weeks, patients will not receive further therapy on study   
● Consent withdrawal by patient 
Enrollment: 
Approximately 34 subjects will be enrolled (32 evaluable) over a period of 24 months, 
with an additional 12 months of follow up 
 
 


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Schema 
 
Potentially Eligible Patients: 
Relapsed AML or MDS post allo HCT 
 
 
Obtain consent and HIPAA 
 
 
 
 
 
Response: BMBX at 4-6 weeks after Cycle 2 Day 1 and 4-6 
weeks after day 1 of last cycle of decitabine 
 
 
                                             Analyze for primary, secondary, and safety endpoints 
 
 
*DLI dose escalation algorithm  
 
MSD 
MUD 
Haploidentical 
DLI #1, x108 CD3/kg 
0.1-1 
0.05-0.5 
0.01-0.1 
DLI #2, x108 CD3/kg 
0.5-5 
0.1-1 
0.05-0.5 
DLI #3, x108 CD3/kg 
1-10 
0.5-5 
0.1-1 
DLI #4, x108 CD3/kg 
5-50 
1-10 
0.5-5 
DLI: Donor lymphocyte infusion; MSD: Matched sibling donor; MUD: Matched unrelated donor  
 
**If CR is achieved after cycle 2, patients will be switched to a 5 day schedule. 
Ruxolitinib
Twice a Day beginning Day 1, Cycle 1 through 6 
months after the end of final cycle
Up to 4 Cycles (28 Days in cycle)
Day 1-10 (Or 5-2-5 schedule):  Decitabine 1x daily. ** 
Within 10 days after last decitabine dose: DLI per 
dose algorithm* 
Between Cycles (Day 29 - 56)
Up to 4 weeks: Continuous rescreening for eligibility 
to continue to additional cycles, or remove from trial 
(due to disease progression, new GVHD, 
prolongation of previous cycle to 8 weeks, or 
inadequte cell dose for further DLI) 
Research 
Specimen 
collections:
50 mL of 
peripheral 
blood: at 
enrollment, 
before each 
cycle; 30, 90, 
180 days after 
first day of last 
cycle; at time 
of 
progression; 
at GVHD onset
BMBX prior to cycle 1 
(optional), time of 
response assessment 
& at progression


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1 Objectives 
1.1 Primary Objective 
To determine the efficacy of combined modality treatment (ruxolitinib, decitabine, 
and DLI) for relapsed AML or MDS post allo-HCT as measured by overall survival (OS) 
at 6 months.  
1.2 Secondary Objectives 
• To evaluate OS  
• To determine cumulative incidence of grade II-IV acute graft-versus-host disease 
(aGVHD II-IV)   
• To evaluate PFS  
• To determine incidence of relapse  
• To determine complete remission (CR)  
• To determine incidence of non-relapse mortality (NRM)  
• To measure best response  
1.3 Correlative Objectives 
• To evaluate incidence and severity of adverse events (AEs) and serious AEs (SAEs) 
until 3 months after day 1 of the last received cycle 
• Correlative studies: T cell and NK cell subset analysis by flow cytometry, 
correlation between TP53 mutation and response, clonal dynamics during and 
after the course of therapy 
2 Background  
Although allo-HCT is a curative treatment approach for AML and MDS, relapse continues to 
be the primary cause of death after allo-HCT, with post-relapse 1-year overall survival of only 
about 20%1,2. Currently there is no standard treatment for post-HCT relapse. Commonly 
practiced 
approaches 
include 
withdrawal 
of 
immunosuppressive 
medications, 
hypomethylating agents, aggressive chemotherapy, second allo-HCT, targeted therapies, DLI, 
or a combination of these3. We will apply a combination approach as detailed in the following 
sections:  
2.1 DLI 
DLI is mechanistically based on the concept of restoration and augmentation of a graft-
versus-leukemia (GvL) effect. However, the success of DLI is limited due to low efficacy 
and high toxicity. As a result, various strategies are implemented to increase DLI 
potency and decrease its toxicity. Examples for the former group of approaches include 


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the use of hypomethylating agents (HMA) or lymphodepleting chemotherapy prior to 
DLI. Lymphodepleting chemotherapy helps with cytoreduction and provides a favorable 
cytokine niche for the T cells of DLI to expand4. However, the use of lymphodepleting 
chemotherapy before DLI has been associated with high incidence of severe GVHD, the 
major toxicity of DLI5.  
2.2 HMAs 
The use of HMAs before or after DLI is a popular and less toxic approach compared to 
lymphodepleting chemotherapy before DLI. HMAs increase antigen expression by 
leukemia cells and may make them more immunogenic, i.e. primed for a robust GvL 
effect from DLI6,7. A recent retrospective multicenter study by the German Cooperative 
Transplant Study Group using azacitidine prior to DLI in 154 patients with relapsed AML 
or MDS after allo-HCT showed that this therapy is well-tolerated and effective, 
particularly in patients with low disease burden. Overall response was achieved in a 
third of the patients and overall survival at 2 years was approximately 30%8. In another 
study using azacitidine prior to DLI in 65 patients with relapse after allo-HCT, there was 
temporary control of leukemia in ~45% of patients, but only 10% achieved a CR9. 
Furthermore, pioneer murine studies by Jaebok Choi have demonstrated that 
azacitidine mitigates GVHD while preserving GVL by peripheral conversion of 
alloreactive effector T cells into regulatory T cells, thus mitigating GVHD without 
sacrificing GVL effect10. Azacitidine after DLI was recently tested in a phase 1 study to 
prevent development of GVHD11. Azacitidine was administrated on days 4, 6, 8 and 10 
after DLI with dose escalation schedule of 30–75 mg/m2 in 39 patients with relapsed 
AML after allo-HCT. None of the patients developed severe acute GVHD.  
 
3 Study Rationale  
In the proposed study, we add two novelties to the HMA-DLI platform with the goals of 
increasing efficacy and decreasing toxicity. First, while azacitidine is the more commonly used 
HMA in combination with DLI, we will replace azacitidine with 10-day courses of decitabine. 
This concept is based on two observations: (i) Unprecedented high response rates (100% in 
the recent report by Washington University investigators) to 10-day decitabine, particularly 
in TP53-mutated MDS/AML12, and (ii) In a recent murine study, decitabine, but not 
azacitidine, potentiated the antileukemic activity of hematopoietic stem and progenitor cell-
derived NK cells. Furthermore, the number of NK cells in the bone marrow was increased 
after decitabine treatment13. The second novelty in this protocol is adding JAK2 inhibitor 
ruxolitinib to the HMA/DLI combination. JAK inhibition has shown clinical activity in the 
treatment of acute GVHD14,15,16. Preliminary studies conducted by Jaebok Choi have shown 




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determined according to a donor-dependent dose-escalation algorithm (schema). If the 
collected cell dose in the DLI is less than the target dose, the patient will receive those 
collected cells and subsequently removed from further treatment cycles. These subjects will 
continue to be followed per protocol. 
 
The expected duration of treatment for each subject is 4 cycles of treatment, each lasting 4-
8 weeks.  
 
Approximately 34 subjects will be enrolled (32 evaluable) over a period of 24 months, with 
an additional 12 months of follow up. 
5 Patient Selection 
Study entry is open to adult patients regardless of gender, race or ethnic background. 
While there will be every effort to seek out and include women and minority patients, the 
patient population is expected to be similar to that of other relapsed AML or MDS studies 
at the University Of Minnesota and other participating institutions.  
5.1 Inclusion Criteria: 
5.1.1 Age ≥12 years 
5.1.2 Have undergone first allo-HCT from a 6/6 matched sibling donor, 8/8 matched 
unrelated donor, or an HLA haploidentical donor. 
5.1.3 History of AML or MDS for which allo-HCT was performed. Overlap MPN/MDS 
is included. 
5.1.4 Untreated relapse of the underlying malignancy as defined by >5% of 
malignant blasts (by morphology and/or flow cytometry) in the bone marrow, 
or myeloid sarcoma. 
5.1.5 Additional cells sufficient for the first DLI available from the same donor, or 
the donor must be willing to donate. Both G-CSF mobilized and unmobilized 
products are allowed and the choice is at the discretion of the treating 
physician. 
5.1.6 Partial (or better) engraftment from the bone marrow showing relapse, 
defined as >50% donor chimerism on non-split RFLP. Patients with chimerism 
of 25-50% may be enrolled with approval of the site PI and 
Sponsor/Investigator. 


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5.1.7 Karnofsky performance status ≥ 50% (appendix I) 
 
5.1.8 Adequate organ function within 14 days of study registration defined as: 
• Total bilirubin < 1.5 x upper limit of institutional normal, unless a diagnosis 
of Gilbert’s disease 
• AST/ALT < 2.5 x upper limit of institutional normal  
• Creatinine clearance ≥40 mL/minute as calculated by the Cockcroft-Gault 
formula. Cockcroft-Gault CrCl = (140-age) * (Wt in kg) * (0.85 if female) / (72 
* Cr). 
 
5.1.9 Peripheral white blood cell count <50 x 109/L. The use of hydroxyurea for 
cytoreduction is allowed and may continue until cycle 2 day 1 
 
5.1.10 Subjects and spouse/partner who are of childbearing potential must be using 
highly effective contraception consisting of 2 forms of birth control (at least 1 
of which must be a barrier method) starting at Screening and continuing 
through the entire study (for at least 3 months after the last dose of ruxolitinib 
if study treatment is stopped early or subject withdraws consent). Highly 
effective contraception is defined as: 
• Established use of oral, injected or implanted hormonal methods of 
contraception. 
• Placement of an intrauterine device or intrauterine system. 
• Double barrier methods of contraception: condom or occlusive cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/suppository (double barrier method will count 
as 2 forms of contraception). 
 
5.1.11 Male subjects must not donate sperm during the Screening and Treatment 
Periods, and for at least 3 months after the last dose of ruxolitinib. 
 
5.1.12 Subjects are willing and able to give written informed consent and to comply 
with all study visits and procedures. Parents or legal guardians will consent for 
minors and minors will be asked to assent, or be given a minor information 
sheet, per institutional IRB requirements. 


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5.2 Exclusion Criteria: 
5.2.1 Active uncontrolled infection at the time of consent. An active uncontrolled 
infection is defined as hemodynamic instability attributable to sepsis or new 
symptoms, worsening physical signs or radiographic findings attributable to 
infection. Persisting fever without signs or symptoms of infection will not be 
interpreted as an active uncontrolled infection. Subjects with a controlled 
infection receiving definitive therapy for 72 hours prior to enrollment are 
eligible. 
5.2.2 History of infection with human immunodeficiency virus (HIV), unresolved 
hepatitis B, or hepatitis C.  
5.2.3 Untreated CNS leukemia  
5.2.4 Untreated or active GVHD (acute or chronic)  
5.2.5 History of grade III-IV acute GVHD at any point in time 
5.2.6 Any form of iatrogenic immunosuppression except <0.5 mg/kg/day of 
prednisone or equivalent at the time of consent.  
5.2.7 Unresolved veno-occlusive disease of the liver, defined as persistent bilirubin 
abnormalities not attributable to GVHD and ongoing organ dysfunction (renal, 
ascites). 
5.2.8 Subjects who are pregnant, breast feeding or sexually active and unwilling to 
use effective birth control for the duration of the study, as agents in this study 
are in pregnancy category C: Animal reproduction studies have shown an 
adverse effect on the fetus and there are no adequate and well-controlled 
studies in humans, and category D: there is positive evidence of human fetal 
risk based on adverse reaction data from investigational or marketing 
experience or studies in humans. 
5.2.9 Radiation therapy within 14 days prior to consent. 
5.2.10 Any prior therapy for relapse after allo-HCT.  
5.2.11 Prior DLI. CD34-selected boost is allowed 
5.2.12 Exposure to any other investigational agent, device or procedure within 14 
days prior to consent 
5.2.13 Patients or donors with any medical or psychological condition that, in the 
opinion of the Investigator, might interfere with the subject’s participation in 


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the trial, pose any additional risk for the patient/donor, or confounds the 
assessments of the subject. 
5.2.14 Subjects with known allergies, hypersensitivity or intolerance to ruxolitinib or 
similar compounds. 
6 Donors 
Additional cells sufficient for a DLI must be available, or the previous donor must be 
willing to donate again.  The required total dose of CD3 cells (x108) per recipient’s body 
weight in kg for 4 DLI procedures is 66, 16.6, and 1.66 for matched sibling, matched 
unrelated, haploidentical donors, respectively. Donor selection will be in compliance with 
21 CFR Part 1271 and institutional guidelines. If requesting additional collections from the 
previous donor, donor assessment and consent process will occur per institutional SOPs 
for related donors or per National Marrow Donor Program (BeTheMatch.org) SOPs for 
matched unrelated donors, in the apheresis center or similar donor facility. No study-
specific consent is needed from donors.  
 
For affiliates: affiliate sites may use their institutional guidelines in evaluating related 
donor eligibility. Matched unrelated donors will be evaluated according to institutional 
and/or National Marrow Donor Program guidelines. The current study does not 
determine any donor-specific eligibility.  
7 Study Registration 
To be eligible for registration to this study, the patient must meet all of the inclusion 
criteria and none of the exclusion criteria listed on the eligibility checklist based on the 
eligibility assessment documented in the patient’s medical record.  
 
The eligibility checklist for both the patient and donor will be completed at the time of 
study registration. 
7.1 Registration with the University of Minnesota 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 in 
OnCore. Complete registration information is found in the study’s Procedures Manual 
for Affiliate Sites. 
 


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Affiliate sites only:  At the time of registration, the signed consents will be uploaded 
into OnCore as an attachment under the appropriate record (patient or donor).  
 
Affiliates are responsible for fulfilling any local registration requirements. 
7.2 
Patients Who Do Not Begin Study Treatment 
If a patient is registered to the study and is later found not able to begin study 
treatment (beginning with the ruxolitinib and decitabine); the patient will be removed 
from the study and treated at the physician’s discretion. The study staff will update 
OnCore of the patient’s non-treatment status (off study). The reason for removal from 
study prior to starting study treatment will be clearly indicated in OnCore. The patient 
will be replaced to complete enrollment.  
 






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8.1 
Chemotherapy Regimen  
The administration of the preparative regimen will follow institutional drug and 
supportive care guidelines. Dose and/or schedule adjustments consistent with the 
standard of care may be made on an individual patient basis as needed for safety.  
 
Ruxolitinib 5 mg twice daily orally beginning Day 1 and through Cycle 1. Consider dose 
increase to 10 mg twice daily in cycles 2 through 4 if platelets recover to over >100 x 
109/L.  Ruxolitinib will continue through six months after the completion of the final 
cycle. See section 8.4 for toxicity dose modification. 
 
Decitabine: 20 mg/m2 IV daily, on the following possible schedules: day 1-10 for 
cycles 1-2 (alternative: day 1-5 and day 8-12 with no weekend infusion); day 1-5 for 
cycles 3-4 (if CR achieved after Cycle 2). There are no dose modifications. 
8.2 
DLI 
Within 10 days after the last dose of decitabine in each cycle, a DLI product from the 
previous donor (either remaining from the original transplant unit, or a new unit) will 
be infused. Donor lymphocytes will be obtained by lymphapheresis from the same 
allogeneic donor used for transplantation. For local related donors, lymphocyte 
collections will be performed using standard automated mononuclear cell collection 
techniques by the University of Minnesota Blood Bank or study affiliate site’s 
institutional guidelines. For unrelated donors or non-local related donors, the 
lymphocyte collection will be performed at an outside facility according to procedures 
set by the National Marrow Donor Program. If the collection is non-local, coordination 
for the timing of the cell collection and the ability to transport the cells to the study 
site is required. Similarly, for local related donors, the timing of collection (same day 
as infusion vs. cryopreserved) is according to the collaborating centers’ institutional 
guidelines.  
 
The duration of DLI will be determined according to the collaborating centers’ 
institutional guidelines.  DLI will be administered according to a donor-dependent 
dose-escalation algorithm (Table 4). In the absence of new GVHD (any grade), the 
dose of DLI for the next cycle will be higher than the previous cycle. Otherwise, the 
dose will remain the same. DLI will be given without adding immunosuppressive 
medications and without conditioning. Addition of immunosuppressive medications 
as indicated to treat grade I acute GVHD or other non-GVHD steroid-responsive 
conditions is allowed.  
 


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Table 4: DLI dose escalation algorithm  
 
MSD 
MUD 
Haploidentical 
DLI #1, x108 CD3/kg 
0.1-1 
0.05-0.5 
0.01-0.1 
DLI #2, x108 CD3/kg 
0.5-5 
0.1-1 
0.05-0.5 
DLI #3, x108 CD3/kg 
1-10 
0.5-5 
0.1-1 
DLI #4, x108 CD3/kg 
5-50 
1-10 
0.5-5 
DLI: Donor lymphocyte infusion; MSD: Matched sibling donor; MUD: Matched 
unrelated donor  
8.3 
Monitoring 
During infusions, patients will be monitored for occurrence of untoward effects of the 
infusion of allogeneic lymphocytes such as rash, acute allergic reaction, 
bronchospasm, respiratory distress, acute vascular leak syndrome, localized or 
systemic infections. 
8.4 
Ruxolitinib Dose modification  
Dose adjustment for ruxolitinib is recommended (Table 5). 
 
Table 5: Ruxolitinib dose adjustment  
CTCAE grade 3 or greater 
bleeding related to low 
platelets 
Non-transfused platelets  
<10 x 109/L 
10-50 x 109/L  
>50 x 109/L 
Hold. Reassess 2 weeks after 
resolution of bleeding 
Hold 
5 mg daily 
5 mg twice 
daily1 
1For cycles 2, 3, and 4, if platelets improve to >100 x 109/L, a dose increase to 10 mg 
twice daily may be considered.  
8.5 
Re-screening Eligibility for Cycles 2- 4 
Patients will be screened for eligibility to continue onto each subsequent cycle of 
therapy. Patients with disease progression, new GVHD (except grade I acute GVHD), 
prolongation of the most recent cycle to more than 8 weeks (for any reason), or 
inadequate cell dose for further DLI will not receive further treatment on study. 
Rescreening will be an ongoing process.  When patients meet the eligibility criteria 
outlined below, they may begin subsequent cycles. 
 
Inclusion Criteria (on or before Day 1 of Cycles 2-4) 
Patients must meet the following criteria within 7 days prior to day 1 of cycles 2-4 
unless otherwise noted. 
 


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8.5.1 Stable disease or better on bone marrow biopsy within 7 days before cycle 3 
(required) and cycles 2 and 4 (if performed). A bone marrow biopsy before 
cycles 2 and 4 is not required.    
8.5.2 Additional cells available from the same donor used for the first DLI or the 
donor willing to donate (Table 4). This dose will allow for at least one more 
DLI. Both G-CSF mobilized and unmobilized products are allowed. If a sufficient 
number of cells for the next DLI is not available, patients will not receive 
further treatment on study.  
8.5.3 Adequate organ function: 
• 
Total bilirubin < 1.5 x upper limit of institutional normal, unless a diagnosis 
of Gilbert’s disease 
• 
AST/ALT < 2.5 x upper limit of institutional normal  
• 
Creatinine clearance ≥40 mL/minute within 3 days prior to day 1, as 
calculated by the Cockcroft-Gault formula. Cockcroft-Gault CrCl = (140-
age) * (Wt in kg) * (0.85 if female) / (72 * Cr). 
8.5.4 Peripheral white blood cell count <50 x 109/L within 3 days prior to day 1. The 
use of hydroxyurea is allowed and may continue until day 1 of cycle 2.  
 
Exclusion Criteria (on or before Day 1 of Cycles 2-4) 
Patients must meet the following criteria at the time of screening for the next cycle 
unless otherwise noted.  
 
8.5.5 Active uncontrolled infection. An active uncontrolled infection is defined as 
hemodynamic instability attributable to sepsis or new symptoms, worsening 
physical signs or radiographic findings attributable to infection. Persisting 
fever without signs or symptoms will not be interpreted as an active 
uncontrolled infection. Subjects with a controlled infection receiving definitive 
therapy for 72 hours prior to screening are eligible. 
8.5.6 Any new GVHD except grade I acute GVHD during the most recent cycle. 
8.5.7 Any form of iatrogenic immunosuppression except <0.5 mg/kg/day of 
prednisone or equivalent.  
8.5.8 Unresolved veno-occlusive disease of the liver, defined as persistent bilirubin 
abnormalities not attributable to GVHD and ongoing organ dysfunction (renal, 
ascites). 
8.5.9 Subjects who are pregnant, breast feeding or sexually active and unwilling to 
use effective birth control for the remaining duration of the study. 
8.5.10 Radiation therapy during the most recent cycle. 


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8.5.11 Disease progression during the most recent cycle.   
8.5.12 Exposure to any other investigational agent, device or procedure during the 
most recent cycle. 
8.5.13 Patients or donors with any medical or psychological condition that, in the 
opinion of the Investigator, might interfere with the subject’s continuation in 
the trial, pose any additional risk for the patient/donor, or confounds the 
assessments of the subject. 
8.5.14 Any condition resulting in prolongation of the most recent cycle beyond 8 
weeks. If in the view of the investigator, postponing the next cycle is justified 
for any reason, this is allowed as long as the current cycle does not exceed 8 
weeks. If longer than 8 weeks, patients will not receive further therapy on 
study. 
8.5.15 Consent withdrawal by patient 
8.6 
Supportive Care 
Supportive care will be provided per institutional guidelines and standard of care. The 
investigator may prescribe any concomitant medications or treatment deemed 
necessary to provide adequate supportive care. Supportive care may include 
antibiotics, anti-fungals, analgesics, transfusions, growth factors.  
 
Patients with recent CNS involvement should continue on CNS therapy 
(chemotherapy or radiation) as medically indicated during the protocol. 
8.7 
General Concomitant Medication Guidelines   
• Coadministration with potent CYP3A inhibitors; consider alternative agents 
with less CYP3A inhibition 
• Coadministration with potent CYP3A4 inducers.  
• If concomitant administration of an anticoagulant/antiplatelet medication is 
indicated, then caution and enhanced monitoring is required. History of 
thrombocytopenia should be a factor in the choice of anticoagulant and dose. 
8.8 
Duration of Study Treatment 
The expected duration of treatment for each subject is 4 cycles of treatment, each 
cycle lasting 4 weeks; with up to 4 weeks of rescreening for eligibility to continue on 
to subsequent cycles; followed by six additional months of ruxolitinib.   The following 
may be reasons for removal from additional study treatment: 
• unacceptable toxicity 
• disease progression  


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• new GVHD (except grade I acute GVHD) 
• prolongation of the most recent cycle to more than 8 weeks (for any reason) 
• inadequate cell dose for further DLI 
• consent is withdrawn or patient is not compliant 
 
Patients who are unable to receive further DLIs after initial cycle(s), may continue to 
receive ruxolitinib as long as the physician believes they are benefiting from the 
treatment, the patient has not withdrawn consent, and they have not developed 
unacceptable toxicity. 
 
All patients receiving at least one cycle of treatment will be followed per Sections 11.1 
and 11.2  and be evaluable per Section 15. 
 
Patients unable to continue DLI may be treated per physician’s choice.  These patients 
will still be followed per Sections 11.1 and 11.2. 
8.9 Duration of Study Participation 
All patients must be followed for 12 months after the last dose of ruxolitinib for 
disease response and survival unless one of the following occurs earlier: 
• consent is withdrawn  
• new anti-cancer treatment is started (follow for survival only), 
• patient is discharged to hospice (terminal) care (follow for survival only)    
9 Expected Adverse Events and Potential Risks 
9.1 
Ruxolitinib 
Refer to the most current IB for the comprehensive list of adverse events. 
 
The followings severe events have been seen in patients being treated for 
myelfibrosis or polycythemia vera and are considered expected: 
 
Very Common (greater than 
or equal to 10%, or 10 or 
more out of 100 people) 
Common (between 1 to 
10%, or between 1 and 10 
out of 100 people) 
Rare (less than 1 out of 100 
people) 
• Ruxolitinib may cause low 
platelet counts 
(thrombocytopenia), low 
red blood cell counts 
• Infection 
• chills 
• aches 
• fever 
• Progressive multifocal 
leukoencephalopathy 
• Non-Melanoma Skin 
Cancer 


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Very Common (greater than 
or equal to 10%, or 10 or 
more out of 100 people) 
Common (between 1 to 
10%, or between 1 and 10 
out of 100 people) 
Rare (less than 1 out of 100 
people) 
(anemia), and low white 
blood cell counts 
(neutropenia) 
• unusual bleeding 
• bruising 
• tiredness 
• shortness of breath 
• fever 
• Cholesterol increases 
• nausea 
• vomiting 
• weakness 
• painful skin rash or 
blisters 
 
The following severe events have been seen in patients being treated for acute or chronic 
GVHD and are considered expected. 
 
Common for acute 
GVHD (1 - 10%) 
Uncommon for 
acute GVHD 
(<1%) 
Common for 
chronic GVHD (1-
10%) 
Uncommon for 
chronic GVHD (<1%) 
• low platelet counts 
(thrombocytopenia), 
and low white blood 
cell counts 
(neutropenia): or 
low red cell, white 
cell, and platelet 
counts 
(pancytopenia) 
• CMV infection 
• Sepsis 
• Septic shock 
• low red blood cell 
counts (anemia) 
• low platelet counts 
(thrombocytopenia) 
• Urinary tract 
infection 
• Sepsis 
• Septic shock 
 
9.2 
Decitabine  
Refer to the most current IB or package insert(s) for the comprehensive list of 
adverse events. 
Very Common (greater than or 
equal to 10%, or 10 or more out 
of 100 people) 
Common (between 1 to 
10%, or between 1 and 
10 out of 100 people) 
Rare (less than 1 out of 
100 people) 
• low platelet count with 
increased risk of 
bruising/bleeding 
• blurred vision 
• pain  
• high blood sugar 
• headache 
• confusion 
• trouble sleeping 
• fluid in the lungs 


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Very Common (greater than or 
equal to 10%, or 10 or more out 
of 100 people) 
Common (between 1 to 
10%, or between 1 and 
10 out of 100 people) 
Rare (less than 1 out of 
100 people) 
• 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 
• 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  
• 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 
 
9.3 
Risks Due to DLI 
Acute Infusion Reaction Following Donor Lymphocytes 
Although infusion of donor lymphocytes has reportedly not been associated with serious 
acute hypersensitivity reactions, patients will be closely watched for the occurrence of 
hypotension, dyspnea and angiodema during the infusion and immediately thereafter.  
Corticosteroids should be avoided and acetaminophen and Benadryl may be 
administered as needed. 
 
Acute Graft-Versus-Host Disease 
Infusion of donor lymphocytes into patients who relapse post allogeneic bone marrow 
transplantation has frequently resulted in development of acute graft-versus-host disease 
with involvement of the skin and liver, often requiring treatment.  Despite treatment, 
some cases of GVHD have been of high grade and deaths from GVHD have been reported.  
GVHD may occur between 1 and 24 weeks post-infusion of the donor lymphocytes.  
Patients will have regular assessment for development of new or worsening of existing 
GVHD during the entire study period.  
 
Bone Marrow Aplasia 
After donor lymphocyte infusions, patients may develop aplasia requiring blood product 
transfusions and/or growth factor support.  This has been reported in 10-15% of reported 




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Incyte Corporation will supply Ruxolitinib at no charge to patients participating 
in this clinical trial.  
 
Ruxolitinib will be supplied as 5 mg tablets packaged in 60-count high-density 
polyethylene bottles.  All tablet excipients comply with the requirements of 
the applicable compendial monographs. 
 
All Incyte product labels will state "Caution: New Drug--Limited by Federal (or 
United States) law to investigational use." 
 
The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, 
distribution, and usage of investigational product in accordance with the 
protocol and any applicable laws and regulations. 
 
10.1.4 Storage Requirements 
Bottles of tablets should be stored at room temperature, 15°C to 30°C (59°F 
to 86°F). 
 
10.1.5 Preparation and Administration 
Tablets can be taken with or without food. Grapefruit juice should not be 
consumed while on Ruxolitinib. 
 
10.1.6 Drug Accountability and Destruction 
Ruxolitinib must be dispensed only from official study sites and to eligible 
patients under the supervision of the site investigator. Ruxolitinib should be 
stored in a secure area according to local regulations.  It is the responsibility of 
the site investigator to ensure that study drug is only dispensed to patients. 
After final drug reconciliation, unused ruxolitinib will be disposed at the site 
following procedures for the disposal of anticancer drugs. 
10.2 Decitabine 
10.2.1 Other Names 
Dacogen 
 
10.2.2 Product Description  
Dacogen™ (decitabine) for Injection contains decitabine (5-aza-2’-
deoxycytydine), an analogue of the natural nucleoside 2’-deoxycytidine. 
Decitabine is a fine, white to almost white powder with the molecular formula 




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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. 
 
10.2.6 Stability 
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. 
 
10.2.7 Drug Accountability 
Decitabine is commercially available and will be procured by the inpatient 
pharmacy per institutional guidelines. 
11 Clinical Evaluations and Procedures  
Scheduled evaluations up to Day +28 in each cycle may be performed +/-3 days from the 
targeted date; evaluations and procedures (including research related) performed after 
Day +28 through end of final cycle may be done +/-7 days of the targeted date. Follow-up 
beginning at 6 months may be done +/- 2 weeks of the targeted date. In addition, targeted 
days may be altered as clinically appropriate.  


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CPRC #2018LS066 
11.1 Required Clinical Care Evaluations  
 
Screening within 28 
days of study 
enrollment (within 14 
days of C1D1 for 
eligibility labs) 
Every Treatment Cycle 
Between study 
cycles (day 29-
56)3 
Post DLI  
Visit 
(4-6 weeks 
after last 
DLI) 
Follow-Up 
Q 3 months from the end 
of last cycle through 12 
months 
During 
Decitabine 
admin 
Day of DLI 
Written Consent 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Histological confirmation of diagnosis 
and staging 
X 
 
 
 
 
 
Prior treatment  
X 
 
 
 
 
 
Physical exam 
X 
X8 
X 
 
X 
X 
Provider assessment 
X 
X8 
X 
 
 
 
Weight (Height also during screen) 
X 
X8 
 
 
 
 
Concomitant medications 
X 
X (day 1 each 
cycle) 
 
 
 
 
Karnofsky performance status 
X 
 
 
X 
 
 
ECG 
X 
 
 
X 
 
 
Type and Screen (ABO/RH/ Indirect 
Antiglobulin) 
X 
 
 
 
 
 
Assessment of AEs 
X 
X 
X 
 
X 
 
Complete Blood Count with diff (CBC) 
X 
X8 
X 
X 
X 
X 
Comprehensive Metabolic Profile 
(CMP)1 
X 
X8 
X 
X 
X 
X 
HIV test 
X 
 
 
 
 
 
Hepatitis B and C 
X 
 
 
 
 
 
Pregnancy test (urine or serum) for 
WOCBP 
X2 
 
 
X 
 
 
Bone Marrow biopsy 
X4 
 
 
X5 
X 
 
Relapse/progression status 
X 
 
 
X 
 
 
Survival status 
 
 
 
 
 
X 


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Screening within 28 
days of study 
enrollment (within 14 
days of C1D1 for 
eligibility labs) 
Every Treatment Cycle 
Between study 
cycles (day 29-
56)3 
Post DLI  
Visit 
(4-6 weeks 
after last 
DLI) 
Follow-Up 
Q 3 months from the end 
of last cycle through 12 
months 
During 
Decitabine 
admin 
Day of DLI 
Study treatment 
Decitabine 
 
X (day 1-10 
or day 1-5 & 
8-12)6 
 
 
 
 
DLI 
 
 
X 
(between 
11-21 or 
13 -22)7 
 
 
 
Ruxolitinib 
 
2 times a day 
 
 
 
Through 6 months 
post end of last cycle 
Research Nurse visit 
 
Every two weeks 
 
X 
X 
1CMP to include sodium, potassium, chloride, creatinine, blood urea nitrogen, and liver function tests including AST, ALT, total bilirubin, and alkaline 
phosphatase  
2For women of childbearing potential (WOCBP): urine or serum pregnancy test within 14 days prior to study registration. If a urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required.  
3Continuous reassessment for eligibility to proceed to subsequent cycles 
4Results taken out of window may used as enrollment verification and will not be considered a deviation. 
5Required prior to cycle 3. This sample will not be taken if not moving on to cycle 3.  
6Day 1-5 in cycle 3 and 4 if CR achieved;  
7Between day 6 and 16 in cycle 3 and 4 if CR achieved  
8 Day 1 of cycle and additional frequency per site institutional guidelines for clinical care. If screening (baseline) labs were performed within 7 days of Day 1 of 
treatment, these do not need to be repeated.  For cycle 2 and later, lab work may be performed up to 3 days prior to the day 1 treatment day.


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11.2 Patient – Research Related 
Note: if a patient is not abiding by the required clinical care calendar (Section 11.1), the collection schedule 
of the toxicity data and research related samples may be altered or discontinued on an individual patient 
basis, as appropriate.   
 
It is recognized that with novel therapies as used 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. 
 
 
Prior to 
Cycle 1 
Every 
Treatment 
Cycle 
Prior 
to 
Cycle 3   
 Post DLI   
(4-6 weeks 
after last 
DLI) 
90 days (+/- 
7 days)  after 
the last day 
of last cycle 
180 days (+/- 
14 days) 
after the last 
day of last 
cycle 
Event Driven 
Event Driven 
Day 1 
At disease 
progression 
At GVHD 
diagnosis 
(+7 days) 
Peripheral blood: 
Four 10 mL heparin 
tubes and one 10 ml 
clot tube 
 
X1 
 
X4 
X 
X 
X4 
X 
Research bone 
marrow aspirate 
samples (max 10 ml, 
transferred to a 
heparin tube)  
 
X2 
 
 
X3 
 
X4 
 
 
 
X4 
 
1  Prior to decitabine and ruxolitinib administration 
2 Optional, Adult patients only 
3 This sample will not be taken if not moving on to cycle 3 
4 At the time of clinical biopsy. If disease progression research samples are taken prior to the post-DLI samples, 
additional samples are not needed 
 
11.2.1 Correlative Studies  
Blood and Bone Marrow samples should be shipped the day of collection (Monday-Thursday) for next 
day delivery to the Masonic Cancer Center’s Translational Therapy Lab (TTL). Refer to the Laboratory 
Manual for additional details. Pre-cycle 1 bone marrow sample is optional as it requires patient to 
undergo additional biopsy, while subsequent research bone marrow samples will be collected when the 
patient is having a bone marrow biopsy as part of clinical care. 
 
TTTL will process the samples to obtain mononuclear cells (MNC) and serum/plasma. TTL will analyze 
MNC by flow cytometry to evaluate NK cells for possible effects of therapy on phenotype and functional 
characteristics. Remaining MNC will be cryopreserved for batch analysis of effects on T cells and for other 
future testing.  
 
Potential mechanisms of action for JAK/STAT inhibition in the prevention of GVHD and augmentation of 
GVL include alterations in cytokine signaling, alterations in T-cell trafficking through CXCR3 expression, 


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effects on cellular differentiation, and effects on antigen presenting cell function. An exploratory 
objective of this study will be to evaluate the effects of the combination on immune effectors and to 
measure changes in biomarkers of GVHD and GVL. To address this objective, correlative studies may 
include: cellular phenotyping; leukemia antigen expression; cytokine and other soluble biomarker 
expression; chemokine receptor expression and RNA transcript analysis. DNA samples may be used to 
test for genetic associations of response to therapy or GVHD. These studies will be performed at 
Washington University at the end of study using batch analysis of banked samples. Remaining 
cryopreserved samples may be used for future research studies at the discretion of the principle 
investigator. 
11.3 Donor – Recommended Standard of Care 
Individual institutions may use local SOPs and clinical care guidelines, and unrelated donors will be 
screened through the NMDP. 
12 Adverse Event Monitoring, Documentation, and Reporting 
Toxicity and adverse events will be classified and graded according to NCI's Common Terminology Criteria 
for Adverse Events V 5.0 (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_50). 
 
The following definitions of adverse events (AEs) and serious adverse events (SAEs) will determine whether 
the event requires expedited reporting via the OnCore SAE Report Form in addition to routine 
documentation in the OnCore AE case report form (CRF).  
 
The reporting timeframes for SAEs, product related issues, and other reportable events are located in 
Section 12.3.   
 
Note:  throughout this section the generic term “study drug” refers to the study related treatment (the 
ruxolitinib, decitabine, and DLI). 
12.1 Adverse Event Terminology 
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. For the purposes of IND safety reporting, "reasonable possibility" means there 


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is evidence to suggest a causal relationship between the drug and the adverse event. Suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, which means any 
adverse event caused by a drug. 
 
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. It does not include an 
adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have 
caused 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 
• An important medical event 
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 
 
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.  
 
Expedited (Rapid) Reporting: Certain events may require rapid notification to entities providing patient 
safety oversight (e.g. IRB) as detailed in Section 12.3. For the IRB this is 5 business days from discovery.  
The categories for AE attribution to study treatment are as follows:  
• 
Definite – clearly related 
• 
Probable – likely related 
• 
Possible – may be related 
• 
Unlikely – doubtfully related 


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• 
Unrelated – clearly not related 
 
The following definitions are from the Masonic Cancer Center’s Standard Operating Procedure (SOP) 
Deviation Reporting: 
Major Deviation: A deviation or violation that impacts the risks and benefits of the research; may impact 
subject safety, affect the integrity of research data and/or affect a subject’s willingness to participate in 
the research. Deviations that place a subject at risk, but do not result in harm are considered to be major 
deviations. 
 
Minor Deviation: A deviation or violation that does not impact subject safety, compromise the integrity 
of research data and/or affect a subject’s willingness to participate in the research. 
12.2 AE Documentation  
AE reporting will occur via data entry into the study eCRF.  AEs reported through expedited processes 
(e.g., reported to Incyte, IRB, FDA, etc.) must also be reported in routine study data submissions.  Patients 
will be monitored for adverse events after the subject has signed the ICF through 30 days after the last 
dose of study drug. Adverse events recorded in the eCRFs include the following: 
 
• CTCAE grade 3 and greater allergic reactions related to ruxolitinib or decitabine occurring until 
30 days after the last treatment on study 
• CTCAE grades 3 and greater organ toxicity (cardiac, dermatologic, gastrointestinal, hepatic, 
pulmonary, renal/genitourinary, or neurologic) occurring until 30 days after the last treatment 
on study 
• aGVHD III-IV occurring until 3 months after the last cycle of treatment  
• CTCAE grade 4 neutropenia lasting more than 14 days, occurring until 30 days after the last 
treatment on study 
• CTCAE grades 3 and greater febrile neutropenia, or grade ≥ 3 neutropenia with documented 
infection, occurring until 30 days after the last treatment on study 
• CTCEA grade 4 thrombocytopenia lasting more than 14 days if pre-treatment platelet count > 100 
x 109/L, occurring until 30 days after the last treatment on study 
 
In addition any event meeting the definition of a serious adverse event (SAE) regardless of attribution 
that occurs during this period will be documented in the source document and recorded in OnCore.  
 
After the final treatment visit, monitoring for adverse event will become less frequent based on the 
schedule in Section 11 and only events at least possibly related to study treatment (based on the table 
above) will be documented upon knowledge. 


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12.3 SAE Documentation and MCC Reporting Requirements 
Individual institution reporting requirements are listed in section 12.5.  
 
All SAEs are documented using the MCC OnCore SAE Report Form and reported within the timeframes 
indicated below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Agency 
Criteria for reporting 
Timeframe 
Form to 
Use 
Submission 
address/ fax 
numbers 
U of MN 
IRB 
Events requiring prompt reporting including, but not 
limited to 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 or any protocol deviation that resulting in 
harm  For a complete list refer to 
http://www.research.umn.edu/irb/guidance/ae.htm
l#.VC7xraI0-sh  
Within 5 
business 
days of 
event 
discovery 
 
MCC SAE 
Report 
Form 
ETHOS 
 
copy SAEs to 
Incyte at  
SafetyReporting
@incyte.com 
(note: Incyte 
does not need 
copies of 
deviations) 
Deviations from the protocol, per current IRB 
reporting requirements 
Deviation 
Report 
FDA 
Unexpected and fatal or unexpected and life 
threatening suspected adverse reaction 
no later than 
7 Calendar 
Days 
MCC SAE 
Report 
Form 
Submit to FDA as 
an amendment to 
IND 
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) 
no later than 
15 Calendar-
Days 
Events that trigger an early study stopping rule. 
no later than 
7 Calendar 
Days 
Event 
Form 
Incyte 
Corporation 
Every SAE, regardless of suspected causality (eg, 
relationship to study drug(s) or study procedure or 
disease progression), occurring after the subject has 
signed the ICF through the last study visit (or 30 
days) after the last dose of study drug, whichever is 
later) must be reported to the Incyte within 24 
hours of learning of its occurrence, Incyte may 
request follow-up and other additional information 
from the Sponsor Investigator. 
Within 24 
hours of 
event 
discovery 
MCC SAE 
Report 
Form 
SafetyReporting@
incyte.com 
Masonic 
Cancer 
Center 
SAE 
Coordinator 
Events that count toward early study stopping rule. 
At time of 
reporting 
Event 
Form 
SAE Coordinator 
mcc-
saes@umn.edu 
with copy to 
Incyte 


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Expedited SAE Reporting Requirements:   
Report Within 24 Hours:  SAEs must be reported expeditiously to the Masonic Cancer Center Affiliate 
Sites Manager within 24 hours of knowledge.  
12.4 Early Stopping Rule Events Documentation and Reporting Requirements 
The following events count toward an early study stopping rule per Section 15.4 and must be reported 
to the MCC Affiliate Sites Manager and to Incyte Pharmaceuticals using the Event Form found OnCore 
under the reports tab: grade III-IV aGVHD until 3 months after the last cycle of treatment. 
 
An event that counts toward an early stopping rule does not necessarily constitute a SAE and should be 
reported as such only if they meet the criteria for reporting as defined in Section 12.3. 
12.5 Institutional Event Reporting Table 
Individual institutional sites will be responsible for reporting any event meeting local reporting 
requirements to their institutional IRB and/or other research oversight committees. 
 
Institutional sites will be responsible for reporting events as defined in sections 12.1, 12.2, 12.3 and 12.4 
within the following time frames to the MCC Affiliate Sites Manager 
 
Event Type 
Reporting Timeframe 
OnCore Form 
to Use 
Report to** 
Any event 
meeting the 
definition of a 
SAE  occurring 
after the subject 
has signed the 
ICF through the 
last study visit 
(or 30 days after 
the last dose of 
study drug, 
whichever is 
later) 
Within 24 hours of 
knowledge 
SAE Report 
Form 
Masonic Cancer Center (MCC) 
Affiliate Sites Manager  
affiliates@umn.edu 
 
The affiliate manager will submit 
SAEs to Incyte 
(SafetyReporting@incyte.com )  
 
Local institutional IRB or other 
entities per institutional policies 
and guidelines 
Stopping Rule 
Events as 
defined in 
section 12.4 
Within 24 hours of 
knowledge 
Stopping Rule 
Event Form 
Major and 
Critical Clinical 
Deviations, as 
defined in 
Section 12.1. 
Within 5 working days 
of knowledge 
Deviation 
Report Form 


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Event Type 
Reporting Timeframe 
OnCore Form 
to Use 
Report to** 
Minor 
Deviations, as 
defined in 
Section 12.1. 
Per Institutional Policy  n/a (record in 
Deviations 
Tab) but it is 
not necessary 
to report the 
event to MCC 
For UMN MCC only: minor 
deviations are reported to the UMN 
IRB by the study’s regulatory 
specialist per IRB reporting 
requirements. 
 
For Affiliate Sites: minor deviations 
are not reportable to the Masonic 
Cancer Center. Report to local 
institutional IRB or other entities 
per institutional policies and 
guidelines. 
**events occurring at the University of Minnesota are reported to the study’s Regulatory Specialist who will submit Incyte and other 
entities as usual 
13 Study Data Collection and Monitoring 
13.1 Data Management 
This study will collect regulatory and clinical data using University of Minnesota CTSI’s instance of 
OnCore® (Online Enterprise Research Management Environment). 
 
The Oncore database resides on dedicated secure and PHI compliant hardware consisting of 3 physical 
servers: dev, DR, and production. The dev server is located in the University of Minnesota (UMN) 
datacenter (WBOB) and houses six database instances (test, train, sandbox, mcc reports, oncdm, and 
vendor) that are backed up locally because the data is refreshed from Oncore production data. The 
production server is located in the UMN datacenter (WBOB). All the data servers are managed by the 
Academic Health Center – Information Systems (AHC-IS) virtual servers which utilize clustered 
infrastructure to provide real-time failover of virtual servers. This real-time clustering is physically limited 
to the UMN data center. All relevant AHC IS procedures related for PHI compliant servers (as required 
by the Center of Excellence for HIPAA Data) apply to Oncore databases. 
 
The integrated data will be stored in PHI compliant servers managed by AHC IS with access given to those 
authorized users in the Clinical and Translation Science Institute Informatics team (CTSI BPIC and MCC 
CISS). The data will be integrated and extracted to researchers through the CTSI Informatics team and 
will be delivered through secure and compliant mechanisms (e.g. AHC IE data shelter, BOX, sftp, etc). If 
data de-identification is needed, then compliant AHC IE data de-identification tools will be used. The 
informatics team will grant the IRB approved study team members access to data. 
 


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Additional data about correlative laboratory samples generated by the Masonic Cancer Center 
Translational Therapy Laboratory (TTL) from the protocol-directed correlative research samples is stored 
in their Laboratory Information Management System (LIMS).The LIMS database application is also stored 
on a production server located in the UMN datacenter (WBOB) and is managed by the Academic Health 
Center 
 
Key study personnel are trained on the use of OnCore and will comply with protocol specific instructions 
embedded within the OnCore. 
13.2 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 specific calendar, and updating the patient record until patient death or end of 
required study participation.  
13.3 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 
https://z.umn.edu/dsmp. 
 
For the purposes of data and safety monitoring, this study is classified as high risk. Therefore the 
following requirements will be fulfilled: 
 
 At least bi-annual review of the study’s progress by the Masonic Cancer Center Data and Safety 
Monitoring Council (DSMC). 
 The PI will comply with at least twice yearly monitoring of the project by the institution’s monitoring 
services. 
 The PI will oversee the submission of all reportable adverse events per Section 12.3 to the Masonic 
Cancer Center’s SAE Coordinator, the University of Minnesota IRB, and the FDA.  
 The PI with the CTO has oversight responsibility for trial monitoring at affiliate sites. 
 
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). 
 
 
 
 


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IND Annual Reports  
In accordance with regulation 21 CFR § 312.33, the Sponsor-Investigator will submit a progress report 
annually. The report will be submitted within 60 days of the anniversary date that the IND went into 
effect. 
13.4 Teleconferences – Lead Site and Affiliate Site  
Regular teleconferences to facilitate communication between participating sites regarding the study’s 
progress, patient updates, summary of safety reports, case report form completion, and other issues for 
discussion. The University of Minnesota Affiliate Manager will be responsible for arranging these 
teleconferences and preparing the agenda. Meetings will occur at least every 3 weeks; however, these 
may be scheduled more or less frequently at the discretion of the lead institution. Participation of a 
minimum of one representative from each affiliate site will be required. These teleconferences are in 
addition to other previously described site interactions including centralized patient registration, 
institutional and MCC required reporting of safety related issues, case report form completion in the 
study’s central database (OnCore) and affiliate oversight through self-monitoring in compliance with the 
Masonic Cancer Center’s Data and Safety Monitoring plan.  
13.5 Affiliate Site Monitoring 
The PI (Dr. Juckett) 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://z.umn.edu/dmsp).  
 
The investigator will permit study-related monitoring, audits, and inspections by the study’s Principal 
Investigator 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 facilities (e.g. pharmacy, diagnostic 
laboratory, etc.) will be available for trial related monitoring, audits, or regulatory inspections. 
13.6 Record Retention 
The investigator will retain study records including source data, copies of case report form, 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.  
 
Please contact the CTO before destroying any study related records. 


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14 Study Endpoints 
14.1 Primary Endpoint 
Efficacy is measured by overall survival (OS) at 6 months.  
14.2 Secondary Endpoints 
Secondary endpoints of safety and efficacy are measured as below. 
• 
OS at 12 months  
• 
Cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD II-IV) at 3 months  
• 
PFS at 6 and 12 months in patients 
• 
Cumulative incidence of relapse at 6 and 12 months  
• 
Complete remission (CR) at 6 and 12 months  
• 
Cumulative incidence of non-relapse mortality (NRM) at 6 and 12 months  
• 
Best response until next line of treatment, death, or last follow up, whichever occurs sooner 
14.3 Correlative Endpoints 
• 
Incidence and severity of adverse events (AEs) and serious AEs (SAEs) until 3 months after day 1 
of the last received cycle 
• 
Correlative studies: T cell and NK cell subset analysis by flow cytometry, correlation between 
TP53 mutation and response, clonal dynamics during and after the course of therapy 
15 Statistical Considerations 
15.1 Objectives and Study Design 
This is a single-arm, open-label, multi-center modified Simon’s two-stage phase II trial of a combined 
modality treatment for relapsed AML and MDS after allo-HCT. The primary endpoint is 6 month OS 
measured from day 1, cycle 1. We expect a total of 34 enrolled subjects will allow us to obtain 32 
evaluable patients. 
 
Patients are considered evaluable if they receive the first dose of decitabine and ruxolitinib. All other 
patients will be replaced.  
15.2 Statistical Analysis 
 
Analysis of the Primary Endpoint 
Overall survival will be estimated by Kaplan-Meier curves along with 95% confidence bands to provide 
precision. 


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Secondary and exploratory analysis 
Analysis of secondary endpoints will be primarily descriptive. Progression-free survival will be estimated 
by Kaplan-Meier curves. Cumulative Incidence will be used to estimate the probability of relapse and 
acute GVHD, treating non-event death as a competing risk. Likewise, relapse will be treated as a 
competing risk when estimating the probability of non-relapse mortality. Response and the number of 
patient in complete remission will be estimated with simple proportions. Summary statistics using 
frequencies and proportions of patients will be used to assess adverse and severe adverse events and 
medians, ranges and descriptive plots for immune therapy. The correlation between TP53 mutation and 
response will be assessed with a chi-square test or Fisher’s exact test depending on expected cell 
frequencies. Similar statistics will be used for the correlation against clonal dynamics curing and after 
the course of therapy. 
 
Subgroup Analysis 
We will assess subgroup analysis of endpoints by donor type. Overall survival is not assumed to differ by 
donor type and this trial is not powered to determine differences within subgroups and will therefore 
be considered exploratory. 
 
15.3 Sample Size 
This study is designed as a two-stage phase II trial to estimate OS.  Since the goal is to estimate the OS 
at a long-term time-point (6 months), our design is a generalization of the Simon design. Rather than 
suspension of the trial for evaluation after stage 1, this design uses an optimal interim analysis for futility 
without suspension of accrual as proposed by Huang et al17. The goal of this design minimizes the 
expected sample size under the assumed parameters. Our trial assumes that a 6-month OS of 25% is 
unacceptably low and a 6-month OS of 50% is a rate worthy of further study. Both the null and alternative 
hypotheses assume that the OS follow an exponential distribution. Given an overall one-sided type I 
error of 5%, 32 evaluable patients will provide 80% statistical power. 
 
When 14 patients have been enrolled (stage 1), it is expected that the accrual will stop if the 6 month 
Kaplan-Meier estimate of OS is less than 30.0%. It is not required that the 14th patient be followed for 6 
months prior to making a decision of whether to continue the trial. Once the 14th patient has been 
enrolled, the statistician can calculate survival to determine if it falls below the cut-point. If the trial 
reaches the end of stage II after 32 evaluable patients, significant clinical activity would require at least 
a 6 month Kaplan-Meier estimate of OS of 39.2%. The probability of stopping at the interim analysis 
under the null hypothesis is 63.5% and 10.9% under the alternative hypothesis. The R package 
‘Optinterm’ with functions ‘OptimDes’ and ‘SimDes’ were used to create design parameters. Assuming 
that 5% of enrolled patients are not evaluable, we expect recruitment of 34 patients. 
 


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Accrual 
We perform approximately 30 DLIs per year at the collaborating institutions combined. Considering 
~50% screen failures and enrollment on competing trials, we expect to complete enrollment in 
approximately 2 years with an additional  year of follow up after the last patient has been enrolled. 
15.4 Stopping Rules     
Toxicity Monitoring and stopping rules 
Monitoring guidelines are developed to monitor excess toxicity using a continuous monitoring strategy 
based on an adaptation of Pocock stopping boundaries20. In the event that a stopping rule is triggered, 
enrollment will be halted and reviewed by the full study committee and if appropriate by the IRB, prior 
to initiation of re-enrollment. Additionally, the FDA will be informed if a stopping rule is triggered. The 
stopping 
rule 
was 
calculated 
using 
the 
following 
website: 
http://cancer.unc.edu/biostatistics/program/ivanova/ContinuosMonitoringForToxicity.aspx 
 
Grade III-IV aGVHD until 3 months after the last cycle of treatment 
Stopping rules were developed for excessive grade III-IV aGVHD. Previous results from trials of HMA plus 
DLI have reported an incidence of ~10% for aGVHD III-IV8,9,18,19. The goal is to construct a boundary based 
on aGVHD grade III-IV such that the probability of early stopping is at most 5% if the true rate is equal to 
10% and our sample size is 34. Given these parameters, the upper stopping boundary for aGVHD grade 
III-IV is 2 events out of 2 patients, 3 out of 6, 4 out of 10, 5 out of 15, 6 out of 21, 7 out of 27 or 8 out of 
33. The probability of early stopping from excessive aGVHD grade III-IV if the true probability is 30% is 
86%. 
16 Ethical and Regulatory Considerations 
16.1 Good Clinical Practice 
The study will be conducted in accordance with the appropriate regulatory requirement(s). 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 
duration of the study and retained according to the appropriate regulations.  
16.2 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.  


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16.3 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. 
 


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17 References  
1  Schmid C, Labopin M, Nagler A, Niederwieser D, Castagna L, Tabrizi R et al. Treatment, risk factors, and 
outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell 
transplantation. Blood 2012; 119: 1599–606. 
2  Bejanyan N, Weisdorf DJ, Logan BR, Wang H-L, Devine SM, de Lima M et al. Survival of Patients with Acute 
Myeloid Leukemia Relapsing after Allogeneic Hematopoietic Cell Transplantation: A Center for 
International Blood and Marrow Transplant Research Study. Biol Blood Marrow Transplant 2015; 21. 
doi:10.1016/j.bbmt.2014.11.007. 
3  Rashidi A, Weisdorf DJ, Bejanyan N. Treatment of relapsed/refractory acute myeloid leukaemia in adults. 
Br J Haematol 2018. doi:10.1111/bjh.15077. 
4  Guillaume T, Gaugler B, Chevallier P, Delaunay J, Ayari S, Clavert A et al. Escalated lymphodepletion 
followed by donor lymphocyte infusion can induce a graft-versus-host response without overwhelming 
toxicity. Bone Marrow Transplant 2012; 47: 1112–7. 
5  Miller JS, Weisdorf DJ, Burns LJ, Slungaard A, Wagner JE, Verneris MR et al. Lymphodepletion followed by 
donor lymphocyte infusion (DLI) causes significantly more acute graft-versus-host disease than DLI alone. 
Blood 2007; 110: 2761–3. 
6  Sánchez-Abarca LI, Gutierrez-Cosio S, Santamaría C, Caballero-Velazquez T, Blanco B, Herrero-Sánchez C 
et al. Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting. 
Blood 2010; 115: 107–21. 
7  Craddock C, Jilani N, Siddique S, Yap C, Khan J, Nagra S et al. Tolerability and Clinical Activity of Post-
Transplantation Azacitidine in Patients Allografted for Acute Myeloid Leukemia Treated on the RICAZA 
Trial. Biol Blood Marrow Transplant 2016; 22: 385–390. 
8  Schroeder T, Rachlis E, Bug G, Stelljes M, Klein S, Steckel NK et al. Treatment of acute myeloid leukemia or 
myelodysplastic syndrome relapse after allogeneic stem cell transplantation with azacitidine and donor 
lymphocyte infusions--a retrospective multicenter analysis from the German Cooperative Transplant Study 
Group. Biol Blood Marrow Transplant 2015; 21: 653–60. 
9  Steinmann J, Bertz H, Wäsch R, Marks R, Zeiser R, Bogatyreva L et al. 5-Azacytidine and DLI can induce 
long-term remissions in AML patients relapsed after allograft. Bone Marrow Transplant 2015; 50: 690–5. 
10 Choi J, Ritchey J, Prior JL, Holt M, Shannon WD, Deych E et al. In vivo administration of hypomethylating 
agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. Blood 2010; 116: 129–
139. 
11 Ghobadi A, Choi J, Fiala MA, Fletcher T, Liu J, Eissenberg LG et al. Phase I study of azacitidine following 
donor lymphocyte infusion for relapsed acute myeloid leukemia post allogeneic stem cell transplantation. 
Leuk Res 2016; 49: 1–6. 
12  Welch JS, Petti AA, Miller CA, Fronick CC, O’Laughlin M, Fulton RS et al. TP53 and Decitabine in Acute 
Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med 2016; 375: 2023–2036. 
13  Cany J, Roeven MWH, Hoogstad-van Evert JS, Hobo W, Maas F, Franco Fernandez R et al. Decitabine 
enhances targeting of AML cells by CD34+ progenitor-derived NK cells in NOD/SCID/IL2Rgnull mice. Blood 
2018; 131: 202–214. 
14  Spoerl S, Mathew NR, Bscheider M, Schmitt-Graeff A, Chen S, Mueller T et al. Activity of therapeutic JAK 
1/2 blockade in graft-versus-host disease. Blood 2014; 123: 3832–3842. 


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15  Carniti C, Gimondi S, Vendramin A, Recordati C, Confalonieri D, Bermema A et al. Pharmacologic 
Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute GVHD While Preserving GVT Effects. 
Clin Cancer Res 2015; 21: 3740–3749. 
16  Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder SK et al. Ruxolitinib in 
corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter 
survey. Leukemia 2015; 29: 2062–2068. 
17  Huang B, Talukder E, Thomas N. Optimal two-stage phase II designs with long-term endpoints. Stat 
Biopharm Res 2010; 2: 51–61. 
18  Schroeder T, Czibere A, Platzbecker U, Bug G, Uharek L, Luft T et al. Azacitidine and donor lymphocyte 
infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation. 
Leukemia 2013; 27: 1229–1235. 
19  Schroeder T, Rautenberg C, Krüger W, Platzbecker U, Bug G, Steinmann J et al. Treatment of relapsed 
AML and MDS after allogeneic stem cell transplantation with decitabine and DLI—a retrospective 
multicenter analysis on behalf of the German Cooperative Transplant Study Group. Ann Hematol 2018; 97: 
335–342. 
20 Ivanova, A., Qaqish, B.F., and Schell, M.J. (2005). Continuous toxicity monitoring in phase II trials in 
oncology. Biometrics 61: 540-545 
 


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Appendix I – Karnofsky Performance Status Scale 
 
Percentage 
 
100 
Normal, no complaints, no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
80 
Normal activity with effort; some signs or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or do active work 
60 
Requires occasional assistance, but is able to care for most of his/her needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled, hospitalization indicated. Death not imminent 
20 
Very sick, hospitalization necessary, active supportive treatment necessary 
10 
Moribund, fatal processes, progressing rapidly 
0 
Dead 
 
REFERENCE 
  
Karnofsky DA:  Meaningful clinical classification of therapeutic responses to anti-cancer drugs. Editorial:  Clin Pharmacol Ther 2:709-712, 1961. 
 


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Appendix II –– GVHD Grading Scales 
Acute GVHD: 
 
Consensus Clinical Stage and Grade of Acute GVHD (Glucksberg et al, 1974; Thomas et al, 1975, Przepiorka et al, 1995) 
Stage 
Skin 
Liver 
Lower Gastrointestinal 
Tract 
Upper Gastrointestinal 
Tract 
1 
Maculopapular rash 
<25% of body surface 
Bilirubin 2.0 – 3.0 
mg/dl 
Diarrhea 500 – 1000 
mL/day or 280 – 555 
mL/m2 
No protracted nausea 
and vomiting 
2 
Maculopapular rash 25-
50% body surface 
Bilirubin 3.1 – 6.0 
mg/dl 
Diarrhea 1000 – 1500 
mL/day or 556 – 833 
mL/m2 
Persistent nausea, 
vomiting or anorexia 
3 
Generalized 
erythroderma 
Bilirubin 6.1 – 15.0 
mg/dl 
Diarrhea >1500 mL/day or 
>833 mL/m2 
 
4 
Generalized 
erythroderma with 
bullous formation and 
desquamation 
Bilirubin > 15 mg/dl 
Severe abdominal pain, 
with or without ileus, or 
stool with frank blood or 
melena 
 
 
 
University Of Minnesota Acute GVHD Grading 
Acute GVHD Grade 
Skin Stage 
Liver Stage 
Lower GI Stage 
Upper GI Stage 
   I 
1-2 
0 
0 
0 
   II 
3 
1 
1 
1 
   III 
- 
2-4 
2-3 
 
   IV 
4 
- 
4 
 
•  Each column identifies minimum criteria for organ grade.  
•  Each grade is based on maximum stage for each individual organ involved 
e.g. Grade II = skin stage 3 and/or liver stage 1 and/or gut stage 1 and/or UGI stage 1 
 
 
 
 





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