Clinical trial NCT03113071
Conditions: Acute Myeloid Leukemia Myelodysplastic Syndromes
Sponsor: Fox Chase Cancer Center
Start date: 2017-06-02; Completion date: 2019-03-11
Enrollment: 1 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary hypothesis is that digoxin can be safely added to decitabine and will increase the response rates in medically unfit patients with newly diagnosed AML/MDS or those with relapsed/refractory AML/MDS. Furthermore, it is hypothesized that the addition of digoxin to decitabine will result in distinct epigenetic alterations in AML/MDS patients.

Detailed description:

Arms: arm 1: For Group#1 a total of 37 patients with newly diagnosed MDL or MDS will be enrolled, including the eligible patients originally enrolled in the phase Ib portion (safe dose group) of the study, with the goal of determining the clinical activity of our experimental regimen. In the phase II segment, all new patients who are enrolled will initially be randomized in a 1 to 1 fashion to receive decitabine alone or decitabine plus digoxin for one cycle before receiving decitabine plus digoxin for all subsequent cycles for a total of 6 cycles. arm 2: or Group#2 the target will be to enroll a total of 60 patients with relapsed or refractory AML/MDS, including the eligible patients enrolled in the phase Ib group. This group will have randomization and treatments similar to Group#1.
Interventions: intervention 1: Decitabine intervention 2: Digoxin
Intervention descriptions: intervention 1: Decitabine will be administered in combination with Digoxin intervention 2: Decitabine will be administered in combination with Digoxin

Protocol documents:
Prot_SAP_000.pdf: 
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HM-091 A Phase Ib/II Study of the Safety and Activity of Digoxin with Decitabine in Adult 
AML and MDS
Sponsor Investigator:
Philip Pancari, MD
Jeanes Hospital of TUHS
7604 Central Avenue
Philadelphia, PA 19111
Phone: 267-858-2687
Fax: 215-214-3127
Email: Philip.Pancari@fccc.edu
Co-Investigators:
Dr. Jean-Pierre Issa 
Fels Institute for Cancer Research and Molecular Biology 
Temple University-Lewis Katz School of Medicine
3500 N. Broad Street 
Philadelphia, PA 19140 
Phone: 215-707-4307
Email: jpissa@temple.edu
Patricia Kropf, MD
Fox Chase Cancer Center
Phone: 215 214-3128
Email: Patricia.Kropf@tuhs.temple.edu
Statistician:
Karthik Devarajan, PhD
Fox Chase Cancer Center
Phone: 215-728-2794
Email: Karthik.Devarajan@fccc.edu
Correlatives Statistician:
Karthik Devarajan, PhD
Fox Chase Cancer Center
Phone: 215-728-2794
Email: Karthik.Devarajan@fccc.edu
Study development:                          Nasheed M. Hossain, MD
                                                            Phone: 607-262-6224
Version Date: 06/02/2017


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Amensment #3 : 02/08/2018


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Schema
Population up to 100 Patients with newly diagnosed or relapsed 
AML/MDS who are deemed unfit for standard cytotoxic chemotherapy 
intervention
Disease Assessment

Evaluate response after cycle 3 and cycle 6 with Bone Marrow Biopsy

During Cycle 1+2 collect PB samples for correlative studies
Continue treatment until:

Disease progression

Unacceptable toxicity

Patient preference

Completion of planned 6 cycles of 
therapy
Follow up
Upon treatment discontinuation, patients will 
be followed up every month for 6 months for 
disease progression
Treatment (28 days per cycle):

Digoxin: 0.5mg PO BID on Day 1 then 0.25mg/d for Days 2-10

Decitabine: 20mg/m2 IV Days 6-10


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Table of Contents
SCHEMA ...........................................................................................................................................III
1.0
INTRODUCTION.......................................................................................................................8
1.1. STUDY DISEASE .....................................................................................................................8
1.2. AGENT UNDER INVESTIGATION/INTERVENTION .......................................................................8
1.3. STUDY RATIONALE.................................................................................................................8
1.4. CORRELATIVE TESTING ........................................................................................................10
2.0
OBJECTIVES..........................................................................................................................11
2.1. PRIMARY OBJECTIVE............................................................................................................11
2.2. SECONDARY OBJECTIVES ....................................................................................................11
2.3. EXPLORATORY OBJECTIVES ................................................................................................11
3.0
STUDY PLAN..........................................................................................................................12
3.1. DESCRIPTION OF STUDY DESIGN, POPULATION AND DURATION OF STUDY THERAPY..........12
4.0
PATIENT SELECTION INCLUSION & EXCLUSION...........................................................13
4.1. INCLUSION CRITERIA ............................................................................................................13
4.2. EXCLUSION CRITERIA...........................................................................................................13
4.3. INCLUSION OF WOMEN AND MINORITIES...............................................................................14
4.4. PREGNANCY.........................................................................................................................14
4.5. PATIENT REGISTRATION.......................................................................................................15
5.0
TREATMENT PLAN ...............................................................................................................16
5.1. TREATMENT ADMINISTRATION..............................................................................................16
5.2. CONCOMITANT MEDICATIONS, SUPPORTIVE CARE, EXCLUDED THERAPIES AND 
RESTRICTIONS......................................................................................................................16
5.3. DURATION OF THERAPY .......................................................................................................17
5.4. DURATION OF FOLLOW UP....................................................................................................17
5.5. CRITERIA FOR DISCONTINUATION.........................................................................................17
6.0
DOSE MODIFICATIONS ........................................................................................................18
6.1. GENERAL PRINCIPLES..........................................................................................................18
6.2. DOSE LEVEL ADJUSTMENT TABLE(S) ..................................................................................18
6.3. SPECIFIC TOXICITIES AND MODIFICATIONS...........................................................................18
6.3.1.
DECITABINE......................................................................................................................18
6.3.2.
DIGOXIN............................................................................................................................19
6.4. DEFINITION OF DOSE LIMITING TOXICITIES (DLTS): .............................................................19
7.0
STUDY AGENT INFORMATION ...........................................................................................19
7.1. DECITABINE FORMULATION, PRODUCT IDENTIFICATION, PACKAGE AND LABELING.............19


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7.1.1.
PRODUCT DESCRIPTION: .................................................................................................19
7.1.2.
AVAILABILITY: ...................................................................................................................19
7.1.3.
SOLUTION PREPARATION:................................................................................................19
7.1.4.
STORAGE REQUIREMENTS: .............................................................................................19
7.1.5.
STABILITY .........................................................................................................................20
7.1.6.
ROUTE OF ADMINISTRATION:...........................................................................................20
7.2. DIGOXIN FORMULATION, PRODUCT IDENTIFICATION, PACKAGE AND LABELING...................20
7.2.1.
PRODUCT DESCRIPTION: .................................................................................................20
7.2.2.
AVAILABILITY: ...................................................................................................................20
7.2.3.
STORAGE REQUIREMENTS: .............................................................................................20
7.2.4.
STABILITY: ........................................................................................................................20
7.2.5.
ROUTE OF ADMINISTRATION:...........................................................................................20
8.0
CORRELATIVE /SPECIAL STUDIES ...................................................................................20
8.1. STUDY CORRELATIVE #1: ASSESSMENT OF GENOME WIDE METHYLATION BEFORE AND 
DURING THERAPY. ................................................................................................................20
8.2. STUDY CORRELATIVE #2: ASSESS GENE-SPECIFIC METHYLATION AND EXPRESSION OF 
TUMOR SUPPRESSOR GENES NORMALLY HYPERMETHYLATED IN MYELOID LEUKEMIA (P15, 
P21, RIL) BEFORE AND DURING THERAPY............................................................................21
8.3. STUDY CORRELATIVE #3: IN-DEPTH EPIGENETIC AND GENE EXPRESSION ANALYSIS OF 
THREE “BEST” AND THREE “WORSE” RESPONDERS TO GENERATE PRELIMINARY DATA ON 
PROFILES THAT MAY PREDICT RESPONSE TO STUDY REGIMEN. ............................................21
8.4. INSTRUCTIONS FOR COLLECTION AND SHIPPING OF BLOOD SAMPLES AND BONE MARROW 
BIOPSIES. .............................................................................................................................22
8.4.1.
BLOOD SAMPLE COLLECTION: ........................................................................................22
8.4.2.
BONE MARROW BIOPSY ...................................................................................................22
9.0
STUDY CALENDAR...............................................................................................................23
10.0 ADVERSE EVENTS................................................................................................................25
10.1. DEFINITIONS .........................................................................................................................25
10.1.1. ADVERSE EVENTS (AE)...................................................................................................25
10.1.2. SERIOUS ADVERSE EVENT (SAE) ..................................................................................25
10.1.3. SEVERITY RATING............................................................................................................25
10.1.4. ATTRIBUTION/RELATIONSHIP TO STUDY DRUG...............................................................25
10.1.5. EXPECTEDNESS ...............................................................................................................26
10.2. RECORDING AND REPORTING RESPONSIBILITIES.................................................................26
10.2.1. INVESTIGATIVE SITE RECORDING RESPONSIBILITIES: ...................................................26
10.2.2. INVESTIGATIVE SITE REPORTING RESPONSIBILITIES:....................................................26
10.2.3. OCR REPORTING RESPONSIBILITIES: ............................................................................27
10.3. PREGNANCY.........................................................................................................................28
11.0 MEASURES OF EFFECT.......................................................................................................28
11.1. DEFINITIONS .........................................................................................................................28
11.2. DISEASE PARAMETERS ........................................................................................................29
11.3. METHODS FOR EVALUATION OF MEASURABLE DISEASE......................................................29


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11.4. RESPONSE CRITERIA............................................................................................................29
11.4.1. PR/CR/CRI/CRP/HI........................................................................................................29
11.4.2. PROGRESSIVE DISEASE (PD) .........................................................................................30
11.4.3. STABLE DISEASE (SD) ....................................................................................................30
11.5. DURATION OF RESPONSE.....................................................................................................30
12.0 STATISTICAL CONSIDERATIONS ......................................................................................30
12.1. STUDY DESIGN/ENDPOINTS..................................................................................................30
12.1.1. STATISTICAL PLAN FOR ASSESSMENT OF DLTS FOR PHASE II PORTION OF THE 
STUDY: .............................................................................................................................31
12.2. ANALYSIS OF SECONDARY ENDPOINTS................................................................................32
12.3. ANALYSIS OF EXPLORATORY ENDPOINTS ............................................................................32
12.4. SAMPLE SIZE/ACCRUAL RATE .............................................................................................33
12.5. STRATIFICATION FACTORS...................................................................................................33
12.6. REPORTING AND EXCLUSIONS..............................................................................................33
12.6.1. EVALUATION OF TOXICITY................................................................................................33
12.6.2. EVALUATION OF RESPONSE.............................................................................................33
13.0 DATA AND SAFETY MONITORING PLAN..........................................................................33
13.1. MONITORING PLAN...............................................................................................................33
13.2. DATA SAFETY MONITORING COMMITTEE..............................................................................34
14.0 ADMINISTRATIVE..................................................................................................................34
14.1. DATA REPORTING ................................................................................................................34
14.2. RETENTION OF RECORDS .....................................................................................................34
14.3. STUDY AGENTS ....................................................................................................................35
14.4. INFORMED CONSENT ............................................................................................................35
15.0 REFERENCES ........................................................................................................................36


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1.0
Introduction
1.1. Study Disease
Acute myeloid leukemia (AML)/Myelodysplastic Syndrome (MDS) is a heterogeneous 
disease group typically treated with chemotherapy and frequently stem cell 
transplantation. However, a certain percentage of patients are considered “unfit” for 
intensive induction chemotherapy. Furthermore, despite an excellent response to initial 
therapy, a significant portion of patients with acute myeloid leukemia [AML] will relapse, 
either after their initial chemotherapy induction or after stem cell transplantation.1 In 
addition, many fail to respond to initial induction therapy and are categorized as 
“refractory.”4 A retrospective study conducted at the MD Anderson Cancer Center, 
looking at the outcomes of 1069 who achieved first complete remission [CR] and did not 
undergo allogeneic stem cell transplantation (SCT), highlighted that the probability of 
relapse-free survival at 3 years was only 29%.2 Patients with relapsed or refractory disease 
are often offered treatment with a hypomethlytaing agent [HMA], such as decitabine or 
salvage chemotherapy, usually utilizing a cytarabine based regimen.8,9 Furthermore, for 
elderly patients stem transplantation is not always a viable option and many are too frail to 
undergo multiple lines of chemotherapy and they too are offered treatment with HMAs or 
low dose cytarabine. While these drugs have clinical activity in AML, with reported 
response rates of 16-60%, neither offers a long term remission or cure.3,6 This has fueled 
the search for novel alternative therapeutic agents, ranging from such targeted therapies as 
FLT3 inhibitors to the novel anti-CD33 monoclonal antibody Gemtuzumab Ozogamicin, 
new purine analogs such as clofarabine and different iterations of various HMAs. 
1.2. Agent under Investigation/intervention
Cardiac glycosides have been shown in vitro to inhibit the differentiation and proliferation 
of tumor cells via multiple pathways, including promotion of cell cycle arrest and 
differentiation via epigenetic pathways. Studies using the human leukemic cell line, HL-
60, demonstrated that the cardiac glycoside, ouabain, at micromolar concentrations 
induces leukemic cell apoptosis (as indicated by nuclear fragmentation, reduced nuclear 
DNA and loss of clonogenic potential).5 In preliminary studies from our laboratory, the 
epigenetic activity of digoxin, alone and in combination with decitabine, was investigated 
utilizing the human cell lines, YB5, HL-60 and K562. In these studies, treatment with 
digoxin, at 10 uM and 50 uM concentrations, led to increased expression of normally 
silenced regulatory genes and was associated with increased tumor cell apoptosis.
1.3. Study Rationale
We initially utilized the human colon cancer cell line, YB5, by incubating with a variety 
of different FDA-approved drugs, obtained from the NCI-Developmental Therapeutics 
Program, at two dosing schedules (72hr treatment at 10 uM or 24hr at 50uM). The cells 
were then analyzed for epigenetic changes in tumor suppressor gene expression by flow 
cytometry to analyze for expression of green fluorescent protein (GFP), which has low 
baseline expression in YB5 cells. This initial analysis highlighted that digoxin exerts an 
epigenetic effect on the tumor cells as indicated by the observation of increased GFP 
expression in cell lines treated with digoxin. Further experiments using specially labeled 
YB5 cell lines helped to delineate that the epigenetic effect of digoxin, in contrast to that 


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of HMAs, is modulated by Ca2+ signaling and activation of Calcium/calmodulin-
dependent protein kinase (CamK). This highlighted that digoxin exerted its epigenetic 
effect via a different pathway than traditional epigenetic agents such as HMAs.  The pre-
clinical studies from our lab suggest that not only does the cardiac glycoside have the 
ability to alter epigenetic pathways in cancer cells but it also appears to work concurrently 
with HMAs. Specifically we observed that greater gene expression and cell apoptosis were 
observed with combinations of digoxin and decitabine than either agent alone.
Our primary hypothesis is that digoxin can be safely added to decitabine and will increase 
the response rates in medically unfit patients with newly diagnosed AML/MDS or those 
with relapsed/refractory AML/MDS. Furthermore, we hypothesize that the addition of 
digoxin to decitabine will result in distinct epigenetic alterations in AML/MDS patients. 
The study population will include newly diagnosed and relapsed/refractory AML/MDS 
patients who are deemed to be unfit for standard induction chemotherapy or further lines 
of standard therapy. We chose to focus on this group given the ongoing need for new 
therapeutic options in this group given the low rates of efficacy with current standard 
treatment options 
Our specific endpoints are to assess the safety of digoxin + decitabine in AML/MDS 
patients and to also assess the epigenetic effects of this combination compared to 
decitabine alone. In addition, as an exploratory aim, for the three “best” and three “worst” 
responders, we aim to carry out in-depth epigenetic and gene expression analysis to 
generate preliminary data on profiles that may predict response to the study regimen. Once 
differences are identified they will be verified using samples from the other patients 
enrolled in the trial.
We chose specifically digoxin as our cardiac glycoside for this study because it is readily 
available for clinical use. Furthermore, there is an extensive cardiology literature on the 
safe dosing and titration of digoxin in the clinical setting. We chose to utilize the 
congestive heart failure dosing for this study because it utilizes a fixed dosing schedule 
and minimizing the risk of having toxic serum levels of digoxin. 
With regards to risk and benefits; an HMA is standard of care for patients who fall into 
our study population and decitabine is commonly utilized in this clinical setting.7 Patients 
will be getting the standard therapeutic treatment and in addition will also be getting 
digoxin, which based on available pharmacological data is not postulated to affect each 
other’s pharmacokinetics. We will be closely monitoring patient’s serum digoxin levels 
and EKGs to minimize the risk of patients developing digoxin toxicity while they are on 
study. 
Despite extensive research efforts, there are a limited number of therapeutic options for 
newly diagnosed and relapsed/refractory AML/MDS patients considered unfit for 
induction chemotherapy or further lines of chemotherapy. Though stem cell 
transplantation remains a potential option for some in this group; donor availability and a 
patient's physical status often limits the accessibility of this option. Therefore, there is an 


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unmet need to expand the treatment options available in order to provide patients with 
better disease control and to potentially act as a bridge to a stem cell transplant. Our 
preliminary in vitro data has already highlighted the epigenetic potential of combining 
digoxin with decitabine and our goal is to assess the safety and clinical activity of digoxin 
combined with decitabine. We also hope to generate preliminary data on the epigenetic 
impacts of this regimen with the future goal of further assessing the epigenetic profiles of 
a larger cohort of patients treated with this regimen in order to develop a biomarker profile 
to guide decision making in selecting treatment regimens and improve outcomes for 
patients with AML. This proposed project strives to increase the number of options 
available for medically unfit or relapsed/refractory AML patients and additionally will 
generate additional epigenetic data that can be utilized in the construction of biomarker 
profiles to guide both treatment choices and insights on clinical outcomes in this difficult 
to treat group of patients.
1.4. Correlative Testing
1. Genome methylation assessment in AML blasts via LINE-1 methylation status 
assessment prior to and during therapy.
LINE-1 methylation is an expedient method of assessing global DNA methylation 
changes. It involves bisulfite treatment of DNA and PCR amplification of repetitive DNA 
elements (specifically long interspersed nucleotide elements, LINE-1) utilizing LINE-1 
specific primers. The results elements are then pyrosequenced. Analysis of these DNA 
elements, which are normally heavily methylated, serves as a substitute marker for global 
genomic methylation. 10,11,12We chose this assay as our method of choice to assess global 
genomic methylation status based on its relatively quick turn-around time, ease use of the 
assay and Dr. Issa’s lab’s expertise in this methodology. 
2. Targeted gene methylation and expression assessment of p15, p21, RIL prior to 
and during therapy.
Decitabine has a clear effect on inducing gene expression of aberrantly silenced genes, 
which may be boosted by the combinations. To study the effects of the combination (vs. 
decitabine alone), we will use real-time PCR to measure expression of p15, p21 and RIL, 
which are known tumor suppressor genes normally hypermethylated in myeloid leukemia. 
We will also assess the methylation status of p15, p21, RIL genes which are known to be 
hypermethylated in AML/MDS and are also postulated to have a prognostic impact on 
outcomes.8,9 We will utilize GAPDH as a control gene during our analysis. The 
methylation assessment will be carried out in a manner similar to that described for LINE-
1 methylation assessment but will utilize RNA and gene specific primers. The assay 
methodology chosen is based on that established in the literature for this type of analysis 
and which Dr. Issa’s lab carries out on a regular basis in their pre-clinical studies. 


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3. For three “best” and three “worst” responders, carry out in-depth epigenetic and 
gene expression analysis to generate preliminary data on profiles that may predict 
response to study regimen.
For these patients we will analyse their bone marrow biopsy material collected at pre-
study, at the end of cycle 3 and cycle 6 to carry out deep sequencing in order to analyze 
their DNA methylation profile, transcriptome profile and exome profile. We will 
determine gene methylation status using the Digital Restriction Enzyme Analysis of 
Methylation (DREAM) technique, which is a simple, cost effective and quantitative 
method of determining differences in gene methylation greater than 10-30% with a low 
false positive rate.16 This assay was first described in Dr. Issa’s lab and its sensitivity, cost-
effectiveness and Dr. Issa’s expertise makes it an ideal assay for this assessment. 
Transcriptome profile will be assessed via RNA sequence analysis. This will be carried 
out based on the standard methodology established at the FCCC Core facility and sample 
processing will be handled by Dr. Issa’s lab. Whole exome profile assessment will be 
carried out by exome sequencing; which  is based on the established literature and will be 
facilitated by the Otogenetics Company. Finally, once differences in profiles are identified 
we will attempt to verify our findings by analyzing samples from the other patients 
enrolled on the trial.
2.0
Objectives 
2.1. Primary Objective
1. To assess the maximum tolerated dose (MTD) of digoxin when added to a standard 
dose of decitabine in patients newly diagnosed AML/MDS or those with 
relapsed/refractory AML/MDS considered unfit for induction chemotherapy.
2. To assess the safety and efficacy of digoxin when added to a standard dose of 
decitabine in patients newly diagnosed AML/MDS or those with relapsed/refractory 
AML/MDS considered unfit for induction chemotherapy.
2.2. Secondary Objectives 
1. To determine the in vivo epigenetic effect of digoxin in AML and MDS by assessing 
overall genome methylation (based on LINE-1 global methylation). 
2. To determine gene-specific methylation and expression of tumor suppressor genes 
normally hypermethylated in myeloid leukemia (p15, p21, RIL). 
2.3. Exploratory Objectives
To carry out in-depth epigenetic and gene expression analysis to generate preliminary 
data on profiles that may predict response to study regimen. 


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3.0
Study Plan 
3.1. Description of Study Design, Population and Duration of Study Therapy 
We will conduct a Phase Ib/II clinical trial to determine the safety and clinical activity of 
digoxin with decitabine. The phase Ib portion of the study will be a safety assessment. 
All patients will receive a standard dose of intravenous decitabine (20mg/m2 IV) daily for 
five total doses and will also receive a dose of digoxin daily, cycled every 4 weeks. 
Patients will take digoxin for a total of ten days, starting five days prior to their first dose 
of decitabine and continuing concurrently with each dose of decitabine. The first day of 
digoxin will consist of a loading dose of digoxin (0.5mg PO BID on day 1) and 
subsequent doses will be 0.25mg/day PO. Patients will have their digoxin level checked 
on the first day of decitabine and on day 13 to ensure that serum  levels of digoxin are not 
toxic (>2ng/mL); they will also have an EKG on the first day of digoxin administration 
and on day 13.  During the first cycle the patients will be monitored for dose limiting 
toxicities (DLTs) which will be defined as any grade III or IV non-hematologic toxicity 
per the NCI CTCAE v4 guidelines. Initially 3 patients will be enrolled onto the phase Ib 
study. If 0 or 1 DLTs are observed then an additional 3 patients will be enrolled and 
monitored for toxicity during their first cycle. If 0 or 1 DLTs are observed in the total 6 
patients enrolled, the combination of digoxin plus decitabine will be considered safe and 
we will proceed to the phase II segment of the study. However, if 2 or more DLTs are 
observed the dose of digoxin will be decreased to 0.125mg/d (with same loading dose of 
0.5mg PO BID on day 1)and the safety study will be repeated with a new group of 6 
patients (enrolled as cohorts of 3 patients). If 2 or more toxicities are encountered with 
the decreased dose then the combination of digoxin and decitabine will be considered too 
toxic for further study. 
Once/if a safe dose is determined we will proceed to the phase II portion of the study. 
This will utilize a Simon’s two stage design for phase II studies. This part of the study 
will be carried out in parallel with two groups; Group#1 will consist of patients with 
newly diagnosed AML or MDS. Group#2 will include patients with relapsed/refractory 
AML or MDS.
For Group#1 our target will be to enroll a total of 37 patients, including the eligible 
patients originally enrolled in the phase Ib portion (safe dose group) of our study, with 
the goal of determining the clinical activity of our experimental regimen. In the phase II 
segment, all new patients who are enrolled will initially be randomized in a 1 to 1 fashion 
to receive decitabine alone or decitabine plus digoxin for one cycle before receiving 
decitabine plus digoxin for all subsequent cycles for a total of 6 cycles. Patients will have 
peripheral blood samples collected (prior to any treatment) on days 1, 6, 13, 20 during the 
first two cycles and Day 1 of cycle 3 for our biologic correlative and comparative studies. 
Patients will have a bone marrow biopsy to assess response to therapy at the end of cycle 
3 and 6 to determine clinical activity of our proposed regimen, with the marrow after 
cycle 3 being utilized to determine response rate and the marrow after cycle 6 will be to 
determine ongoing response to therapy. The study is designed such that patients will 
receive a total of 6 cycles of the experimental treatment regimen.


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For Group#2 our target will be to enroll a total of 60 patients, including the eligible 
patients enrolled in the phase Ib group. This group will have randomization and 
treatments similar to Group#1. Samples will be collected for comparative and correlative 
studies as previously described for Group#1 and response to therapy will be assessed in a 
similar fashion. 
4.0
Patient Selection Inclusion & Exclusion
4.1. Inclusion Criteria  
4.1.1 Patients must have a confirmed diagnosis of one of the following:

Newly diagnosed AML (excluding APL) 

Newly diagnosed intermediate-2 (INT-2) or high-risk MDS

Relapsed or Refractory AML, or INT-2 or high-risk MDS
4.1.2 For patients with refractory disease they must be at least 4 weeks out from most 
recent therapeutic intervention.
4.1.3 Age > 18 years.
4.1.4 ECOG performance status 0 – 2.
4.1.5 Patients must have normal organ function as defined below:

Total bilirubin
within normal institutional limits

AST/ALT (SGOT/SGPT)
< 2 times institutional normal limits

Creatinine
within normal institutional limits
OR

Creatinine clearance
> 60 mL/min/1.73 m2 for patients 
with creatinine levels above institutional normal
4.1.6 Ability to understand and willingness to sign a written informed consent and HIPAA 
consent document.
4.1.7 Agreement on the part of any male participant to use effective contraception during 
sexual activity throughout the duration of treatment and for 2 months after 
discontinuation, for protection against the risk of embryofetal toxicity.
4.2. Exclusion Criteria  
4.2.1 Patients who have had chemotherapy or radiotherapy within 4 weeks prior to 
entering the study or those who have not recovered from adverse events (less than or 
equal to Grade 1 toxicity) due to agents administered more than 4 weeks earlier.
4.2.2 Patients receiving any other investigational agents.
4.2.3 Patients with known brain metastases, active infection, or untreated CNS leukemia.


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4.2.4 Patients with prior or current history of digoxin exposure.
4.2.5 Patients requiring treatment with one or more medications known to interact 
adversely with digoxin, namely thiazide and/or loop diuretics, quinidine, ritonavir, 
amiodarone, cyclosporine, itraconazole, propafenone, spironolactone, verapamil.
4.2.6 Patients requiring treatment with one or more beta-blockers (metoprolol, atenolol, 
propranolol) or calcium channel blockers with AV-nodal blocking activity 
(verapamil, diltiazem). Patients being treated with AV nodal blocker (β-blocker or 
calcium channel blocker) are allowed if the agent is being used only for correcting 
hypertension, and if an acceptable alternative is available (for example, transitioning 
from a drug such as atenolol to Lisinopril or amlodipine) prior to starting treatment 
on therapy.
4.2.7 Patient with history of prior exposure to decitabine.
4.2.8 Patients eligible for intensive induction chemotherapy and “Medically unfit” based 
on a TRM score ≥ 13.1*
* TRM Score= A scoring model which predicts early death following intensive 
induction chemotherapy in newly diagnosed AML.
-Model looks at ECOG PS, Age, Platelet Count, Albumin, 2nd AML, WBC, % 
Peripheral Blasts, Creatinine
-Score above 13.1 associated with 31%+ chance of death after induction
4.2.9 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements.
4.2.10 Known HIV-positive patients on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with digoxin. In addition, 
these patients are at increased risk of lethal infections when treated with marrow-
suppressive therapy.
4.2.11 Pregnant or breast feeding. Refer to section 4.4 for further detail.
4.3. Inclusion of Women and Minorities
Men and women, regardless of race, ethnic group or sexual orientation are eligible for this 
study.  
4.4. Pregnancy
The effects of digoxin on the developing human fetus at the recommended therapeutic 
dose are unknown.  For this reason and because hypomethylating agents like decitabine 
used in this trial are known to be teratogenic, women of child-bearing potential (WOCBP) 
and men must agree to use adequate contraception (hormonal or barrier method of birth 


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control; abstinence) prior to study entry, for the duration of treatment, and for at least 3 
months after the completion of treatment. Should a woman become pregnant or suspect 
she is pregnant while participating in this study, she must inform her treating physician 
immediately.
Prior to study enrollment, WOBCP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. In additional, men enrolled on this study should understand the risks to any 
sexual partner of childbearing potential.
All WOCBP must have a negative pregnancy test within 72 hours prior to receiving the 
first dose of the investigational agent(s). If the pregnancy test is positive, the patient must 
not receive protocol treatment and must not be enrolled in the study.
WOCBP is defined as follows: Any female who has experienced menarche and who has 
not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or a 
bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea > 12 
consecutive months, or women on hormone replacement therapy (HRT) with documented 
plasma follicle-stimulating hormone (FSH) level > 35 mIU/ml). Even women who are 
using oral, implanted, or injectable contraceptive hormones or mechanical products 
(diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or 
where partner is sterile (e.g. vasectomy), should be considered to be WOCBP.
4.5. Patient Registration
Participants may be registered from 8:00 am to 4:00 pm EST excluding holidays by 
emailing the Investigator-Sponsored Research Unit (ISRU) at: 
FCCC.MONITOR@fccc.edu. Eligible participants will be entered on study centrally 
once the following items have been received by email:

Completed registration form 

Consent and HIPAA signature pages 

Eligibility checklist
Following registration, participants must begin protocol treatment within 14 calendar 
days of registration.  Issues that would cause treatment delays must be discussed with the 
Sponsor-Investigator.  If a registered participant does not receive protocol therapy 
following registration, the participant will be recorded as withdrawn from study.  The 
Study Monitor must be notified as soon as possible if a participant does not begin 
protocol treatment as scheduled. For additional registration questions, please email 
FCCC.MONITOR@fccc.edu 
The FCCC ISRU will notify the site by email once registration is confirmed and the 
sequence number has been assigned.  Participants must be registered and have received a 
sequence number prior to the initiation of treatment.  
Exceptions to the current registration policies will not be permitted. 


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5.0
Treatment Plan
Patients will be stratified by diagnosis at time of study enrollment. Treatment will be 
administered on an outpatient basis, and will proceed for a planned total of 6 cycles in the 
absence of any event or delay as detailed below in section 5.3. During the phase II portion 
of the study, randomization to standard decitabine versus digoxin will dictate treatment 
only for the first cycle, after which both study arms will receive combined digoxin plus 
decitabine for the remainder of the cycles as depicted in the phase II schema on page 4. 
Treatment will be administered during each respective cycle as described below; with 
initial loading of digoxin given as two 0.5mg doses on Day 1. Dose delays and 
modifications will only be done following protocol guidelines described. Missed days will 
not be made up. If treatment delays are > 4 weeks study therapy will be discontinued.  
5.1. Treatment Administration
Regimen description
Agent
Premedications, 
precautions
Dose
Route
Schedule
Cycle 
Length
Decitabine
Premedicate 
with Zofran 
16mg IV prior 
to decitabine
20 mg/m2 in 
100 cc NS
IV 
over 1 hrs
Days 6-10,
Digoxin
N/A
1mg Loading Dose 
(administered as 
two 0.5mg doses)
0.25mg
PO
PO
Day 1
Of each cycle 
of Phase 1b 
and Phase II
Days 2-10
4 weeks 
(28 days)
5.2. Concomitant Medications, Supportive Care, Excluded Therapies and Restrictions
The investigator will be permitted to prescribe supportive treatment(s) at his or her 
discretion. Appropriate hydration and supportive care (eg, antiemetics and blood and 
platelet transfusions) may be administered according to study center standards. Aggressive 
surveillance, prophylaxis, and the treatment of bacterial, fungal, viral, and opportunistic 
infections are essential to prevent morbidity and mortality. Any supportive treatment or 
infusion should be recorded in the patient record.
Antibiotics may be utilized to prevent or manage febrile neutropenia based on institutional 
standard practice. Febrile neutropenia is defined as temperature at least 38.5ºC when the 
ANC is < 1000 μL. Febrile subjects are to be evaluated by physical examination, CBC 


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with differential, and blood culture. Subjects with febrile neutropenia or suspected sepsis 
on the basis of the physical examination are to be hospitalized for appropriate broad 
spectrum antibiotic coverage, consistent with local pathogen sensitivities.
Prohibited concomitant therapies while on study are: radiation therapy, chemotherapy, 
immunotherapy, hematopoietic growth factors unless for emergency use or if judged by 
the investigator to be clinically necessary (erythropoietin can be used after Cycle 1), or 
any experimental therapy.
In vitro studies in human liver microsomes suggest that decitabine is unlikely to inhibit or 
induce cytochrome P450 enzymes. However based on standard guidelines the combination 
of decitabine with clozapine or dipyrone should be avoided due to increased risk for 
agranulocytosis and pancytopenia.
For Digoxin, standardized precautions should be taken to avoid concomitant 
administration of digoxin with a variety of drugs without close supervision by the treating 
physician. 
5.3. Duration of Therapy
In the absence of treatment delays due to adverse events, treatment may continue for 6 
cycles or until one of the following criteria applies:

Disease progression

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse events

Patient required  > 3 dose reductions of decitabine or >1 dose reductions of digoxin

Treatment held  ≥ 4 Weeks 

Patient becomes pregnant

Patient decides to withdraw from the study or

General or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment in the judgment of the investigator
5.4. Duration of Follow up
Patients will be followed every month for 6 months upon discontinuation of study 
treatment for disease assessment and survival. Patients removed from study for 
unacceptable adverse events that are related to the study treatment will be followed until 
resolution or stabilization of the adverse event.
5.5. Criteria for Discontinuation
Patients will be removed from study when any of the criteria listed in Section 5.3 applies.  
The reason for study removal and the date the patient was removed must be documented 
in the source documents and case report form.


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6.0
Dose Modifications
6.1. General Principles 
Dose modifications will be made based only on the guidelines described in Section 6.0.  
Dose reductions are permanent, there are no dose re-escalations. Patients requiring > 3 
dose reductions of decitabine or >1 dose reductions of digoxin must discontinue protocol 
treatment.  Missed doses are not to be made up. Patients requiring treatment to be held > 4 
weeks for recovery from toxicity must discontinue protocol treatment.
6.2. Dose Level Adjustment Table [Dose Adjustment for Subsequent Cycle]
During the phase 1b portion of the study:
Dose level
Digoxin Dose
-3 dose level
n/a
-2 dose level
n/a
-1 dose level
0.125mg/d
0 (baseline)
0.25mg/day
During the phase II portion of the study:
Dose level
Decitabine Dose
Digoxin Dose
-3 dose level
5 mg/m2
n/a
-2 dose level
10 mg/m2
n/a
-1 dose level
15 mg/m2
n/a
0 (baseline)
20 mg/m2
0.25 or 0.125 mg/day
6.3. Specific Toxicities and Modifications
6.3.1. Decitabine
If myelosuppression is present, subsequent treatment cycles of decitabine will be 
delayed until there is hematologic recovery (ANC ≥ 1,000/μL platelets ≥ 50,000/μL).
Once hematologic recovery has been achieved the dose of decitabine will be 
decreased by one dose level for the subsequent cycle.
During the Phase II portion of the study; if grade III or IV non-hematologic toxicities 
are encountered, further treatment will be delayed until patients have recovered to 
grade 0 or 1 before initiation of further treatment. At time of start of next course of 
treatment, the dose of decitabine will be decreased by 1 dose level. 


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6.3.2. Digoxin
If 2 or more DLTs are encountered during the phase 1b part of the study, the dose of 
digoxin will be decreased to 50% of starting dose and the safety study will be 
repeated with a new group of 6 patients.
For the Phase II portion of the study no digoxin dose modifications will be made for 
toxicities encountered, all modification will be made with decitabine dose as 
appropriate.
At time of serum digoxin check, if serum digoxin is at upper limit of normal (normal 
range: 0.8-2 ng/mL) then subsequent doses for cycle will be held. 
6.4. Definition of Dose Limiting Toxicities (DLTs):
Dose limiting toxicities (DLTs) will be defined as any grade III or IV non-hematologic 
toxicity per the NCI CTCAE v4 guidelines during Phase Ib and cycle 1 of Phase II. Also 
qualifying as a DLT will be grade IV neutropenia lasting for 28 days or longer from the 
start of any given cycle of therapy, in the absence of evidence of active AML/MDS and 
any treatment-related deaths.
7.0
Study Agent Information
7.1. Decitabine Formulation, Product identification, Package and Labeling
7.1.1. Product description: 
Antimetabolite, DNA hypomethylating agent
Molecular Formula:  C8H12N4O4   M.W.: 228.21 g/mol
7.1.2. Availability: 
Decitabine is commercially available and FDA approved for MDS. The literature 
supports its use in AML as well.
7.1.3. Solution preparation: 
When reconstituted with 10 mL of sterile water for injection each mL will contain 5 
mg of decitabine, 6.8 mg of KH2PO4, and approximately 1.1 mg NaOH. The pH of 
the resulting solution is 6.5 - 7.5. The reconstituted solution can be further diluted to 
a concentration of 1 mg/mL or 0.1 mg/mL in cold infusion fluids (0.9% Sodium 
Chloride Injection USP, 5% Dextrose in Water Injection, USP, or Lactated Ringer's 
Injection USP).
7.1.4. Storage requirements:
The intact vials should be stored under refrigeration (2-8°C; 36-46°F) in the original 
package.


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7.1.5. Stability
The intact vials are stable for at least 1 year at room temperature (22-25°C), 2 years 
at 2-8°C or 6 months at -40° C. Reconstitution and dilution of the powder for 
injection (with 10mL of sterile water for injection) results in a rapidly decomposing 
solution. The concentration of decitabine in the reconstituted and diluted solution 
decreases about 10 % after 4 hours at 25°C or about 10% after 24 hours at 4°C. 
Since 10% is the maximum allowable decomposition, and the solution will also 
decompose during administration (infusion), the solution will be prepared just prior 
to administration. If this is not possible the solution should be prepared at least twice 
a day and kept in a refrigerator (2-8°C) until administration. Furthermore, the 
solution will be prepared only with cold infusion fluids at a temperature of 2-8°C; 
(36-46°F). This solution can be infused over a maximum period of 3 hours.
7.1.6. Route of administration: 
Intravenous
7.2. Digoxin Formulation, Product Identification, Package and Labeling
7.2.1. Product description: 
Antiarrhythmic Agent, Miscellaneous; Cardiac Glycoside
Molecular Formula:  C14H64O14  M.W.: 780.94 g/mol
7.2.2. Availability: 
Commercially available 
7.2.3. Storage requirements: 
Store at controlled room temperature, 25 degrees C (77 degrees F); range of 
temperatures where it can be stores is 15 to 30 degrees C (59 to 86 degrees F). 
Protect from light and from moisture.
7.2.4. Stability: 
Stable at above noted temperature range and when protected from light and moisture 
7.2.5. Route of administration: 
PO
8.0
Correlative /Special Studies
8.1. Study Correlative #1: Assessment of genome wide methylation before and during 
therapy.

This will be done at Dr. Issa’s lab at Temple University. 

This will be carried out via bisulfite/PCR/pyrosequencing analysis of LINE1 
methylation of peripheral blood samples collected (prior to any treatment) on days 
1, 6, 13, 20 during the first two cycles and day 1 of cycle 3. 


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
All bisulfite pyrosequencing analyses will be done in triplicate for each sample and 
the methylation degree will be computed as the average of the three measurements. 
To avoid small changes related to batch effects and PCR biases, all samples from 
each patient will be analyzed in the same run. We will express changes in DNA 
methylation after treatment as relative change (%), computed by the following 
formula: 100*([Methylation on a given post-treatment day] – [Baseline 
methylation])/[Baseline methylation].
8.2. Study Correlative #2: Assess gene-specific methylation and expression of tumor 
suppressor genes normally hypermethylated in myeloid leukemia (p15, p21, RIL) 
before and during therapy. 

This will be done at Dr. Issa’s lab at Temple University. 

We will utilize real-time PCR to measure expression of a predefined set of genes 
of interest (p15, p21, RIL).

Will carry out bisulfite/PCR/pyrosequencing analysis to determine methylation 
status of the above mentioned genes of interest.

All analysis will be carried out on peripheral blood samples collected (prior to any 
treatment) on days 1, 6, 13, 20 during the first two cycles and day 1 of cycle 3. 
8.3. Study Correlative #3: In-depth epigenetic and gene expression analysis of three 
“best” and three “worse” responders to generate preliminary data on profiles that 
may predict response to study regimen.

For the three best and three worse responders we will analyse their bone marrow 
biopsy material collected at pre-study, at the end of cycle 3 and cycle 6 to carry out 
deep sequencing in order to analyze their DNA methylation profile, transcriptome 
profile and exome profile. 

We will determine gene methylation status using the Digital Restriction Enzyme 
Analysis of Methylation (DREAM) technique. This assay will be performed at Dr. 
Issa’s lab. 

Transcriptome profile will be assessed via RNA sequence analysis. This will be 
carried out based on the standard methodology established at the FCCC Core 
facility and sample processing will be handled by Dr. Issa’s lab. 

Whole exome profile assessment will be carried out by exome sequencing; which 
is based on the established literature and will be facilitated by the Otogenetics 
Company. Dr. Issa’s lab will do sample processing prior to shipping the samples to 
the company for analysis. Finally, once differences in profiles are identified we 
will attempt to verify our findings by analyzing samples from the other patients 
enrolled on the trial.


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8.4. Instructions for collection and shipping of blood samples and bone marrow 
biopsies.
8.4.1. Blood Sample Collection:
For each patient, peripheral blood samples will be collected (prior to any treatment) 
on days 1, 6, 13, 20 during the first two cycles and day 1 of cycle 3.

2 vials of venous blood 12ml EDTA purple top tubes

1 vial of venous blood in PAX Gene RNA tube
8.4.2. Bone marrow biopsy
Bone marrow biopsies from the three best and three worse responders 

1 vial of bone marrow 12ml EDTA purple top tubes

1 vial of bone marrow in PAX Gene RNA tube
Blood and biopsy samples will be shipped to Dr. Issa’s lab at Temple University. All 
samples will be anonymized and distributed based on their sequence number.


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9.0
Study Calendar
Pre-Study A
Cycle 1 and 2
Cycle 3
Cycle 4 -6
Biopsy 
Visit
End of 
Treatment
Safety
Follow up
Follow 
up
Days
-28 to 1
1
6
13
21
1
6
13
21
1
6
13
21
7 days
Post 
cycle 6
30 days
post EOT
Informed Consent
X
Medical History
X
Physical exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs C
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test D
X
CBC
X
X
X
X
X
X
X
X
X
X
X
X
X
X
XF
CMP B
X
X
X
X
X
X
X
X
X
X
X
X
X
X
LDH
X
EKG
X
X
X
X
X
X
X
X
ECOG
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Bone marrow biopsyE
X
X
X
Blood draw
X
X
X
X
X
PO Digoxin H
X
X
X
X
X
X
IV Decitabine I
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum digoxin
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Survival status
XG
A.
Pre-study H&P, all labs and EKG must be < 28days prior to study drug initiation.  Pre-study assessments may be used for C1D1 assessments if completed < 7days of 
treatment initiation.


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B.
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], 
sodium 
C.
Vital signs consist of temperature, pulse, respiration, and blood pressure.
D.
Serum pregnancy test (women of childbearing potential) must be completed < 72 hours before treatment initiation.
E.
Bone marrow biopsy will be performed Pre-study, at the end of cycle 3 and 6. Pre-study bone marrow should be done at least a week in advance of starting trial, Cycle 3 
bone marrow should be done 1-2 days prior to start of cycle 4 and cycle 6 bone marrow should be done  1 week after Day 28 of Cycle 6.
F.
Upon treatment discontinuation, patients will be assessed every month for 6 months for disease progression.
G.
Follow up every month for 6 months for survival.
H.
Digoxin given daily Day 1-10; on Day 1 will get 0.5mg PO BID as a loading dose, on Days 2 – 10 will get 0.25 mg QD. This regimen will be followed for all the cycles where 
Digoxin plus decitabine is given in both Phase 1b and Phase II.
I.
Decitabine administered as IV infusion Day 6-10


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10.0 Adverse Events 
10.1. Definitions
10.1.1. Adverse Events (AE)
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, treatment, or procedure regardless of whether it is 
considered related to the medical treatment or procedure (NCI CTEP Guidelines 
March 28, 2011).
10.1.2. Serious Adverse Event (SAE)
Serious Adverse Event (SAE) is an AE that results in the following outcomes-

Death

Life threatening adverse event

Requires inpatient hospitalization or prolongation of existing hospitalization 
(for > 24 hours), 

A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions,

Congenital anomaly/ birth defect. 
A “life-threatening” adverse event places the patient at immediate risk of death in the 
judgment of the investigator or sponsor.
NOTE: Important medical event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical intervention 
to prevent any of the above outcomes.  
10.1.3. Severity Rating 
The investigator will evaluate the severity of each adverse event. NCI Common 
Terminology Criteria for Adverse Events (CTCAE v.4.0) or study specific toxicity 
tables provided in the protocol define severity. If not included in CTCAE v.4.0, 
severity is expressed in numerical grade using the following definitions:

Grade 1: Mild-asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.

Grade 2: Moderate-minimal, local or noninvasive intervention indicated; limiting 
age appropriate instrumental ADL.

Grade 3: Severe-severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL.

Grade 4: Life-threatening consequences; urgent intervention indicated. 


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
Grade 5: Death related to AE.
10.1.4. Attribution/Relationship to study drug 

Definite – clearly related

Probable – likely related

Possible – may be related

Unlikely – doubtfully related

Unrelated – clearly not related
10.1.5. Expectedness
An Expected Adverse Event is one where the specificity or severity is consistent 
with the current information available from the resources.
An Unexpected Adverse Event is one where the nature, severity, or frequency of 
the event is related to participation in the research is not consistent with either:
1. The known or foreseeable risk of adverse events associated with the 
procedures involved in the research that are described in (a) the protocol-
related documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved informed 
consent document, and (b) other relevant sources of information, such as 
product labeling and package inserts: or
2. The expected natural progression of any underlying disease, disorder, or 
condition of the subject (s) experiencing the adverse event and the subjects(s) 
predisposing risk factor profile for the adverse event.
(OHRP Guidance on reviewing unanticipated problems 2007).
10.2. Recording and Reporting Responsibilities
10.2.1. Investigative Site Recording Responsibilities:
1. Upon identification of an AE or SAE, the site investigator will utilize the 
above definitions to properly classify the event. Each category listed above 
must be recorded for each event.
2. All AEs and SAEs will be recorded in the “AE case report forms” (CRF) and 
in progress reports with details about the grade and attribution of each 
episode, action taken with respect to the study drug, and the patient’s 
outcome will be recorded in the CRF. All events will be recorded on case 
report forms for the duration of the study until they resolve.
3. All SAEs will be recorded on the FDA MedWatch form 3500a.  The 
attribution and expectedness must be recorded on the MedWatch form. If this 
information is not available at the time of initial reporting, a final report must 


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be documented with attribution and expectedness.  It may be necessary to 
submit follow up reports to the Sponsor should the event require further 
investigation. All subsequent SAEs must be recorded for up to 30 days after 
the last treatment.
4. All patient data must be recorded in eCRFs by the investigative site within 7 
days of the patient’s visit. eCRFs will be available through Oncore electronic 
data capture system.
10.2.2. Investigative Site Reporting Responsibilities:
1. The investigator/ site is responsible to report all SAEs that occur on or after 
the first day of study treatment to the sponsor within 24 hours of becoming 
aware of the event. All subsequent SAEs must be reported for up to 30 days 
after the last treatment.
2. Each investigator is responsible to report all AEs/SAEs to their local IRB 
following guidelines set by that IRB. The FCCC OCR reserves the right to 
request an event be reported to the IRB at their discretion. Copies of events 
reviewed by the IRB must be sent email to SAE.FCCC@fccc.edu. 
3. If the investigator or IRB feels the event warrants a revision to the informed 
consent that was not already initiated by the ISRU, draft revisions will be 
made in track changes and submitted to the ISRU for consideration. Any 
consent revisions must receive ISRU approval prior to submission to the 
IRB.
4. Any investigator who is in doubt of whether a particular AE needs to be 
reported is directed to call the Study Monitor for confirmation with the 
Sponsor Investigator.
5. If the results of an investigator or ISRU investigation show an adverse event 
not initially determined to be reportable is so reportable, the investigator will 
report the event following the above guidelines based on the date the 
determination is made.
6. Copies of all related correspondence and reporting documents must be 
submitted to the ISRU and will be maintained in the trial master file. 
Participating sites will report events to:
Investigator-Sponsored Research Unit
Office of Clinical Research
 
           Fox Chase Cancer Center
SAE.FCCC@fccc.edu


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10.2.3. Sponsor Reporting Responsibilities:
1. Adverse events which meet all of the following criteria must be reported to 
all participating institutions for IRB submission within 2 weeks of 
notification of the event:  
a.
Unexpected (in terms of nature, severity, or frequency) given 
i. (a) the research procedures that are described in the protocol-
related documents, such as the IRB-approved research protocol 
and informed consent document; and 
ii. (b) the characteristics of the subject population being studied;
b. Possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and
c.
Serious (refer to above definition) or otherwise one that suggests that the 
research places subjects or others at a greater risk of physical or 
psychological harm than was previously known or recognized.
2. If the adverse event requires modification of the study protocol and informed 
consent, these changes will be provided to all participating institutions in the 
form of an amendment from the ISRU for each site’s IRB of record along 
with the report of the adverse event. 
3. All participating sites must be notified of all amendments approved by FCCC 
IRB; or if the study is suspended such that the participating sites cannot 
accrue patients in the study until further notification.
4. All participating sites must be notified when the study is closed by IRB.  
5. Copies of all related correspondence and reporting documents will be 
maintained in a centralized regulatory file for this study at ISRU.
6. SAEs that are related, unexpected, fatal, and  life-threatening are reportable 
through the Food and Drug Administration (FDA) MedWatch program by 
telephone or fax no later than 7 calendar days after initial receipt of the 
information. Further information on the timing of submissions as directed by 
FDA guidelines can be found in the following link: 
(https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugs
areDevelopedandApproved/ApprovalApplications/InvestigationalNew
DrugINDApplication/ucm362555.htm).  
Serious, unexpected events that suggest significant clinical risk will be 
submitted to within 15 calendar days after initial receipt of this information.
The FAX number for reporting SAE to FDA can be found in the FDA 
“Study may proceed” letter. 


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The SAE report can also be submitted by email to the Regulatory 
Project Manager and/or the Chief, Project Management Staff described 
in the “Study May Proceed” letter
10.3. Pregnancy 
All WOCBP should be instructed to contact the Investigator immediately if they suspect 
they might be pregnant (e.g., missed or late menstrual period) at any time during study 
participation.
In the event of a confirmed pregnancy in a patient participating in the study, the 
Investigator must immediately notify the Fox Chase Cancer Center Study Monitor who 
will notify Dr. Philip Pancari.
11.0 Measures of Effect
International Working Group (IWG) standardized  response criteria for MDS and AML will 
be utilized to objectively assess response to our experimental therapeutic regimen.13,14 
Assessments will be performed after cycles 3 and 6 of therapy via analysis of peripheral blood 
counts and bone marrow biopsy. Once protocol treatment has been completed patients will be 
assessed at the end of the trial and every month for 6 months.  
11.1. Definitions
Evaluable for adverse events.  All patients will be evaluable for adverse events from the 
time of their first treatment with Digoxin + Decitabine.
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below. (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.)
11.2. Disease Parameters
Disease status will be based on analysis of patient’s bone marrow and patient’s    
peripheral blood counts per IWG criteria.
11.3. Methods for Evaluation of Measurable Disease
Evaluation of disease will be based upon assessment of peripheral blood counts and 
assessment of patient’s bone marrow prior to start of the clinical trial and at predefined 
points during the course of the trial.


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11.4. Response Criteria
11.4.1. PR/CR/CRi/CRp/HI
These variables will be assessed per standard guidelines 
(refer to Table 1 and Table 2 below).
Table 1: IWG MDS Response Criteria13
Table 2: IWG AML Response Criteria14
11.4.2. Progressive Disease (PD)
In AML it is defined as lack of any response after 3 Treatment cycles, or 
reappearance of blasts post CR. In MDS it is defined as doubling in bone marrow 
blasts from baseline to at least 10% or progression to AML.
11.4.3. Stable Disease (SD)
Defined as failure to achieve at least a PR but without progression of disease for 8+ 
weeks.


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11.5. Duration of Response
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started).
Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 
12.0 Statistical Considerations
12.1. Study Design/Endpoints
The phase Ib portion of this aim is a safety analysis. As previously described, all patients 
will be monitored for DLTs, defined as any grade III or IV non-hematologic toxicity per 
the NCI CTCAE v4 guidelines. If 0 or 1 patients have toxicity at the starting digoxin dose, 
that dose will be determined “safe” for the phase II portion. However, if a greater number 
of DLTs are observed then the dose of digoxin will be decreased to 0.125mg/d and the 
safety study will be repeated with a new cohort of 6 patients. If 2 or more toxicities are 
encountered with the decreased dose then the combination of digoxin and decitabine will 
be considered too toxic for further study. 
The phase II portion utilizes a Simon Two-Stage Phase II study design. The phase II 
portion will be carried out with two Groups. Group#1 will consist of patients with newly 
diagnosed AML or MDS, and Group#2 will consist of patients with relapsed/refractory 
AML or MDS. Our primary endpoint will be the CR+CRi rate. 
For Group#1, our null hypothesis is a CR+CRi rate ≤ 20% (per historical controls) and our 
alternative hypothesis is a CR+CRi rate ≥ 40%, with 90% power and Type I Error of 10%. 
We will need to enroll a total of 37 patients, including eligible patients from the phase Ib 
segment. Initially, we will need to enroll a total 17 patients (including those carried over 
from the phase Ib portion) to assess for response at cycle 3. If ≥ 4 patients have a CR or 
CRi we will enroll an additional 20 patients and re-assess response after three cycles. If ≥ 
11 of the 37 patients have a CR or CRi after three cycles of therapy the regimen will be 
considered a clinically effective regimen which requires further assessment in a larger 
trial.
For Group #2, our null hypothesis is a CR rate ≤ 5% (based on historical controls) and our 
alternative hypothesis is a CR rate ≥ 15%, with a 90% power and Type I Error of 10%. 
Based on this design we will need to enroll a total of 60 patients, which includes patients 
enrolled in the phase Ib segment. For the initial stage of the phase II trial, we will need to 
enroll a total 39 patients (including those carried over from the phase Ib portion) to assess 
for response at cycle 3. If ≥2 patients have a CR or CRi we will enroll an additional 21 
patients and re-assess response after three cycles. If ≥ 6 of the 60 patients have had a CR 


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or CRi after three cycles of therapy the regimen will be considered a clinically effective 
regimen which requires further assessment in a larger trial.
The statistical design for the Phase II portion of the study is based on the assumption, as 
established in the literature, that randomization of the treatment rendered during the first 
cycle will not impact the results of response assessment conducted at the end of Cycle 3 
and Cycle 6. 
12.1.1. Statistical Plan for Assessment of DLTs for Phase II portion of the Study:
Group 1:
Patients treated in cycle 1 with both Decitabine and Digoxin will be assessed for 
DLTs. If 4 of the first 9 experience DLT (these patients are mostly in the initial set 
of 17 patients), the trial will be terminated. If ever 5 of 18 experience DLT the same 
decision will be made. Patients randomized to Decitabine alone will not be counted 
unless they experience DLTs, in which case these will be added to the total DLTs as 
if they were in the two-regimen group. DLT rate of 15% will be considered 
acceptable, but 35% too toxic. The chance of early termination when the true DLT 
rate is 35% is 39%. The overall chance of declaring the treatment too toxic is 82% in 
this case. The chance of early termination in error is 3.4% and final termination in 
error is 12.7%.
Group 2:
Similar to Group 1, if 7 of the initial 19 two-regimen patients (mostly in the first 
patient group of 39 patients) the trial will be terminated. If 9 of all two-regimen 
patients experience DLT the treatment will be considered too toxic. Again, single 
regimen patients will be counted only if they experience DLTs. The chance of early 
termination is 52% when the treatment is too toxic. The chance of early terminating 
in error is 1.6%. The chance of final decision of toxicity is 79% when the true DLT 
rate is 35% and 3.4% when it is 15% (in error). 
These computations are only approximate since the exact numbers of patients 
randomized to both regimens is unknown.
12.2. Analysis of Secondary Endpoints 
Patients will be classified as responders or non-responders based on analysis of their 
peripheral counts and their bone marrow biopsies done at various pre-defined points 
during their treatment course. The statistical objectives of this portion of the study are 
exploratory in nature. After pre-processing of raw data, variance stabilizing and 
normalizing transformations will be applied as needed. As and when appropriate, analysis 
of variance or its non-parametric equivalent will be used to compare various groups. For 
each patient sample, gene expression measurements will be obtained using the Illumina 
HiSeq 2500 system on days 1, 6,13, 20 during the first two cycles and day 1 of cycle 3 
(prior to any treatment). Gene expression data will be summarized using descriptive 
statistics at each time point and cycle and trends in gene expression over time will be 
graphically presented. Unsupervised clustering of gene expression profiles will be 
performed using methods such as two-way hierarchical clustering, K-means etc. in order 


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to identify sub-groups of genes that may be associated with responders and non-
responders.17 
Genome-wide methylation studies will be performed on days 1, 6, 13, 20 during the first 
two cycles and day 1 of cycle 3 (prior to any treatment) and methylation levels  will be 
compared at each time point. Changes in DNA methylation after treatment will be 
expressed as relative change (%) for each gene. The degree of genome-wide and gene-
specific methylation will be compared between arms at the end of cycle 1.The Mann-
Whitney-Wilcoxon test will be used to identify methylated genes as well as differentially 
expressed targeted genes. For our analysis, we will define hypermethylation as a 2-fold 
increase of the Cy5 leukemia signal over the Cy3 control based on previous validation 
experiments. In order to increase the accuracy of all measurements and any observed 
correlations all test will be done in triplicate to reduce the risk of variance secondary to 
operatory or machine error. 
12.3. Analysis of Exploratory Endpoints
Furthermore, the three best and three worst responders to treatment will be identified at 
the end of cycle 3 and methylation analysis using the DREAM technique as well as exome 
and transcriptome analyses will be performed on samples obtained from these responders. 
These analyses will be exploratory in nature and will primarily consist of descriptive 
summaries. 
All statistical tests will be two-sided and the Benjamini-Hochberg method will be used to 
account for multiple hypotheses.18 The R statistical language and environment will be used 
in the computations.17
12.4. Sample Size/Accrual Rate
Planned sample size: 100
Accrual Rate: 2 patients per month
12.5. Stratification Factors
Patients will be stratified based upon disease state (newly diagnosed vs relapsed) and 
diagnosis (AML vs MDS) at the time of enrollment on the trial. However, interim 
monitoring and efficacy determination will be done for all enrollees for our primary aim. 
Based upon the distribution of patients there is a possibility of subgroup analysis based 
upon original diagnosis. 
12.6. Reporting and Exclusions
12.6.1. Evaluation of toxicity
All patients will be evaluable for toxicity from the time of their first treatment with 
Digoxin + Decitabine.


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12.6.2. Evaluation of response
All patients included in the study must be assessed for response to treatment, even if 
there are major protocol treatment deviations. Each patient will be assigned one of 
the following categories: 1) complete remission 2) partial remission 3) stable 
disease, 4) progressive disease, 5) early death from malignant disease, 6) early death 
from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.]
All of the patients who met the eligibility criteria (with the possible exception of 
those who received no study medication) will be included in the main analysis of the 
response rate. Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression). Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  
Precise definitions for categories 4-9 will be protocol specific. 
13.0 Data and Safety Monitoring Plan
13.1. Monitoring Plan 
FCCC ISRU will monitor the medical and study records of each participant accrued 
throughout the course of the study. In addition, the IRU will collect and report data to the 
study Sponsor Investigator who will review these data on a regular basis at a rate 
dependent on subject accrual. All serious adverse events (SAEs) will be reviewed on a real 
time basis first by the study site PI and subsequently by the ISRU and Sponsor 
investigator as applicable.
13.2. Data Safety Monitoring Committee  
Interim analysis of toxicity, outcome, and ongoing scientific investigations may be 
performed at least every 3 months by the Fox Chase Cancer Center Data Safety 
Monitoring Board (FCCCDSMB). In this capacity the FCCCDSMB will serve as an 
advisory committee to the sponsor-investigator. The FCCCDSMB will review those 
aspects of this trial that are outlined in the responsibilities section of the Data and Safety 
Monitoring Plan (DSMP). If the committee decides that changes should be made to this 
trial, it will make recommendations in writing to the Sponsor Investigator, the Associate 
Director of Clinical Research, and the Protocol Management Executive Committee, 
which, in turn, have the authority to approve or disapprove these recommendations. These 
changes will be discussed with the Sponsor-Investigator before they are implemented. 
These changes may include early termination of accrual. Other changes might include 
altering the accrual goals or changing the eligibility criteria for the trial.
14.0 Administrative  
This study will be conducted in accordance with local, state and Federal regulations and 
according to accepted good clinical practice guidelines.


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14.1. Data Reporting
The FCCC Study Monitor will request case report forms to be completed within 2 weeks 
of the protocol visit. Participating sites are responsible to respond to queries prior to the 
next scheduled monitoring visit.  
The ISRU Staff is responsible for compiling and submitting data to the Sponsor 
Investigator and statistician on an ongoing basis for monitoring as described in the data 
safety monitoring plan and reporting to the Data and Safety Monitoring Board.
All patient information will be stored in an EDC system accessible only to the study team 
members for the purpose of entering, reviewing and analyzing data. Any paper records, 
such as case report files, produced will be stored in a secure location. 
The ISRU is responsible for distributing and tracking review of all IND Action Letters, 
Safety Reports, study specific Serious Adverse Events
14.2. Retention of Records  
Time points for the retention of records are described in detail in the contract between the 
grantor and the OCR and passed on to the participating site. Please refer to the study 
specific terms for specific time points.  In all cases the Study Monitor must be notified of 
any plans to move records to an offsite location prior to doing so.
14.3. Study Agents
Any study agent supplied through the OCR from the manufacturer or a third party 
distributor may not be used for any purpose outside the scope of this protocol. The agent 
may not be transferred to any party not participating in the clinical trial.
14.4. Informed Consent
The IRB approved informed consent documents must be signed by the patient, or the 
patient’s legally authorized representative, before his or her participation in the study. The 
case history for each patient shall document that informed consent was obtained prior to 
participation in the study. A copy of the informed consent documents must be provided to 
the patient or the patient’s legally authorized representative. If applicable, they will be 
provided in a certified translation of the local language.
Original signed consent forms must be filed in each patient’s study file or medical record 
with a copy in the study file.


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15.0 References
1. Kantarjian H, Ravandi F, O'Brien S, Garcia-Manero G, Andreeff M, Konopleva M, 
Jabbour E, Pierce SR, Borthakur G, Cortes JE. Survival Outcomes In 
Relapsed/Refractory Acute Myeloid Leukemia Patients Who Achieve Less-Than-
Complete Response After Salvage Therapy. Blood Nov 2013,122(21)2654.
2. Yanada M, Garcia-Manero G, Borthakur G, Ravandi F, Kantarjian H, Estey E. Potential 
cure of acute myeloid leukemia : analysis of 1069 consecutive patients in first complete 
remission. Cancer. 2007 Dec 15; 110(12):2756-60.
3. Issa JPJ, Garcia-Manero G, Giles FJ, Mannari R, Thomas D, Faderl S, et al. Phase 1 
study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2’-
deoxycytidine (decitabine) in hematopoietic malignancies. Blood 2004; 103:1635-40
4. Ravandi F, Cortes J, Faderl S, O'Brien S, Garcia-Manero G, Verstovsek S, Santos FPS, 
Shan J, Brandt M, de Lima M, Pierce S, Kantarjian H. Characteristics and outcome of 
patients with acute myeloid leukemia refractory to 1 cycle of high-dose cytarabine-based 
induction chemotherapy. Blood Dec 2010,116(26)5818-5823.
5. M Tailler, L Senovilla, E Lainey, S The´pot, D Me´ tivier, M Se´bert, V Baud, K Billot, P 
Fenaux, L Galluzzi, S Boehrer, G Kroemer, O Kepp. Antineoplastic activity of ouabain 
and pyrithione zinc in acute myeloid leukemia. Oncogene (2012) 31, 3536–3546.
6. Stoiser B, Knöbl P, Fonatsch C, Haas OA, Mitterbauer G, Weltermann A,  Geissler K, 
Valent P, Sperr W, Pabinger I, Lechner K, Jaeger U. Prognosis of patients with a second 
relapse of acute myeloid leukemia. Leukemia. December 2000, Volume 14, Number 12, 
Pages 2059-2063
7. Kroeger H, Jelinek J, Estécio MRH, et al. Aberrant CpG island methylation in acute 
myeloid leukemia is accentuated at relapse. Blood 2008;112(4):1366-1373.
8. Boumber Y, Kantarjian H, Jorgensen J, et al. A Randomized Study of Decitabine Versus 
Conventional Care for Maintenance Therapy in Patients with Acute Myeloid Leukemia in 
Complete Remission. Leukemia 2012;26(11):2428-2431.
9. Bravo, G. M., Lee, E., Merchan, B., Kantarjian, H. M. and García-Manero, G. Integrating 
genetics and epigenetics in myelodysplastic syndromes: advances in pathogenesis and 
disease evolution. British Journal of Haematology 2014; 166: 646–659.
10. Yang, AS, Estecio MR, Doshi, K. et al. A simple method for estimating global DNA 
methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res. 2004 
Feb 18;32(3):e38.
11. Shen L, Kondo Y, Guo Y, et al. Genome-wide profiling of DNA methylation reveals a 
class of normally methylated CpG island promoters. PLoS Genet. 2007;3:2023–2036; 2. 
12. Estecio MR, Yan PS, Ibrahim AE, et al. High-throughput methylation profiling by MCA 
coupled to CpG island microarray. Genome Res. 2007;17:1529–1536.
13. Cheson, B.D., et al., Clinical application and proposal for modification of the 
International Working Group (IWG) response criteria in myelodysplasia. Blood, 2006. 
108(2): p. 419-25.


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14. Cheson, B.D., et al., Revised Recommendations of the International Working Group for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting 
Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol, 2003. 
21(24): p. 4642-4649.
15. Dacogen, Dacogen (decitabine for injection) Prescribing Information. 2010.
16. Jelinek J, Liang S, Lu Y. et al. Conserved DNA methylation patterns in healthy blood 
cells and extensive changes in leukemia measured by a new quantitative technique. 
Epigenetics. 2012 Dec 1;7(12):1368-78. doi: 10.4161/epi.22552. Epub 2012 Oct 17.   
17. R Core Team (2014). R: A language and environment for statistical  computing. R 
Foundation for Statistical Computing, Vienna, Austria.  URL http://www.R-
project.org/.
18. Y. Benjamini and Y. Hochberg (1995). Controlling the False Discovery Rate: A practical 
and powerful approach to multiple testing, Journal of the Royal Statistical Society, Series 
B, 57 (1): 289-300.

ICF_001.pdf: 
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INFORMED CONSENT DOCUMENT
A Phase Ib/II Study of the Safety and Activity of Digoxin with Decitabine in Adult AML and 
MDS 
Supported by: Fox Chase Cancer Center
Principal Investigator:  Dr. Philip Pancari
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial to 
you.  Clinical trials include only people who choose to take part.  Please take your time to make 
your decision about taking part.  You should discuss your decision with your friends and family.  
You will also discuss it with your health care team.  If you have any questions, you can ask your 
study doctor for more explanation.  
You are being asked to take part in this research study because you either have newly 
diagnosed or relapsed/refractory AML (Acute Myeloid Leukemia) or MDS (Myelodysplastic 
Syndrome. MDS/AML is a form of cancer of blood and bone marrow in which bone marrow does 
not produce enough healthy blood cells.
The sponsor of this study is Fox Chase Cancer Center.
Why is this research study being done?
The purpose of this research study is to:

Test different doses of digoxin with standard dose of decitabine to find which dose is 
safer in patients with newly diagnosed or relapsed/refractory AML/MDS. Digoxin is not 
normally used in the treatment of AML/MDS. Digoxin is approved by Food and Drug 
Administration (FDA) to treat heart failure. Adding digoxin to your treatment is 
considered experimental

Test if the combination of digoxin and decitabine is safe and effective in treating patients 
with newly diagnosed or relapsed/refractory AML/MDS.
How many people will take part in this research study?
Up to 100 people will take part in this research study.
What will happen if you take part in this research study?
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Screening before you begin the research study
You will need to have the following exams, tests or procedures to find out if you can be in the 
research study.  These exams, tests or procedures are part of regular cancer care and may be 
done even if you do not join the research study.  If you have had some of them recently, they 
may not need to be repeated.  This will be up to your study doctor.

We will ask you about your medical history 

We will do a physical exam and vital signs 

We will ask about your ability to do your daily activities

Routine blood tests (1 tablespoon)

Blood pregnancy test (2 teaspoon), if you are a female and able to become pregnant.

We will evaluate your cancer by doing a bone marrow biopsy

We will check your heart by performing an EKG.
o EKG is a test to measure the electrical activity of your heart
During the research study
If the exams, tests and procedures show that you can be in the research study, and you choose 
to take part, then you will take study treatment and you will need some tests and procedures.  
We will ask you about the medicine you are taking
We will do a physical exam and vital signs
We will ask about your ability to do your daily activities
Routine Blood tests (1 tablespoon).
We will check your heart by performing an EKG.
We will ask you about any side effects you may be experiencing
We will evaluate your cancer by doing a bone marrow biopsy at the end of cycle 3 and 
cycle 6
Blood for research – 9 times during the study (2 tablespoons/time-point). Blood will be 
collected on days 1, 6, 13, 21 of cycle 1 and 2 and once on day1 of cycle 3.
This study has two phases: Phase Ib is to determine the combination dose of decitabine and 
digoxin that is safe and tolerable, while Phase II is to determine the efficacy of the combination 
treatment. Phase Ib portion of the study will only have 1 cycle while Phase II portion of the study 
will have a up to 6 cycles.
Randomization
If you are enrolled in Phase II portion of this study you will be randomized into one of the two 
groups. Patients in group A will receive decitabine alone while patients in group B will receive 
decitabine with digoxin. Randomization means that you will be placed in a group by a computer 
program by chance and neither you nor your study doctor can decide which group you will be 
place in. You will have equal chance of being in one of the research groups. Patients in group A 
will receive decitabine alone only for cycle 1. Starting from cycle 2 patients in group A will also 
receive decitabine with digoxin.
Treatment 
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You will receive a one-time only loading dose of digoxin, to be taken orally on day 1 and then 
you will be asked to take digoxin orally every day from day 2 through day10 of a 28 days cycle, 
for a total of 6 cycles. In addition you will be administered decitabine through your vein over 1 
hour every day from day 6 through day10 of a 28 days cycle, for a total of 6 cycles.
Possible use of a port
If the doctors or nurses cannot draw blood or give you medicine through your veins, you may be 
asked to have minor surgery to place an “indwelling catheter port” into a large vein in your 
chest. Medical staff will use the “port” to give you medicines and to draw blood.  You will be 
asked to sign a separate consent form for this procedure, and the “port” will not be used unless 
you agree.  If a port is necessary and you do not agree to its use, you may be unable to 
continue as part of the research study.
After you stop taking the study drug
We will perform the following when you discontinue the study treatment

We will ask you about the medicine you are taking

We will do a physical exam and vital signs

We will ask about your ability to do your daily activities

Routine Blood tests (1 tablespoon).

We will check your heart by performing an EKG.

We will ask you about any side effects you may be experiencing
Follow-Up 
After you are finished taking the study drug, we will perform a safety follow-up, 30 days after 
discontinuation and ask you about any side-effects that you may be experiencing.  We will 
monitor your cancer by assessing your blood every month for 6 months after discontinuation. 
After that we would follow up with you every month for 6 months by phone call to monitor your 
overall health.
Study Plan 
Another way to find out what will happen to you during the research study is to read the chart 
below. Start reading at the top and read down the list, following the lines and arrows. 
You decide to participate in the study and you sign informed consent
Screening show that you can take part in the study
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Medicines used in this study
Digoxin given on Days 1-10 of a 28 days cycle for a total of 6 cycles. 
Decitabine given on Days 6-10 of a 28 days cycle for a total of 6 cycles.
During treatment
 You will be monitored for any side effects you may be 
experiencing
Your disease will be monitored to determine if it is getting 
better, staying the same or getting worse.  
Follow up to monitor your overall healt
     
How long will you be in the research study?
You may be in the study for approximately 12 months, or until your disease gets worse or you 
experience intolerable side effects.
Can you stop being in the research study?
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about 
stopping or decide to stop.  He or she will tell you how to stop safely. 
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
study drugs can be evaluated by your doctor.  Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow-up care and testing could be most helpful for 
you.
Can you be removed from this research study?
The study doctor may stop you from taking part in this research study at any time if he/she 
believes it is in your best interest; if you have side effects that you cannot tolerate; if you do not 
follow the research study rules; or if the research study is stopped.
What side effects or risks can you expect from being in the research study?
You may have side effects while on the research study.  Everyone taking part in the research 
study will be watched carefully for any side effects.  However, doctors don't know all the side 
effects that may happen.  Side effects may be mild or very serious.  Your health care team may 
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give you medicines to help lessen side effects.  Many side effects go away soon after you stop 
taking the study drugs.  In some cases, side effects can be serious, long lasting, or may never 
go away. 
You should talk to your study doctor about any side effects that you have while taking part in the 
research study. 
Risks and side effects related to decitabine include those which are:
Likely (≥ 20%)
Leukopenia/Neutropenia: (low white blood cell count) A low white blood cell count makes it 
hard for you to fight infections
Thrombocytopenia (low platelet count) Platelets are important in stopping bleeding. A low 
platelet count can increase and prolong bleeding
Anemia (low hemoglobin, low hematocrit or low red blood cell count) Red blood cells carry 
oxygen and nutrients throughout the body. Symptoms that may be experienced as a result of 
low red blood cell counts may include feeling tired and weak, shortness of breath, increased 
heart rate, dizziness or lightheadedness, headache, chest pain and pale skin
Superficial bleeding under the skin which results in pin point flat round red spots
Headache
Constipation (difficulty having a bowel movement)
Nausea (feeling sick to your stomach)
Vomiting (throwing up)
Diarrhea
Cough
Fever
Chills
Joint/muscle pain
Fatigue (feeling of being overly tired and lacking energy)
Insomnia (difficulty sleeping or falling asleep)
Hyperglycemia (high blood sugar) Symptoms of high blood sugar may include increased 
hunger, increased thirst, dry mouth and increased urination
Hypomagnesemia (low magnesium level in the blood) – symptoms may include muscle 
cramps, weakness, tremors and abnormal heart beats
Hypokalemia (low levels of potassium) – symptoms may include muscle weakness, 
cramping, leg discomfort, an irregular heart beat and confusion
Hyperkalemia (elevated levels of potassium) – symptoms may include nausea, diarrhea, 
fatigue, muscle weakness or a tingling sensation, chest pain and heart palpitations
Hypocalcemia (low calcium levels in the blood) – symptoms of a low calcium level may 
include numbness and tingling in the hands and feet, muscle cramps, twitches and spasms, 
fatigue, confusion, disorientation and seizures.
Hypoalbuminemia (low levels of albumin in the blood) – albumin is a protein that is found in 
the blood. Low levels of albumin may produce no symptoms, unless your blood albumin 
levels are very low. Symptoms associated with low albumin may include poor appetite, 
swelling that is all over the body or in a certain part of the body such as the legs or abdomen, 
muscle weakness, fatigue or cramps.
Peripheral edema – swelling of the hands, feet, ankles, or lower legs
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Hyponatremia (low sodium levels in the blood) – symptoms may include nausea and 
vomiting, loss of appetite, headache, confusion, fatigue, restlessness and irritability, muscle 
weakness, spasms or cramps, decreased consciousness, seizures or coma.
Less Likely (between 5% and 19%)
Anxiety
Confusion
Dizziness
Blurred vision
Rash
Itching
Mucositis/stomatitis – sore in the lining of your mouth and/or throat that can be painful and 
make it hard to swallow
Indigestion
Stomach pain
Loss of appetite
Shortness of breath
Hypotension (low blood pressure) – you may experience dizziness or feel like you are going 
to pass out
Heart murmur
Chest pain
Fast heart rate
Hair loss
Elevated liver enzymes – liver enzymes are proteins made by the liver that are measured in 
the blood, with a blood draw. Liver enzymes indicate how well your liver is functioning. 
Elevated liver enzymes may cause no symptoms, however higher liver enzyme levels may 
cause you to feel overly tired or weak, you may bruise or bleed more easily, and you may 
experience abdominal pain or have a yellowing of the skin or eyes. 
Rare But Serious (< 5%)
Kidney damage
Heart failure – a lowered ability of the heart to pump blood
Infections
Severe bleeding in the brain 
Risks and side effects related to digoxin include those which are:
Changes in heart rhythm, including irregular heartbeat
Fast or slow heartbeat.
Facial swelling
Dizziness
Changes in mood and mental alertness, including confusion, depression and lost interest in 
usual activities
Anxiety
Headache
Fever
Hallucinations (seeing or hearing things that are not there)
Rash and itching
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Nausea, vomiting and diarrhea
Belly pain
Not hungry
Weakness
Visual problems, including blurry vision and yellow halos
Growth or enlargement of breast tissue in men (gynecomastia) (< 1%)
Low platelet count (< 1%)
Signs of Digoxin Toxicity
Signs of digoxin toxicity include inability or unwillingness to eat (anorexia), nausea, vomiting, 
and/or new visual changes such as double vision or blurriness. Palpitations (the sensation of 
your heart pounding within your chest) may indicate an abnormal heart rhythm brought on by 
the digoxin. 
Patients at greatest risk for digoxin toxicity include those with very low body weight, those who 
are very elderly, those with pre-existing kidney damage, and those with a history of difficulty 
maintaining normal electrolyte levels (potassium, calcium or magnesium).
If you experience persistent or repeated vomiting, sudden changes in your vision, palpitations or 
chest pain, you should call for immediate medical help.
Blood Draw Risks

Fainting

Bleeding at the site of blood draw

Bruising at the place on your arm where the blood was drawn or needle inserted

Pain at the site of blood draw

Swelling at the site of blood draw

Infection (rare)
Biopsy Risks 

Bleeding

Pain

Infection, which can be life-threatening or fatal in rare cases
Reproductive Risks

Study treatments may make you sterile (unable to have children).

The drugs in this study may affect a baby, before or after the baby is born.

You should not become pregnant or father a baby while on this research study because 
the drugs you take could possibly hurt an unborn baby.

If you are pregnant now or if you are breast-feeding now, you may not take part in this 
research study.

If you become pregnant while you are on the research study, you may not continue to 
take part in the research study.
For women who can become pregnant:

You should not become pregnant while you are in this study.

You should not breast-feed your baby while taking drugs for this research study.
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
If you are having sex that could lead to pregnancy, you should use birth control during 
the study and for at least 3 months after the end of study treatment.
For men:

You should not make a woman pregnant while you are in this study.

If you are having sex that could lead to pregnancy, you should use birth control during 
the study and for at least 2 months after the end of study treatment.
For women and men:

Check with the study doctor about birth control methods. Some methods might not be 
approved for use in this study.  
Are there benefits to taking part in the study?
Taking part in this study may or may not make your health better. It is possible that your 
condition will get better, but it is also possible that there will be no effect on your condition or 
that your condition will get worse. While doctors hope that the combination of digoxin and 
decitabine will be more useful against cancer compared to the usual treatment, there is no proof 
of this yet.  We do know that the information from this study will help doctors learn more about 
the combination of digoxin and decitabine as a treatment for cancer.  This information could 
help future cancer patients.
What other choices do you have if you do not take part in this research study?
Your other choices may include:

Getting treatment or care for your cancer without being in a study 

Taking part in another study 

Getting no treatment 

Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat the 
cancer directly, but instead tries to improve how you feel.  Comfort care tries to keep you as 
active and comfortable as possible. 
Talk to your doctor about your choices before you decide if you will take part in this study.
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used. 
Organizations that may look at and/or copy your medical records for research, quality 
assurance, and data analysis include:

Fox Chase Cancer Center and affiliated Joint Centers, The Institutional Review Boards of 
The Fox Chase Cancer Center and Temple University, Temple University, Temple University 
Health system, Inc., and its affiliates or subsidiaries and other authorized representatives of 
these organizations.
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
The National Cancer Institute (NCI) and other government agencies, like the Food and Drug 
Administration (FDA), involved in keeping research safe for people 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.
You will be given a separate form to review regarding the steps we will take to guard your 
privacy as part of your participation in the research study.  By signing that additional 
authorization, you will be providing your consent to use and disclose information described in 
that form connected with your participation in this research study.
What are the costs?
 
You and/or your health plan/insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost 
of getting regular cancer treatment.
Fox Chase Cancer Center will provide digoxin at no charge while you take part in this study.  
You or your health insurance company will need to pay for decitabine, check with your health 
plan or insurance company to find out if they will pay for decitabine.
If your insurance will not pay for medicines you may need to help with side effects, you may 
have to pay for them.
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .  You 
can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site.
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy.
Will you be compensated?
You will not be paid for taking part in this study.
What if you are injured while taking part in this research study?
If you are injured as a result of your participation in this research study, seek immediate medical 
care.  Temple University Health System or its subsidiaries will treat the injury, though there is no 
commitment to provide monetary compensation or free medical care. Other financial 
compensation (such as lost wages or pain and suffering) for such injuries is not available.  
What are your rights if you take part in this research study?
Taking part in this research study is your choice.  You may choose either to take part or not to 
take part in the research study.  If you decide to take part in this study, you may leave the study 
at any time.  No matter what decision you make, there will be no penalty to you and you will not 
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lose any of your regular benefits.  Leaving the study will not affect your medical care.  You can 
still get your medical care from our institution. 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form. 
New findings
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study.
Who can answer your questions about the research study?
Important Contact Numbers
If you have questions about:
Please Call:
This study, including if you get sick or hurt
Dr. Philip Pancari  at 215-728-4300
If you have a concern or complaint
Risk Management Department at 215-728-2591
Your rights as a research participant on this study 
FCCC Institutional Review Board at 215-214-3754
Your bills or health insurance coverage
Clinical Trial Financial Counselor at 215-214-3768
Where can you get more information?
You may call the National Cancer Institute's Cancer Information Service at: 
1-800-4-CANCER (1-800-422-6237) 
You may also visit the NCI website at http://cancer.gov

For NCI's clinical trials information, go to: http://cancer.govclinicaltrials/ 

For NCI's general information about cancer, go to: http://cancer.gov/cancerinfo/ 
By signing below, you tell us that you have gotten all of the information you need; that you have 
received clear answers to your questions, and that you agree to take part in the research study.  
You will receive a copy of this form.  You may also request a copy of the research plan. 
___________________                    ________________________              _____________
Signature of Participant
Print Name of Participant                       Date
By signing this form the Physician obtaining consent indicates that the research participant has 
been fully informed of all aspects of the research study.
____________________________   _______________________            ____________
Signature of Physician
Print Name of Physician 
                   Date
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Obtaining Consent
Obtaining Consent
By signing this form the person obtaining consent indicates that the research participant has 
been fully informed of all aspects of the research study.
____________________________   _______________________              ____________
Signature of Person
Print Name of Person 
                    Date
Obtaining Consent
Obtaining Consent
____________________________________________________               _________________
Signature of Legally Authorized Representative (LAR)                                  Date
___________________________________                 _________________________________________
    Print Name of LAR                                                          Relationship of LAR to Participant                         
(Indicate why the LAR is authorized to act as a surrogate health care decision-maker under the 
Commonwealth of Pennsylvania)
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Authorization (Permission) to Use or Disclose (Release) Protected Health Information 
(PHI) for Research
IRB# and Protocol ID:
16-1061
Study Title: 
HM-091: A Phase Ib/II study of the safety and activity of Digoxin 
with Decitabine in adult AKL and MDS
Principal Investigator:
Philip Pancari, MD
Sponsor:
Philip Pancari, MD at Fox Chase Cancer Center
1.
What is the purpose of this form?
This form is required by the Health Insurance Portability and Accountability Act of 1996.  
Specifically the privacy regulation (HIPAA) permits the research investigators listed above to 
use and disclose health information about you for the research study identified above which has 
been approved by the Fox Chase Cancer Center Institutional Review Board.
The sponsor is an organization/person that does research to learn about the causes of cancer, 
and how to prevent and treat cancer. Researchers would like to use your protected health 
information for research. The elements of protected health information as defined by HIPAA are:
Data Elements for Protected Health Information (PHI)

Names

All geographic subdivisions smaller than a state (except for the first 3 digits of the zip 
code in some cases)

All elements of dates (except year) for dates directly related to an individual (e.g., birth 
date, admission date, discharge date, date of death) and all ages over age 89 and dates 
indicative of that age

Telephone numbers

Fax numbers

E-mail addresses

Social security numbers

Medical record numbers

Health plan beneficiary numbers

Account numbers

Certificate/license numbers

Vehicle identifiers and serial numbers, including license plate numbers

Device identifiers and serial numbers

Web Universal Resource Locators (URL)

Internet Protocol (IP) addresses

Biometric identifiers, including finger and voice prints

Full face photos and any comparable images
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
Any other unique identifying number, characteristic, or code
2. What protected health information do the researchers want to use?
The researchers want to copy and use the portions of your medical record that they will need for 
their research. If you enter a research study, medical information that will be used and/or 
released may include the following:

The history and diagnosis of your disease

Specific information about the treatments you received, including previous treatment(s) 
you may have had

Information about other medical conditions that may affect your treatment

Medical data, including laboratory test results, tumor measurements, CT scans, MRIs, x-
rays, and pathology results

Long-term information about your general health status and the status of your disease

Data that may be related to tissue, urine and/or blood samples that may be collected 
from you
You may request a blank copy of the data forms from the study doctor or his/her research staff 
to learn what information will be shared.
3. Why do the researchers want my protected health information?
Fox Chase Cancer Center will collect your protected health information and share it with the 
sponsor, as applicable, if you enter a research study. The centers will use your information in 
their cancer research study.
4. Who will be able to use my protected health information?
Fox Chase Cancer Center, Temple University, Temple University Health System affiliates, and 
Temple University Clinical Faculty Practice Plan will use your health information for research. As 
part of this research, they may give your information to the following groups taking part in the 
research. Fox Chase Cancer Center and Temple University may also permit these groups to 
come in to review your original records that are kept by Fox Chase Cancer Center so that they 
can monitor their research study.

The Fox Chase Cancer Center IRB

Public Health agencies and other government agencies (including non-U.S.) as 
authorized or required by law

Other people or organizations assisting with research efforts of the sponsor

Central laboratories, central review centers, and central reviewers. The central 
laboratories and review agencies may also give your health information to those groups 
listed above
5. How will information about me be kept private?
The sponsor will keep all patient information private to the extent possible, even though the 
sponsor is not required to follow the federal privacy laws. Only researchers working with the 
sponsor will have access to your information. The sponsor will not release personal health 
information about you to others except as authorized or required by law. However, once your 
information is given to other organizations that are not required to follow federal privacy laws, 
we cannot assure that the information will remain protected. However, the laws of the 
Commonwealth of Pennsylvania or your state of residence may provide further privacy 
protection.
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6. What happens if I do not sign this permission form?
If you do not sign this permission form, you will not be able to take part in the research study for 
which you are being considered.
7. If I sign this form, will I automatically be entered into the research study?
No, you cannot be entered into any research study without further discussion and separate 
consent. After discussion, you may decide to take part in the research study. At that time, you 
will be asked to sign a specific research consent form.
Treatment by your physician will not be affected by whether you provide authorization for the 
requested use or disclosure except if your treatment is related to research.
8. What happens if I want to withdraw my permission?
You can change your mind at any time and withdraw your permission to allow your protected 
health information to be used in the research. If this happens, you must withdraw your 
permission in writing.  Beginning on the date you withdraw your permission, no new protected 
health information will be used for research. However, researchers may continue to use the 
protected health information that was provided before you withdrew your permission.  If you sign 
this form and enter the research study, but later change your mind and withdraw your 
permission, you will be removed from the research study at that time.
To withdraw your permission, please contact the person below. She will make sure your written 
request to withdraw your permission is processed correctly.
Contact Name:
Philip Pancari, MD
Contact Address: 
333 Cottman Avenue
Philadelphia, PA 19111
Contact Phone and 
FAX:
215-728-4300 and 215-728-3639
9. How long will this permission last?
If you agree by signing this form that researchers can use your protected health information, this 
permission has no expiration date. However, as stated above, you can change your mind and 
withdraw your permission at any time.
10. What are my rights regarding access to my personal health information?
You have the right to refuse to sign this permission form. You have the right to review and/or 
copy records of your protected health information kept by Fox Chase Cancer Center and 
Temple University affiliates. However, while the research study is in progress, you may not be 
able to access your protected health information in order to preserve the integrity of the 
research.  You will be able to access this information when the study is completed. You do not 
have the right to review and/or copy records kept by the sponsor or other researchers 
associated with the research study.
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*************************************************************************************************************
********
Signatures
I agree that my protected health information may be used for the research purposes described 
in this form.
___________________________   ________________________           _____________
Signature of Participant
Print Name of Participant              Date
By signing this form the physician indicates that the research participant has been fully informed 
of all aspects of the research study.
_______________________       _______________________
         ____________
Signature of Physician               Print Name of Physician                         Date
____________________________   _______________________           ____________
Signature of Person
Print Name of Person 
               Date
Obtaining Consent
Obtaining Consent
      __________________________                                                    _________________
Signature of Legally Authorized Representative (LAR)                              Date
_______________________                              ________________________________
Print Name of LAR                                               Relationship of LAR to Participant                                       
(Indicate why the LAR is authorized to act as a surrogate health care decision-maker under the 
Commonwealth of Pennsylvania)
*********************************************************************************************************************
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