Metabolically Optimized, Non-cytotoxic Low Dose Weekly Decitabine/Venetoclax in MDS and AML
Phase: PHASE2
Conditions: Myelodysplastic Syndromes, Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia
Sponsor: Montefiore Medical Center

Title: Metabolically Optimized, Non-cytotoxic Low Dose 
Weekly Decitabine/Venetoclax in MDS and AML
NCT05184842
IRB#: 2021-13466
IRB Approval Date: 12/18/2024
IRB NUMBER: 2021-13466
IRB NUMBER: 2021-13466
IRB NUMBER: 2021-13466
IRB NUMBER: 2021-13466
IRB APPROVAL DATE: 12/18/2024
IRB APPROVAL DATE: 12/18/2024
IRB APPROVAL DATE: 12/18/2024
IRB APPROVAL DATE: 12/18/2024

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Protocol Version 4.0, Date: April 02, 2023
STUDY NUMBER: 2021-13466
ClinicalTrials.gov NCT #:  NCT05184842
Version Date: April 02, 2023
Version Number: 5.0
STUDY TITLE: Metabolically Optimized, Non-cytotoxic Low Dose Weekly 
Decitabine/Venetoclax in MDS and AML 
PRINCIPAL INVESTIGATOR: 
Mendel Goldfinger, MD 
Montefiore/Einstein Cancer Center
Address: 111 East 210 street 
Bronx, NY 10467
Phone: 718-920-4826
Fax: 718-798-7474
Email: mgoldfin@montefiore.org 
CO-INVESTIGATORS:
Marina Konopleva, MD
Amit Verma, MD
Noah Kornblum, MD
Kira Gritsman, MD 
Ulrich Steidl, MD 
Aditi Shastri, MD
Ioannis Mantzaris, MD
Roberto Alejandro Sica, MD
Swati Goel, MD 
Nishi Shah, MD 
Lauren Shapiro, MD
Ridhi Gupta, MD 
David Levitz, MD 
Stephen Peeke, MD
Yang Shi, MD 
Brian Jonas, MD. University of California, Davis. Sacramento, CA
Joshua Raff, MD. White Plains Hospital Center 
IRB NUMBER: 2021-13466
IRB APPROVAL DATE: 12/18/2024
IRB NUMBER: 2021-13466
IRB APPROVAL DATE: 12/18/2024
IRB NUMBER: 2021-13466
IRB APPROVAL DATE: 12/18/2024
IRB NUMBER: 2021-13466
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Protocol Version 4.0, Date: April 02, 2023
STATISTICIAN:
Xiaonan (Nan) Xue, PhD
Professor in Biostatistics
Department of Epidemiology & Population Health
Albert Einstein College of Medicine
Bronx, NY 10461
Tel. 718-430-2431
Email. Xiaonan.xue@einsteinmed.edu
RESEARCH NURSE:
Anne Munoz
Karen Fehn
STUDY COORDINATOR:
Aradhika Dhawan
Joel Victor
REGULATORY CONTACT:
Rikin Gandhi
SPONSOR: Montefiore-Einstein Center for Cancer Care
SUPPLIED AGENT(S):
Not applicable
IND #: 
IND Exempt 
OTHER AGENTS:
Venetoclax
Decitabine
Title: 
 
Metabolically 
Optimized, 
Non-cytotoxic 
Low 
Dose 
Weekly 
Decitabine/Venetoclax in MDS and AML  
Principal Investigator: Mendel Goldfinger, MD
IRB NUMBER: 2021-13466
IRB APPROVAL DATE: 12/18/2024
IRB NUMBER: 2021-13466
IRB APPROVAL DATE: 12/18/2024
IRB NUMBER: 2021-13466
IRB APPROVAL DATE: 12/18/2024
IRB NUMBER: 2021-13466
IRB APPROVAL DATE: 12/18/2024

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Protocol Version 4.0, Date: April 02, 2023
PRINCIPAL INVESTIGATOR SIGNATURE:
_______________________________________
Date: ___________________
Document History and SUMMARY OF CHANGES
Protocol 
Version 
Version Date
Section
Change
Front Page
-
Added 
MECCC 
co-
investigators Ridhi Gupta, 
MD, David Levitz, MD, 
and Stephen Peeke, MD.
-
Added 
White 
Plains 
Hospital site PI name- Dr.  
Joshua Raff.
-
Removed 
Dr. 
Suman 
Kambhampati as the study 
will not be opened at Sarah 
Cannon, Kansas City, MO
Study Schema
Updated study schema to reflect 
appropriate days for Decitabine 
administration.
2.2
Secondary Objective (s) updated:
-Removed the requirement to complete 
the Global Health Quality Of Life 
Questionnaire (GHS/QOL) as the IRB 
approval for the document was not 
obtained.
3.0
Study Design updated: to remove the 
quality of life from the secondary 
objectives.
4.2
Exclusion criteria to include other 
chemotherapy agents like cytarabine, 
cladribine and Gemtuzumab which we 
often use to cytoreduce new AML 
patients who have rapidly proliferative 
disease.
5
June 17, 2024
Section 5
Registration: Removed Sarah Cannon 
Cancer Center and added White Plains 
Hospital Center for Cancer Care as the 
participating site.
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Protocol Version 4.0, Date: April 02, 2023
6
Added 
below 
to 
Concomitant 
Treatment section:
-
In patients with aggressive 
high 
bulk 
disease 
as 
determined 
by 
the 
investigator and PI, may 
receive 
debulking 
chemotherapy with either 
Gemtuzumab ozogamicin, 
Cladrabine or Cytarabine 
prior 
to 
starting 
decitabine/venetoclax. Also 
patients 
who 
have 
mutations in either  FLT3 
(ITD or TKD), JAK2, 
IDH1 or IDH2  mutation 
may receive concomitant 
inhibitors (as outlined in the 
table below) at any point 
during the protocol as 
determined by the PI.  Other 
than 
HU 
and 
above-
mentioned drugs, no other 
concomitant 
disease 
modifying 
therapy 
is 
permitted.  
-
Added a table of the 
allowed 
mutation 
and 
concomitant medication.
Updated Section 6.1.1 :
-
Decitabine 
dosing 
and 
schedule to on days 1, 8, 15, 
28 (+/- 3 days).
Added to section 6.1.4 – 
- Its at discretion of the treating 
physician  based on clinical benefit to 
the patient, as to when  to go back to 
the full dose of Decitabine or keep at 
reduced dose.  
Updated section 6.1.5 – Table 1to add 
some clarification and guidance.
Updated section 6.4- Duration of 
Follow Up: from every 8 weeks to 4 
weeks. 
7
Section 7.3 - SAE Report Form
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Protocol Version 4.0, Date: April 02, 2023
-
the section updated to add 
“in Velos and reported to 
the DSMC. If needed, the 
SAE will also be reported to 
Einstein IRB and removed 
“on the FDA Form 3500A  
(MedWatch) but should 
only 
be 
reported 
as 
instructed 
below. 
The 
electronic 
FDA 
SAE 
reporting forms should not 
be used”
Section 7.4.1 – SAE Reporting 
Requirements:
-
Added DSMC and removed 
FDA, 
external 
collaborator(s).
9
Section 9.2 – Analytical Laboratory:
-
Dr. Amit Verma and Dr. 
Marina 
Konopleva 
Lab 
names added.
10
Study 
Parameters 
and 
Calendar 
updated 
to 
provide 
clarification, 
remove the requirement to collect some 
unnecessary labs, allow buffer for 
visits to occur +/- 3 days.
Added to foot note # 1 “Pre-
study/screening starts from when 
patient signs the consent”.
Added foot note # 11 Bone marrow 
biopsy done before enrolling in the 
study done within 28-days of starting 
study therapy is acceptable 
Front page
Added Research Nurse Anne Munoz , 
Study Coordinator Aradhika Dhawan, 
and Regulatory Contact Rikin Gandhi
Added 2 external Sites
1. Sarah Canon, Kansas City, 
MO
2. University of California, 
Davis, Sacramento, CA
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Protocol Version 4.0, Date: April 02, 2023
Protocol 
Summary 
Sample size updated to 75 patients
3.1
Total patient to be enrolled updated  
and added Sarah Cannon, Kansas 
City, MO and University of 
California, Davis, Sacramento, CA as 
an external enrolling sites
5.0 Registration
Added Sarah Cannon, Kansas City, 
MO and University of California, 
Davis, Sacramento, CA
9.1 Methods
Added Bone marrow aspirates 
collection 
12.2.4
Added Montefiore Einstein Cancer 
Center to allow the Quality Assurance 
team to monitor and audit the study at 
external sites
4
April 11, 2023
13.0
Sample Size Calculation : text added 
“After the 19 patients were enrolled 
and 16 patients were evaluable after a 
12-week induction, there were with no 
safety concerns. An amendment will be 
added for additional 40 patients (above 
the originally planned 33 patients) to 
gather more data on safety and 
efficacy”
Front Page
Added Dr Konopleva as a Co-PI and 
removed Dr Braunschweig
Protocol schema
Decitabine days changed from 2,9, 
16,23 to 1,8, 15, 22
Section 14.0
Funding: Added funding information
3
February 03, 
2023
Section 4.1
Added CMML into inclusion
2
April 21, 2022
Section 4.1
Change 
in 
Eligibility 
Criteria 
(inclusion #4 states subjects should 
have an ECOG PSD of ≥3 and was 
changed to ≤3)
1
November 09, 
2021
Original Protocol
IRB NUMBER: 2021-13466
IRB APPROVAL DATE: 12/18/2024
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Protocol Version 4.0, Date: April 02, 2023
ABBREVIATIONS
AZA
5-zacitidine 
AE
Adverse event
AEs
Adverse events 
Allo-HCT
Allogeneic hematopoietic stem cell transplant
AML
Acute myeloid leukemia
AML-MRC
AML with myelodysplastic related changes 
CML
Chronic myeloid leukemia
CMML
Chronic myelomonocytic leukemia
CR
Complete response
CRi
Complete remission with incomplete marrow 
recovery
DEC
Decitabine 
DNMT1
DNA methytransferase 1
DOR
Duration of response
Dctp
Deoxycytidine triphosphate
EFS
Event-free survival
ELN
European Leukemia Net
FDA
Food and Drug Administration
FOCBP
Females of child bearing potential
GHS
Global health status  
HI
Hematologic Improvement
HMA
Hypomethylating agents 
ICF
Informed Consent Form
IRB
Institutional Review Board
IWG
International Working Group
NOS
Not otherwise specified
MDS
Myelodysplastic syndrome
MDS/MPN
Myelodysplastic and myeloproliferative 
overlap syndrome
MPN
Myeloproliferative neoplasm
MF
Myelofibrosis
ORR
Overall response rate 
PR
Partial remission
QOL
Quality of life
RARS-T
Refractory anemia with ringed sideroblasts 
and essential thrombocytosis
R/R
Relapsed refractory
SAE
Severe adverse event
SOC
Standard of Care
ULN
Upper limit of normal
Ven
Venetoclax
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Protocol Version 4.0, Date: April 02, 2023
STUDY SCHEMA
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Protocol Version 4.0, Date: April 02, 2023
PROTOCOL SUMMARY
Protocol Number/Title
Proof-of-concept study of metabolically optimized, non-
cytotoxic low-dose weekly decitabine and venetoclax in myeloid 
malignancies
Study Phase
Proof-of-concept clinical trial
Brief Background
The combination of Azacitidine and venetoclax is FDA 
approved for patients AML > 75 and/or unfit for induction 
chemotherapy. However, majority of patients receiving standard 
dosing of Aza/Ven require dose interruptions, treatment delays 
and dose reductions. In addition, Aza/ven has limited activity in 
various subgroups of myeloid malignancies such as P53 mutant 
MDS/AML. 
The severe cytopenias encountered with Aza/ven is particularly 
challenging for patients with poor hematopoietic bone marrow 
reserve such as MDS and MF. Also some elderly patients with 
comorbidities cannot tolerate the prolonged cytopenias caused 
by Aza/ven.  This pilot clinical trial will evaluate the tolerability 
of a non-cytotoxic regimen for patients with myeloid 
malignancies who either cannot tolerate or are not known to 
benefit from standard Aza/ven dosing. 
Rationale
Noncytotoxic dosing of decitabine given weekly at a dose of 
0.2 mg/kg induces depletion of DNA methyltransferase 1 
(DNMT1) while minimizing the toxicity and myelosuppression 
seen with standard HMA dosing regimens. This approach has 
been shown to be effective in a wide spectrum of patients with 
myeloid malignancies, including patients with resistant disease 
such as P53 mutations.  
Preclinical studies have demonstrated that adding a dose of 
venetoclax prior to administering decitabine enhances the anti-
leukemic activity of HMAs  by inhibiting  de novo pyrimidine 
synthesis, which is a major mechanism of resistance to HMA in 
MDS/AML. Decreasing the dose of venetoclax to a weekly 
schedule also spares normal myelopoiesis. Therefore, a weekly 
dosing of decitabine/venetoclax is a very attractive option for a 
patient population who cannot tolerate or are not known to 
benefit standard Aza/ven.
Primary Objective 
Primary Endpoint
Percentage of participants who are able to continue on 
treatment without dose interruptions or delays. Defined as 
delaying or interrupting treatment due to toxicity or 
intolerability during the induction phase (weeks 1-12)
Secondary Objective(s)
Secondary Endpoints:  (1) Cumulative incidence of response 
for both CR, CRi and overall response; (2) Event free survival 
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Protocol Version 4.0, Date: April 02, 2023
(EFS);  (3)  Complete remission or complete remission with 
partial hematologic recovery rate (CR+CRh); (4) Post baseline 
transfusion dependence rate; (5) Fatigue/quality of life (QoL); 
(6) Rate of hospitalization; (7) Infection rate 
  Scientific Correlates:  
Correlation of DNMT1 depletion with clinical response criteria
Sample Size
 85 patients 
Disease sites/Conditions
Myeloid malignancies: ≥MDS, AML, MDS/MPN overlap 
syndrome 

Interventions

Venetoclax 400 mg po on days 1, 8, 15 and 28 of each 
cycle (28day cycle) (+/- 1 day allowed).

Decitabine 0.2 mg/kg SQ on days 1, 8, 15, 22 (for 
aggressive disease will add decitabine on days 2, 9, 
16, 23)
IRB NUMBER: 2021-13466
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Protocol Version 4.0, Date: April 02, 2023
TABLE OF CONTENTS
SUMMARY OF CHANGES .........................................................................................................................3
ABBREVIATIONS.........................................................................................................................................5
STUDY SCHEMA..........................................................................................................................................6
PROTOCOL SUMMARY.............................................................................................................................7
TABLE OF CONTENTS...............................................................................................................................9
1.0
INTRODUCTION...............................................................................................................................12
1.1
BACKGROUND..................................................................................................................................12
1.1.1
Diseases– Myeloid malignancies: Acute Myelogenous Leukemia (AML) and Myelodysplastic 
Syndromes (MDS) and Myeloproliferative neoplasms (MPN).........................................................................12
1.1.2
Treatment of myeloid malignancies ....................................................................................................12
1.2
STUDY RATIONALE..........................................................................................................................14
1.2.1
Rationale for low dose non-cytotoxic weekly Decitabine dosing:......................................................14
1.2.2        Rationale for non-cytotoxic Venetoclax Priming of Decitabine: .....................................................15
1.3
Rationale for subgroups of patients with myeloid malignancies who may benefit from a noncytotoxic 
HMA/ven regimen ..............................................................................................................................................16
1.3.1
Patients who are unfit and cannot tolerate prolonged cytopenias from standard dosing of Aza/ven:
17
1.3.2          Patients with antecedent Myeloproliferative disorders:..................................................................17
1.3.3        Molecular subgroups that are not known to respond well to Aza/ven:............................................18
1.3.4
High risk MDS:....................................................................................................................................18
1.4
BACKGROUND AND RATIONALE OF CORRELATIVE STUDIES .........................................................19
1.4.1
DNMT1 expression ..............................................................................................................................19
2.0 OBJECTIVES......................................................................................................................................20
2.1
PRIMARY OBJECTIVE......................................................................................................................20
2.2
SECONDARY OBJECTIVE(S).............................................................................................................20
3.0
STUDY DESIGN .................................................................................................................................21
3.1
NUMBER OF SUBJECTS ....................................................................................................................21
3.2
REPLACEMENT OF SUBJECTS..........................................................................................................22
3.3 
EXPECTED DURATION OF TREATMENT AND SUBJECT PARTICIPATION .......................................22
4.0
PATIENT SELECTION.....................................................................................................................22
4.1
INCLUSION CRITERIA......................................................................................................................22
4.2
EXCLUSION CRITERIA.....................................................................................................................23
4.3
INCLUSION OF WOMEN AND MINORITIES..........................................................................................25
5.0
REGISTRATION................................................................................................................................25
6.0
TREATMENT PLAN .........................................................................................................................25
6.1
TREATMENT REGIMEN OVERVIEW................................................................................................25
6.1.1
Decitabine dosing and schedule ..........................................................................................................26
All patients will receive at least one dose Decitabine every week. If decided by treating physician that the 
patient needs a more rapid debulking of high disease burden, a second dose can be added. If Decitabine is 
given twice a week, should preferably be given on two consecutive days. .........................................................26
6.1.2
Venetoclax dosing and schedule .........................................................................................................26
Venetoclax is dosed at 400 mg by mouth one day a week a day prior to the first decitabine dose. If patients are 
taking another CYP3A4 inhibitor dose adjustments should be made as recommended by pharmacist for a goal 
dose of venetoclax of 400 mg. .............................................................................................................................26
If patient receives two days of decitabine a week, they still only take venetoclax on the day prior to the first 
dose of decitabine................................................................................................................................................27
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6.1.3
Treatment phase...................................................................................................................................27
6.1.4
Dose adjustments for hematologic toxicity .........................................................................................27
6.1.5
Adjustments for non-hematologic toxicity ≥ Grade 3.........................................................................28
6.2
GENERAL CONCOMITANT MEDICATIONS AND SUPPORTIVE CARE GUIDELINES ........................32
6.3
CRITERIA FOR REMOVAL FROM STUDY.........................................................................................32
6.4
DURATION OF FOLLOW UP .............................................................................................................34
6.5
SAFETY RUN-IN AND EARLY STOPPING RULE...............................................................................34
6.6
EARLY STOPPING RULE FOR EXCESSIVE TOXICITY FOLLOWING SAFETY RUN-IN ....................34
7.0
ADVERSE EVENTS AND POTENTIAL RISKS............................................................................35
7.1              AGENT ADVERSE EVENTS..........................................................................................................35
7.2
DEFINITIONS....................................................................................................................................36
7.2.1
Adverse Event........................................................................................................................................36
7.2.2
Serious Adverse Events........................................................................................................................36
7.2.3
Adverse Event Evaluation....................................................................................................................38
THE INVESTIGATOR OR DESIGNEE IS RESPONSIBLE FOR ENSURING THAT ALL ADVERSE EVENTS (BOTH SERIOUS AND 
NON-SERIOUS) OBSERVED BY THE CLINICAL TEAM OR REPORTED BY THE SUBJECT WHICH OCCUR AFTER THE 
SUBJECT HAS SIGNED THE INFORMED CONSENT ARE FULLY RECORDED IN THE SUBJECT’S MEDICAL RECORDS. 
SOURCE DOCUMENTATION MUST BE AVAILABLE TO SUPPORT ALL ADVERSE EVENTS................................38
ANY GRADE LABORATORY INVESTIGATION ABNORMALITY CONSIDERED CLINICALLY SIGNIFICANT SHOULD BE 
REPORTED AS AN ADVERSE EVENT, WITH EXCEPTIONS AS NOTED ABOVE...................................................38
THE INVESTIGATOR OR SUB-INVESTIGATOR (TREATING PHYSICIAN IF APPLICABLE) WILL PROVIDE THE FOLLOWING 
FOR ALL ADVERSE EVENTS (BOTH SERIOUS AND NON-SERIOUS):................................................................38

EVENT TERM (AS PER CTCAE).........................................................................................................38

DESCRIPTION OF THE EVENT .............................................................................................................38

DATE OF ONSET AND RESOLUTION....................................................................................................38

EXPECTEDNESS OF THE TOXICITY..................................................................................................38

GRADE OF TOXICITY .......................................................................................................................38

ATTRIBUTION OF RELATEDNESS TO THE INVESTIGATIONAL AGENT - (THIS MUST BE ASSIGNED BY AN 
INVESTIGATOR, SUB-INVESTIGATOR, OR TREATING PHYSICIAN)............................................................38

ACTION TAKEN AS A RESULT OF THE EVENT, INCLUDING BUT NOT LIMITED TO; NO CHANGES, DOSE 
INTERRUPTED, REDUCED, DISCONTINUED, ETC. OR ACTION TAKEN WITH REGARD TO THE EVENT, I.E. NO ACTION, 
RECEIVED CONCOMITANT MEDICATION OR OTHER INTERVENTION, ETC.....................................................38

OUTCOME OF EVENT .........................................................................................................................38
DESCRIPTIONS AND GRADING SCALES FOUND IN THE NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS (CTCAE) VERSION 5.0 WILL BE UTILIZED FOR AE REPORTING.....................................................38
AN EXPECTED ADVERSE EVENT IS AN EVENT PREVIOUSLY KNOWN OR ANTICIPATED TO RESULT FROM 
PARTICIPATION IN THE RESEARCH STUDY OR ANY UNDERLYING DISEASE, DISORDER, OR CONDITION OF THE 
SUBJECT. THE EVENT IS USUALLY LISTED IN THE PACKAGE INSERT FOR DECITABINE OR VENETOCLAX, CONSENT 
FORM OR RESEARCH PROTOCOL..................................................................................................................38
AN UNEXPECTED ADVERSE EVENT IS AN ADVERSE EVENT NOT PREVIOUSLY KNOWN OR ANTICIPATED TO RESULT 
FROM THE RESEARCH STUDY OR ANY UNDERLYING DISEASE, DISORDER, OR CONDITION OF THE SUBJECT.39
ATTRIBUTION IS THE RELATIONSHIP BETWEEN AN ADVERSE EVENT OR SERIOUS ADVERSE EVENT AND THE STUDY 
DRUG.  ATTRIBUTION WILL BE ASSIGNED AS FOLLOWS: .............................................................................39

DEFINITE – THE AE IS CLEARLY RELATED TO DECITABINE/VENETOCLAX. ......................................39

PROBABLE – THE AE IS LIKELY RELATED TO DECITABINE/VENETOCLAX. .......................................39

POSSIBLE – THE AE MAY BE RELATED TO DECITABINE/VENETOCLAX. ............................................39

UNLIKELY – THE AE IS DOUBTFULLY RELATED TO DECITABINE/VENETOCLAX...............................39

UNRELATED – THE AE IS CLEARLY NOT RELATED TO DECITABINE/VENETOCLAX..........................39
PROTOCOL MUST SPECIFY IF ATTRIBUTION IS REQUIRED FOR INDIVIDUAL COMPONENTS OF THE TREATMENT 
REGIMEN OR THE TREATMENT REGIMEN AS A WHOLE.................................................................................39
7.3
 SAE REPORT FORM .......................................................................................................................39
7.4
 REPORTING PROCEDURES FOR SERIOUS ADVERSE EVENTS........................................................39
7.4.1
SAE Reporting Requirements..............................................................................................................39
7.5
SAES AND ONCORE ........................................................................................................................40
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7.6
DATA SAFETY AND TOXICITY COMMITTEE...................................................................................40

7.7 DATA AND SAFETY MONITORING PLAN (DSMP) ....................................................................40
8.0
PHARMACEUTICAL INFORMATION .........................................................................................41
8.1 INVESTIGATIONAL AGENTS................................................................................................................41
8.1.1 
Name of Agent: Decitabine..................................................................................................................41
8.2.1 
Name of Agent: Venetoclax.................................................................................................................42
9.0
CORRELATIVE STUDIES ...............................................................................................................42
9.1
METHODS.........................................................................................................................................42
9.1      Analytical Laboratory..............................................................................................................................43
10.0 STUDY PARAMETERS AND CALENDAR ...................................................................................43
11.0 MEASUREMENT OF EFFECT........................................................................................................45
12.0 DATA REPORTING / REGULATORY CONSIDERATIONS .....................................................51
12.1 DATA REPORTING ...........................................................................................................................51
12.2 REGULATORY CONSIDERATIONS....................................................................................................52
12.2.1
Written Informed consent...............................................................................................................52
12.2.2
Subject Data Protection ..................................................................................................................52
12.2.3
Retention of records ........................................................................................................................52
12.2.4 
Audits and inspections ....................................................................................................................53
13.0 STATISTICAL CONSIDERATIONS...............................................................................................53
14. FUNDING
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1.0
INTRODUCTION 
1.1
Background
1.1.1
Diseases– Myeloid malignancies: Acute Myelogenous Leukemia 
(AML) and Myelodysplastic Syndromes (MDS) and 
Myeloproliferative neoplasms (MPN)
Myeloid malignancies are a heterogeneous group of clonal bone marrow disorders 
that include myeloproliferative neoplasms (MPN’s), myelodysplastic syndromes 
(MDS), and acute myeloid leukemia (AML). Myelodysplastic syndromes are 
clonal malignancies characterized by dysplastic marrow and ineffective 
hematopoiesis.  Myeloproliferative neoplasms (MPNs) are a group of disorders 
caused by overproliferation of bone marrow stem cells which can lead to 
development of myelofibrosis (MF), blast phase-MF and AML. The MDS/MPN 
overlap syndromes are a more heterogeneous group that have features of MDS, 
usually marrow dysplasia but also features such a proliferative component and 
marrow fibrosis.  They include distinct entities such as chronic myelomonocytic 
leukemia (CMML), atypical or BCR-ABL negative chronic myelogenous leukemia 
(aCML), MDS with refractory anemia with ringed sideroblasts and thrombocytosis 
(MDS-RARS-T), and MDS/MPNs not-otherwise specified (NOS). Myeloid 
malignancies as a group lead to the clinical features of peripheral blood cytopenias 
resulting in transfusion dependence, infections, and bleeding. They have highly 
variable prognostic features based on cytogenetic changes and molecular 
mutations.  Several validated prognostic classification systems are available, but no 
standardized guidance has been established on their usage.  All types of MDS and 
MPN’s are at increased risk of progression to AML, with some types such as p53 
mutation and/or complex cytogenetics being at higher risk.   Confirmed cases must 
present both clinical and morphologic criteria as defined by FAB 
and WHO guidelines. 
1.1.2
Treatment of myeloid malignancies
Treatment options for myeloid malignancies are highly dependent on patient-
related factors, such as comorbidities and the impact on quality of life and disease-
related factors, particularly the higher incidence of adverse-risk cytogenetic 
abnormalities which are resistant to standard intensive chemotherapy regimens and 
elderly patients have relatively decreased tolerance to these agents. Using a 
number of validated prognostic schemes, of which the most commonly used is the 
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International Prognostic Scoring System (IPSS), patients with MDS are typically 
grouped into two major risk groups: higher risk and lower risk. 
Treatment objectives for lower risk MDS are to reduce symptoms and improve 
quality of life.  For higher risk MDS, the therapeutic objective is to 
aggressively modify the natural history of the disease, i.e., to increase survival, and 
decrease risk of progression to AML.  Critical issues in determining therapeutic 
strategies for patients with MDS include disease heterogeneity, lack of clear 
pathogenic understanding, tolerability of therapy in the elderly population and a 
dearth of effective treatments. MDS therapies include: supportive care with 
transfusion therapy, growth factors (EPO, G-CSF), antibiotics and HMA’s 
(Azacitidine and Decitabine). The only curative therapy for high risk MDS is 
allogeneic stem cell transplant which has a high morbidity/mortality and therefore 
not an option for elderly or patients with high comorbidities. Treatment for AML 
includes induction chemotherapy with cytarabine plus 
anthracycline, investigational drugs, hematopoietic stem cell transplantation 
(HSCT), FLT3 and IDH inhibitors in patients whose disease harbor these 
mutations. Lower intensity regimens using hypomethylating 
agents (HMA; azacitidine or decitabine) or low-dose cytarabine (LDAC), in 
combination with venetoclax are now FDA approved for patients over age 75 or 
younger patients who cannot tolerate cytotoxic chemotherapy. 1 In practice some 
clinicians will also use HMA/venetoclax for younger patients with diseases known 
to have a poor response to chemotherapy, such as patients who 
harbor P53 mutations and patients with MPN’s that transform to AML for whom 
there is currently no universally accepted standard of care. The combination of 
Azacitidine/venetoclax received FDA approval for AML based the VIALE-A 
trial which randomized newly diagnosed AML patients older than age 75 or 
younger patients ineligible for standard induction therapy because of 
coexisting medical conditions, 
to Azacitidine/Venetoclax or Azacitidine/placebo and showed an improvement in 
OS (14.7 vs. 9.6 months), CR (36.7% vs 17.9%) and composite CR 
(complete remission or complete remission with incomplete hematologic 
recovery) of 66.4% vs. 28.3%. While the VIALE-A has established 
Azacitidine/ventoclax as a new standard for some  patients > age 75 and for 
younger patient’s ineligible for intensive chemotherapy;  a major limitation of this 
regimen is dose limiting toxicities due to cytopenias requiring dose interruptions 
and delays leading to increased risk of disease progression. A modification of 
HMA/ven regimen which can limit dose interruptions due to cytoepanias has the 
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potential to increase the durability of responses.  In addition, majority of responses 
seen with standard doses of HMA/ven are in patients with NPM1, IDH1, IDH2, or 
DNMT3A mutations; with limited activity in patients with P53, RAS and RUNX1 
mutations. 2 An unmet need remains for patients with AML who either cannot 
tolerate standard dosing of Aza/ven or patients who have disease characteristics 
which have not shown to have a benefit from standard dosing Aza/ven. 
1.2
Study Rationale 
1.2.1
Rationale for low dose non-cytotoxic weekly Decitabine dosing:
Decitabine is a nucleoside analogue which depletes the epigenetic regulator DNA 
methyltransferase 1 (DNMT1). It is routinely dosed in myeloid malignancies to 
generate dose-dependent DNA damage in malignant cells that then triggers 
apoptosis (cytotoxicity). However, with this approach normal dividing 
hematopoietic cells are unfortunately also simultaneously destroyed causing 
prolonged cytopenia’s and the myelotoxicity that result from it. In fact, in the 
VIALE-A trial where “standard” myelotoxic doses of HMA/ven were combined, 
24% of patients had to discontinue treatment due to adverse events and more 
importantly 72% of patients required dose interruptions between cycles due to 
adverse events. 1 While some patients can get an initial response to high doses of 
HMA/ven, dose interruptions decrease the durability of many responses. An 
approach of continuous drug exposure for suppression of clones which spares 
preserved non-clonal hematopoietic stem cells may allow continuous dosing 
without interruptions due to cytoepnias and may lead to more durable remissions. 
Weekly low doses of Decitabine administered as a subcutaneous injection has been 
shown to cause on target DNMT1-depletion (even cytoreduce p53-null myeloid 
malignancies) while sparing normal hematopoiesis. Saunthararajah et al identified 
the minimum doses of decitabine (0.1–0.2 mg/kg) can cause molecular targeted 
DNMT1 depletion via terminal differentiation, instead of apoptosis, while sparing 
normal 
hematopoiesis 
by 
limiting 
the 
off-target 
anti-metabolite 
effects/cytotoxicity.3,4  These doses are given 1–2 times a week to increase S-phase 
dependent DNMT1-depletion.  Long term followup (up to 6.5 years) using this 
approach (weekly SQ decitabine of 0.1-0.2 mg/kg), has demonstrated durable 
responses in myeloid malignancies across the clinicopathologic spectrum of diseases 
which include MDS, MDS/MPN overlap, MPN or AML, which is not surprising 
given the ability to continue weekly dosing without dose interruption due to 
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cytopenias. These responses were also in a diverse group of genetic abnormalities 
— consistent with scientific data implicating DNMT1 as a mutation-agnostic target 
that operates in a final common pathway of myeloid transformation.4,5 In a cohort of 
69 patients treated at the Cleveland clinic with low dose weekly decitabine for 
myeloid malignancies, Awada et al reported ~ 40% response rate despite 
approximately 50% of patients having disease that was relapsed/refractory to 5-
azacytidine, lenalidomide and/or cytarabine. 5 
1.2.2        Rationale for non-cytotoxic Venetoclax Priming of Decitabine:
Decitabine is a pro-drug which is processed by pyrimidine metabolism into its active 
form - a deoxycytidine analog. Resistance to decitabine emerges from adaptive 
responses of the pyrimidine metabolism network causing shifts in expression of key 
pyrimidine metabolism enzymes in directions adverse to the pro-drug activation, 
such that decitabine processing into DNMT1-depleting nucleotide is forestalled 
(Figure 1). Continuous pro-drug exposure stabilizes these adaptive metabolic 
responses and thereby prevents DNMT1-depletion.6 A key element in this auto-
resistance is upregulated de novo pyrimidine synthesis which has an electron-
transport dependent mitochondrial step executed by dihydroorotate dehydrogenase 
(DHODH) (see figure below). Venetoclax has shown to inhibit DHODH/pyrimidine 
synthesis and thereby inhibits de novo pyrimidine synthesis.7 Therefore adding 
venetoclax as a single dose primer 24 hours prior to decitabine can counter this mode 
of resistance and enhance the activity of decitabine’s anti-AML activity. This 
strategy overcomes and avoids the toxicity of myelosuppression seen with standard 
cytotoxic dosing of Aza/ven. 
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1.3
Rationale for subgroups of patients with myeloid malignancies who 
may benefit from a noncytotoxic HMA/ven regimen
Hypomethylating agents (decitabine and azacytidine) are approved for the 
treatment of MDS and AML. Venetoclax is approved for AML at and 
often used in the treatment of MDS. The combination of HMA/ventoclax 
at approved doses are cytotoxic causing severe and prolonged 
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cytopenias. However, MDS and AML are heterogenous diseases and 
there are many subgroups of patients for whom standard dosing of HMA 
+/- venetoclax have not been shown to be effective and therefore these 
patients currently do not have standard of care options available for 
them. In addition, there are subgroups of patients who are unable to 
tolerate the toxicities of standard HMA/venetoclax dosing and inevitably 
receive substandard doses of therapy due to dose delays and 
interruptions and therefore are unable to receive effective therapies. A 
non-cytotoxic weekly dosing schedule may be the only effective or 
practical therapy for these subgroups. Below we give a background on 
the rationale for each of these subgroups for who we plan to enrol in this 
study because they currently do not have a standard of care treatment 
option available to them either because there is no known benefit for 
their subtype of MDS/AML and/or they are unable to receive currently 
approved dosing schedules of HMA/venetoclax due to toxicity.
1.3.1 Patients who are unfit and cannot tolerate prolonged cytopenias from 
standard dosing of Aza/ven:
The standard dosing of Aza/ven used in the VIALE-A trial is Azacitidine 75 mg per 
square meter of body-surface area subcutaneously or intravenously on days 1 
through 7 every 28-day cycle, venetoclax 400 mg orally once daily, in 28-day 
cycles. 1 A major challenge with “standard dosing” of Aza/ven is severe and 
prolonged cytopenias,8  leading to transfusion dependence, increased risk of 
bleeding, 
infections, hospitalizations and poor 
quality of 
life. For 
example, 
in VIALE-A grade 3 neutropenia was 
observed 
in 42% of 
patients and 
over 
50% required a reduction in the duration of venetoclax.  Similarly, in clinical 
practice clinicians have been struggling with dose limiting cytopenias leading to 
dose reductions and treatment interruptions. Various algorithms are being suggested 
how to best dose, and interrupt regimens of Aza/ven, with majority suggesting 
shorter durations of venetoclax than was used in VIALE-A trial. 8 It’s therefore not 
surprising that the real-world experience with standard dosing HMA/ven have 
reported outcomes to be inferior to the clinical trials. 9 This has been most 
challenging for elderly patients with multiple comorbidities and for patients with 
antecedent bone marrow disorders who have poor hematopoietic reserve,  many of 
whom cannot tolerate standard Aza/ven dosing. 
1.3.2          Patients with antecedent Myeloproliferative disorders:
Patients with MPN’s who transform to MF, blast phase-MF or full blown AML have 
a very poor prognosis and there is currently no established standard of care for this 
population. The major challenge has been that these patients have marrow fibrosis 
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with poorly preserved hematopoietic cell function and treatments with cytotoxic 
doses of therapy are poorly tolerated.  Like many AML trials, VIALE-A also 
excluded patients with any history of MPN’s (including MF, PV, ET, CMML and 
CML) and the use of HMA/ven combination in this population has only been 
reported in a small single institution retrospective series demonstrating mild 
activity.10 A noncytotoxic regimen for this population is an urgent unmet need. 
1.3.3        Molecular subgroups that are not known to respond well to Aza/ven:
Responses to standard dosing of HMA/ven have been most robust in AML with 
NPM1, IDH1, IDH2, or DNMT3A mutations. Primary or early resistance to 
HMA/ven have been reported in patients with FLT3, C-KIT and TP53 mutations.2 
As described above, the non-cytotoxic regimen of weekly decitabine has shown to 
be effective in myeloid malignancies independent of mutations which are known to 
confer resistance to standard dosing which depends on cytotoxic effects. 
1.3.4
High risk MDS:
Decitabine and Azactidine are the only drugs approved by the FDA for treatment 
of high risk MDS. Response to these agents occurs in ∼50% of patients, duration 
of response is transient and all patients eventually progress.11,12 Outcomes after 
HMA failure are particularly poor, with a median overall survival (OS) of 4 to 6 
months.13,14More  recently the addition of venetoclax to Azacitidine is being 
evaluated in a phase 1b trial for patients with R/R MDS with a reported  40% 
CR/marrow CR in R/R MDS patients in phase 1b trial. 15 However, ≥ grade 3 
cytopenia’s were seen in 50% of patients.  In practice clinicians have been adding 
ventoclax to HMA for patients with HR-MDS (extrapolating from AML). A multi-
institutional realworld experience using HMA/ven for MDS reported an ORR of 
59% [14% CR, 27% marrow CR with hematologic improvement (HI), and 18% 
with a marrow CR without HI], with poor risk cytogenetics being associated with 
poor outcomes.16  In this cohort delays in treatment were seen in 67% of patients, 
venetoclax interruption in 29% and discontinuation of ventoclax because of 
adverse events was 20%. While the exact causes for this were not reported, given 
the known major dose limiting toxicity of venEtoclax are cytopenias it’s likely that 
this was the cause in the vast majority of patients. Therefore, a non-cytotoxic 
approach with the addition of venetoclax would be of great interest in this 
population. 
1.3.5        AML with MDS Related Changes (AML-MRC):
AML-MRC is a distinct biologic subtype of AML that represents approximately 
1/3 of the cases and is associated with e inferior outcomes compared to non-MRC 
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AML. Typically, patients with AML-MRC are older (median age 73) and  
experience low remission rates following intensive chemotherapy with  a median 
overall survival of  9–12 months.17 The only approved agent for this population is 
Vyxeos (CPX-351) which  is a liposomal encapsulation of cytarabine and 
daunorubicin and is only an option for fit patients who can tolerate intensive 
chemotherapy. AML/MRC patients represented a 1/3 of the VIALE-A cohort and 
was one of the few subgroups who did not demonstrate a statistically significant 
survival benefit (HR 0.73, CI 0.48–1.11). The major challenge in the use of 
standard Aza/ven in this population is prolonged cytopenias requiring dose 
reductions and prolonged dose delays so a continuous noncytotoxic approach is a 
rationale approach for patients who cannot tolerate vyxeos. 
1.4
Background and rationale of correlative studies
1.4.1
DNMT1 expression
The intended molecular target of decitabine therapy is the key epigenetic regulator 
DNMT1. In order to deplete DNMT1, decitabine, a pro-drug, is processed via 
pyrimidine metabolism into a nucleotide Aza-dCTP that incorporates into the newly 
synthesized DNA strand during cellular S-phase. Natural deoxycytidine (dCTP) 
directly competes with Aza-dCTP for incorporation into DNA, and accordingly, a 
major mechanism by which malignant cells evade DNMT1-depletion by decitabine 
is by upregulating de novo pyrimidine synthesis that synthesizes dCTP from 
glutamine and aspartate building blocks. We hypothesize that a single dose of 
venetoclax once a week prior to subcutaneous decitabine the next day counters this 
mechanism of resistance by temporarily inhibiting de novo pyrimidine synthesis, 
that requires intact mitochondrial membrane potential. Thus, the key correlative 
study in this study is measurement of DNMT1 levels in the bone marrow. By 
confirming the ability of to maintain DNMT1 depletion in a clinical setting, this 
study aims to be foundational in future studies by demonstrating appropriate testing 
intervals for biological correlates. Moreover, monitoring the DNMT1 repletion over 
time along with at the time of progression or relapse will indicate mechanisms of 
resistance to this therapeutic strategy.  In other words, whether relapse was 
specifically associated with a failure to maintain DNMT1 depletion or another 
mechanism.  DNMT1 protein levels will be measured in bone marrow biopsy 
specimens using immunohistochemistry (IHC), complemented by flow cytometry 
analysis of peripheral blood white cells that are in G1. The correlatives will be done 
at the Cleveland clinic laboratory of Dr Yogen Saunthararajah.
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1.4
Rationale for cohort expansion (ammendment):
In aa retrospective cohort of patients treated at Montefiore-Einstein with this 
regimen of weekly low dose decitabine/venetoclax (LDDec/VEN) 
wecompared the experience with the  low dose regimen to a cohort of 
contemporaneous patients treated with standard dosing HMA/VEN per the 
VIALE-A trial ( Levitz et al CCR in press) .  The ORR for frontline AML and 
MDS patients for LDDec/VEN was 88% and 64% respectively, similar to the 
standard dosing regimen. Importantly, we showed that the LDDec/VEN 
cohort had a much longer time on therapy when compared to patients who 
received standard VIALE-A dosing  (175 vs 78 days; p= 0.014) and a 
numerical trend toward a higher rate of transfusion independence (53% vs 
26%), although this did not reach statistical significance (p=0.33). A 
preliminary analysis of the data from the initial 17 evaluable patients enrolled 
in this protocol (patients who completed 12 week of induction), 
demonstrated that only one patient had a dose interruption during induction 
(one dose held) and no patients required dose reductions. The majority of 
these patients had AML (n=11) with an ORR of 64% (7/11)and 6/7 responses 
are ongoing.  Given the early  high  tolerability  of the low dose regiment 
(primary endpoint) and encouraging activity (secondary endpoint), 
combined with our reported in retrospective data referenced above, adding 
additional patients in selected subsets of patients will allow further 
confirmation of the safety and tolerability of this novel low dose metronomic 
regimen as well as to to generate preliminary efficacy data (secondary 
endpoints) to guide sample size estimates for further clinical development 
Data from these additional patients will  also help in defining the safety and 
efficacy profile of this regimen to allow for rationale design of future 
combination trials using the low dose metronomic HMA/VEN  backbone with 
additional agentsto achieve further progress in clinical outcomes for patients 
with MDS and AML.  
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2.0 
OBJECTIVES
2.1
Primary Objective 
1. Percentage of MDS and AML participants who are able to continue on 
treatment without dose interruptions or delays, defined as delaying or 
interrupting treatment due to toxicity or intolerability for more than two 
weeks
2.2
Secondary Objective(s)
1. Percentage of MDS participants with complete remission (CR) and complete 
remission with incomplete marrow recovery (CRi) 
2. Percentage of AML participants with complete remission (CR) and complete 
remission with incomplete marrow recovery (CRi) 
3.
This will be calculated based on current International Working Group (IWG) 
criteria. CR is defined as absolute neutrophil count > 1000/ microliter 
(mcL), platelets > 100k/mcL, red cell transfusion independence, and bone 
marrow with < 5% blasts. CRi is defined as bone marrow with less than 5% 
blasts, and absolute neutrophils of <= 10000/mcL or platelets <= 100k/mcL
4. Event-free survival (EFS) 
EFS will be defined as the number of days from randomization to the date 
of progressive disease, relapse from CR or CRi, treatment failure or death 
from any cause.
5. Complete remission or complete remission with partial hematologic 
recovery rate (CR+CRh) 
A response of CRh is defined as Bone marrow with <5% blasts, peripheral 
blood neutrophil count >0.5*10^3/mcL and peripheral blood platelet count 
>0.5*10^5/mcL.
6. Post baseline transfusion independence rate 
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Transfusion Independence is defined as a period of 56 days with no 
transfusion between first dose of study drug and the last dose of study 
drug + 30 days. The rate of conversion for red blood cells (RBC) and 
platelets is defined as percentage of participants being post-baseline 
transfusion independent from baseline transfusion dependence.
7. Rate of Hospitalization
Defined as hospitalization for complication related to myeloid malignancy or 
treatment. Initial admission for diagnosis or initiation of therapy will not be 
considered an event. 
8. Infection rate requiring hospitalization
Defined as being hospitalized due to an infection or sepsis.
3.0
STUDY DESIGN
This will be a single arm, open label pilot study of weekly dosing of subcutaneous 
decitabine and venetoclax 
Patients will be treated for a minimum of 12 weeks in the absence of clear 
evidence of progressive disease.  Patients who have any response will be permitted 
to continue treatment until relapse or progression of disease.  Primary endpoint will 
be the percentage of patients who will require dose interruptions due to cytopenias. 
Secondary endpoints will include assessment of response rates, transfusion 
dependence, rate of infections and hospitalizations. 
Exploratory endpoints will include assessment of the ability of weekly low doses 
of Dec and Ven to cause DNMT1 depletion on bone marrow samples. 
3.1
Number of Subjects
 In the initial safety and tolerability phase of the study, 33 patients will be enrolled 
on this study, accounting for need for replacement subjects to evaluate endpoints. 
In the second expansion phase of the study up to    85  patients (including patients 
from the 1st stage),  will be enrolled to obtain additional safety, tolerability and 
preliminary efficacy of the low dose regimen in selected subsets of patients with 
myeloid malignancies. 
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3.2
Replacement of Subjects 
As the treatment with HMAs requires extended drug exposure for efficacy, patients 
who do not complete 12 weeks of therapy for reasons other than disease 
progression and who do not complete therapy due to toxicity will be replaced.  Any 
patient who starts therapy will be evaluable for safety.
3.3 
Expected Duration of Treatment and Subject Participation
In the absence of overt disease progression or dose limiting toxicity, patients would 
be anticipated to remain on treatment for at least 12 weeks.  After 12 weeks, 
patient may continue therapy if felt to be experiencing clinical benefit.
4.0
PATIENT SELECTION
Each of the criteria in the sections that follow must be met for a subject to be 
considered eligible for this study. 
Subject’s Name _____________________________________________________________
Medical Record # ___________________________________________________________
Research Nurse / Study Coordinator Signature: 
_________________________________________________
Date __________
Treating Physician [Print] ____________________________________________________
Treating Physician Signature: _________________________________________________
Date __________
4.1
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for 
enrollment: 
1. 
Patient must have a diagnosis of MDS, AML, CMML or MDS/MPN with a 
histopathologic diagnosis confirmed by hematopathology review 
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AND
2.  
Indication for therapy with potential sensitivity to HMA therapy, defined as 
prior published evidence of response to HMA. 
AND
3. 
Patients must be 18 years of age or older
AND
4. 
Patients must have an ECOG performance status of ≤ 3
AND
5.
Patients must have adequate end organ function defined as.  
•
AST and ALT < 4× the upper limit of normal (ULN)
•
Bilirubin ≤ 2× the ULN.  If elevated bilirubin is due to impaired 
conjugation (e.g Gilbert’s disease or concomitant medication) or 
disease related hemolysis, then direct bilirubin ≤ 1.5× the ULN.
•
As decitabine and venetoclax have little renal metabolism, and have 
proven safety even in dialysis patients, renal function with a 
creatinine clearance ≥30 mL/min or on dialysis is allowed.18 
AND
6. 
Subjects must have the ability to understand and the willingness to sign a 
written informed consent document and complete study related procedures.
4.2
Exclusion Criteria
1. APL
2. Core binding factor AML who are candidates for intensive chemotherapy 
3. Prior Treatment with azacitidine, decitabine or venetoclax 
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4. No other disease directed therapy, save for hydroxyurea, cytarabine, 
Cladribine, Gemtuzumab ozogamicin including experimental or 
investigational drug therapy for 14 days prior to study entry.
5. Currently pregnant or breast-feeding.  Females of child bearing (FOCBP) 
potential must have negative serum pregnancy test within 72 hours from 
treatment start.  (NOTE: FOCBP is any biologic female, regardless of 
sexual or gender orientation, having undergone tubal ligation, or remaining 
celibate by choice, who has not undergone a documented hysterectomy or 
bilateral oophorectomy or has had a menses any time in the preceding 12 
months (therefore not naturally post-menopausal for > 12 months)
6. Uncontrolled intercurrent illness that could limit life expectancy or ability 
to complete study correlates.  This includes, but is not limited to: 
a. Ongoing or active infection.  As patients with myeloid malignancies 
are prone to infections, if patients are actively being treated with 
appropriate antibiotics or antifungal therapy with clinical evidence 
of infection control, then they will be considered eligible for study.
b. Uncontrolled concurrent malignancy
c. Congestive heart failure of NYHA class III/IV.  Patients with 
compensated heart failure are permitted.  
d. Unstable angina pectoris
e. New or unstable cardiac arrhythmia.  Stable or controlled 
arrhythmias are permitted
f. Decompensated liver cirrhosis (Child-Pugh score ≥12 or a MELD 
score ≥21
g. Psychiatric illness/social situations that would limit compliance 
with study requirements. 
h. Any other prior or ongoing condition, in the opinion of the 
investigator, that could adversely affect the safety of the patient or 
impair the assessment of study results. 
7. WOCBP and males that are unwilling to agree to use dual contraceptive 
measures (i.e., hormonal or barrier method of birth control; abstinence, 
condom) prior to study entry and for the duration of study participation. 
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Should a female subject become pregnant or suspect she is pregnant while 
participating in this study, she should inform the treating physician 
immediately 
8. Sexually active male who is unwilling to use a condom when engaging in 
any sexual contact with a female with child-bearing potential, beginning at 
the screening visit and continuing until 4 weeks after taking the last dose 
of Decitabine/venetoclax.
9. Patients with uncontrolled active HIV infection, as this will further 
increase the risk for opportunistic infections.  However, patients with HIV 
with undetectable viral load by PCR, without opportunistic infection, and 
on a stable regimen of antiretroviral therapy would be eligible.
10.Known allergy or hypersensitivity to any component of decitabine or 
venetoclax formulations
4.3
Inclusion of Women and Minorities 
Men, women and members of all races and ethnic groups are eligible.
5.0
REGISTRATION
Subjects will be recruited at Montefiore/Einstein Cancer Center, University of 
California Davis,  and White Plains Hospital Center for Cancer Care.  All subjects 
who have been consented are to be registered in REDCap. Database. For those 
subjects who are consented, but not enrolled, the reason for exclusion must be 
recorded.
All subjects will be registered through Montefiore/Einstein Cancer Center and will 
be provided a study number by contacting the study coordinator listed on the cover 
page. 
6.0
TREATMENT PLAN
6.1
Treatment Regimen Overview
Administration: Decitabine is reconstituted with 5 ml sterile water to facilitate 
subcutaneous administration. Decitaboine is given by subcutaneous injection. 
Venetoclax is taken as a tablet prepared by patients pharmacy.  
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Venetoclax is given at a dose of 400 mg po once per week concurrently with the 
Decitabine dose (+/- 1 day allowed ). 
All treatment regimens may be continued indefinitely.
Concomitant Treatment: Hydroxyurea is permitted to control leukocytosis and 
thrombocytosis. In patients with aggressive high bulk disease as determined by the 
investigator and PI, may receive debulking chemotherapy with either Gemtuzumab 
ozogamicin, Cladrabine or Cytarabine prior to starting decitabine/venetoclax. Also 
patients who have mutations in either  FLT3 (ITD or TKD), JAK2, IDH1 or IDH2  
mutation may receive concomitant inhibitors (as outlined in the table below) at any 
point during the protocol as determined by the PI.  Other than HU and above 
mentioned drugs, no other concomitant disease modifying therapy is permitted.  No 
additional investigational study is permitted and concurrent participation in other 
interventional trials are not permitted.  Participation in registry or non-interventional 
studies is permitted.
Mutation
Medication
FLT3 ITD
Midostaurin
Gilteritinib
Quizartinib
FLT3 TKD
Midostaurin
Gilteritinib
IDH1
Ivosidenib
Olutasidenib
IDH2
Enasidenib
JAK2
Jakafi
Induction phase: The initial 12 weeks of therapy is considered an induction phase 
during which dose modifications or holds are discouraged except for severe toxicity 
severe, non-hematologic adverse events, as per figure study schema.  However, if 
myelosuppression from medications are suspect, treatment holds and dose 
modifications may be considered in consultation with the study chairs.  Desired 
treatment holds or dose modifications should be reviewed as soon as possible with 
the study chairs to determine whether dose hold/modification is acceptable. The 
purpose of the induction phase is to produce relatively rapid reduction of tumor 
burden to a level that will permit recovery by more functional hematopoiesis that 
can relieve cytopenias.  
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Long Term Treatment phase: After a 12 week induction phase, persistent 
treatment without holds could result in severe, treatment related cytopenias.  
Conceptually, targeted DNMT1 depletion may result in differentiation that could 
result in hematologic improvement with evidence of persistent marrow disease.  Full 
response to therapy may not occur within 12 weeks as sometimes six months or 
longer is required for maximal response to HMAs.  Thus, the goal should be to 
maintain dose while ensuring optimal hematologic improvement from therapy.  
6.1.1
Decitabine dosing and schedule 
Decitabine is given at  a dose of 0.1–0.2 mg/kg/day on days 1, 8, 15, 28 (+/- 3 days).. 
All patients will receive at least one dose Decitabine every week. If decided by 
treating physician that the patient needs a more rapid debulking of high 
disease burden, a second dose can be added. If Decitabine is given twice 
a week, should preferably be given on two consecutive days.  
6.1.2
Venetoclax dosing and schedule 
Venetoclax is dosed at 400 mg by mouth one day a week concurrently with the first 
decitabine dose (+/- 1 day allowed ).. If patients are taking another CYP3A4 inhibitor 
dose adjustments should be made as recommended by pharmacist for a goal dose of 
venetoclax of 400 mg.
If patient receives two days of decitabine a week, they still only take venetoclax on 
the day ofthe first dose of decitabine (+/- 1 day allowed ). 
6.1.3
Treatment phase
Each treatment cycle is 28 days. Treatment is given weekly and continued without 
any interruptions 
6.1.4
Dose adjustments for hematologic toxicity
The starting dose of decitabine being administered (0.2 mg/kg) and the dose of 
venetoclax of 400 mg  have been identified by previous pharmacokinetic, 
pharmacodynamic and clinical studies (administering the drugs singly) as the 
minimal biologically active doses needed to produce the intended therapeutic 
molecular pharmacodynamic effect. Based on our experience using this regimen, 
an anticipated side-effect is neutropenia. However, neutropenia is frequently 
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caused by the myeloid malignancy being treated. Since doses are already minimal 
biologically active doses, it is important not to prematurely dose-reduce if 
neutropenia is from disease and not from therapy: 
•
To avoid premature dose reduction from already minimal 
biologically active doses, this protocol incorporates an Induction 
Phase (week 1-12) during which doses should not be held except for 
clinically exigent circumstances. After the induction phase, the 
treating clinical team will need to exercise judgement to distinguish 
between Grade 4 neutropenia (ANC < 0.5 x109/L) caused by disease 
vs treatment, aided if necessary with repeat bone marrow aspirate 
and biopsy. 
•
If Grade 4 neutropenia is judged to be from treatment, the first step 
is to hold treatment until recovery of the ANC to > 0.5 x109/L. If 
neutropenia recurs, then the next step is to decrease decitabine doses 
by 25% (0.15 mg/kg). 
•
If neutropenia recurs even on the reduced dose of decitabine, then 
decrease dose of decitabine by another 25% (0.1 mg/kg). If 
neutropenia persists even at this dose and is felt to be from treatment 
and not from disease, treatment should be held until recovery of the 
ANC to > 0.5 x109/L. Only continue therapy if it is considered to be 
in the best interests of the patient. Its at discretion of the treating 
physician  based on clinical benefit to the patient, as to when  to go 
back to the full dose of Decitabine or keep at reduced dose.  
•
To reduce risks from baseline neutropenia caused by the disease, 
that may deter or hinder administration of potentially beneficial 
therapy, this protocol permits concurrent administration of G-CSF 
(filgrastim or biosimilar ~5 µg/kg) if thought to be safe by the 
treating physician 
•
Venetoclax can also cause cytopenias but less so with once weekly 
dosing. If cytopenias are thought to be due to venetoclax, can first 
decrease dose by 50% (200 mg daily) and if cytopenias persist and 
is thought to be due to venetoclax,  hold venetoclax and continue 
decitabine single agent. Can restart venetoclax based on the clinical 
judgment of the treating physician 
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6.1.5
Adjustments for non-hematologic toxicity ≥ Grade 3
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Low doses of decitabine and weekly venetoclax  have low risk of renal toxicity, and 
are not felt to be renally toxic.  There is concern that decitabine has hepatotoxicity 
at standard dosing, but risk should be nominal in the setting of very low doses.  In 
general, workup for alternative causes for non-hematologic toxicity should be 
strongly considered, and decitabine and venetoclax is only dose reduced in the 
absence of alternative explanation.  However, doses should be reduced for toxicity 
considered at least possibly related to decitabine and venetoclax.  This includes 
laboratory abnormalities.    
Infections in patients with myeloid malignancies are common and should be treated 
accordingly.  Infections do not require dose adjustments unless there is clear 
evidence of relation to decitabine or venetoclax toxicity leading to the associated 
infection.  In other words, most infections should not warrant dose modification.  
Table 1: Adjustments for non-hematologic toxicity
Serum 
creatinine 
(Renal Toxicity)
If 
pretreatment 
creatinine is < 0.5, and 
increased in creatinine 
to ≥ 1.5  
If 
pre-treatment 
creatinine 
0.6-0.8 
mg/dL, an increase to 
≥1.7 mg/dL
For 
pretreatment 
creatinine of 0.9 to 3.0, 
and 
a 
doubling 
of 
creatinine, or > 5.0.
If no alternative cause 
identified and toxicity 
felt at least possibly 
related, hold decitabine 
and venetoclax until 
recovered 
below 
threshold and restarted 
with 
a 
25% 
dose 
reduction. Can go back 
to full dose when felt 
safe to do so by treating 
physician. 
 
If toxicity recurs after 
dose reduction without 
an identifiable alternate 
cause and is thought to 
be related to decitabine 
or venetoclax, patient 
should 
be 
removed 
from protocol
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Hepatotoxicity
AST or ALT ≥ 3× ULN
OR
Direct 
Bilirubin 
2× 
ULN
If no alternative cause 
and toxicity felt at least 
possibly 
related 
to 
study drug: 
Hold until recovery to 
below threshold and 
restart decitabine and 
venetoclax with 25% 
dose reduction. Can go 
back to full dose when 
felt safe to do so by 
treating physician.
If toxicity recurs after 
dose reduction without 
an identifiable alternate 
cause and felt to be 
related to Decitabine or 
Venetoclax, 
patient 
should 
be 
removed 
from protocol
Any other grade 3 and 4 
adverse events at least 
possibly 
related 
to 
decitabine/venetoclax 
(No adjustments for 
alopecia) 
If no alternative cause 
suspected or identified : 
Hold until recovery to 
grade 1 and restart at 
25% dose reduction
If toxicity recurs after 
dose 
reduction 
and 
thought to be related to 
Decitabine 
or 
Venetoclax, 
patient 
should 
be 
removed 
from protocol
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6.1.5.1 
Identification of differentiation syndrome
The differentiation syndrome is a potentially fatal complication observed in the 
treatment of acute promyelocytic leukemia with tretinoin, but has also been 
reported in therapies with epigenetic effects, such as IDH inhibitors.19,20  Although 
rare, there are case reports of differentiation syndrome in patients with HMA 
therapy.21  In general, differentiation syndrome has not been described in other low 
dose HMA studies, and is not an anticipated adverse event.  However, with the 
proposed treatment schedule of decitabine/ven  is effective in promoting 
differentiation of myeloblasts and cytokine release occurs from these cells, this is a 
potential complication that requires awareness by treating physicians.
The differentiation syndrome is characterized by fever, dyspnea, possible 
hypoxemia and respiratory distress with pulmonary infiltrates, peripheral edema, 
hypotension and renal and hepatic insufficiency.  If differentiation syndrome is 
suspected, treatment with corticosteroids should be started promptly. The 
corticosteroid of choice is Dexamethasone 10mg IV twice daily, which should be 
continued until resolution of symptoms, signs and laboratory abnormalities related 
to differentiation syndrome.  Hydroxyurea would be permitted in this setting to 
control leukocytosis.
Decitabine/venetoclax may be continued unless it is a severe case of differentiation 
syndrome as determined by the treating physician or if there is no improvement 
after treatment with corticosteroids. If discontinued, decitabine/ven may be 
resumed without dose adjustment after resolution of differentiation syndrome.  
6.2
General Concomitant Medications and Supportive Care Guidelines
Antimicrobial prophylaxis: 
Patients with hematologic illnesses should be offered antimicrobial prophylaxis 
(antiviral, antifungal, antibacterial) per institutional standards. 
Supportive care: 
G-CSF can may be considered for any patient with < 5% bone marrow blasts who 
has a baseline ANC < 1.5 x 109/L during the induction phase, but should be held if 
the most recent ANC is ≥ 1.5 x 109/L.  During the long-term treatment phase, G-
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CSF could be administered for neutropenia (ANC < 1 x 109/L), not  felt to be due 
to active disease. 
Concomitant erythropoietin analogues are permitted at physician discretion for 
transfusion dependent patients with EPO level < 500.  
Patients with advanced myeloid malignancies often require frequent clinical visits 
and CBC evaluation for supportive transfusions.  Patients should be monitored as 
per local standards and treating physicians’ standard practice.  A weekly CBC at 
minimum during the induction phase of treatment is suggested.
No antiemetic therapy is required per protocol, but any is permitted at treating 
physician’s discretion.
At higher doses, decitabine is known to cause gastrointestinal toxicity, including 
constipation.  Though not anticipated at provided doses, patients should be 
monitored and treated as indicated for gastrointestinal toxicity.  
The need for central venous access can be determined on a case by case basis, per 
physician discretion, as central lines carry both benefits and risks to patients.  
However, decitabine should be given subcutaneously in this setting.
6.3
Criteria for Removal from Study
In the absence of treatment delays due to adverse events, treatment may continue as 
long as patient is receiving benefit from treatment (see section 6.4), or in the event 
of the following:
•
Disease progression unresponsive to dose adjustment, or 
progression at maximum dose level
•
Intercurrent illness that prevents further administration of 
treatment,
•
The investigator considers it, for safety reasons, to be in 
the best interest of the subject. 
•
Any toxicity or adverse event that leads to delay in drug 
administration of greater than 6 weeks
•
Subject decision to withdraw from treatment or from the 
study 
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o In accordance with the Declaration of Helsinki and 
the guidelines of the country of the participating  
Clinical Study Center, each subject is free to 
withdraw from the study at any time.  An 
investigator also has the right to withdraw a subject 
from the study in the event of the patient suffering 
an intercurrent illness, adverse events, or other 
reasons concerning the health or well-being of the 
patient, or in the case of lack of cooperation by the 
patient. All serious adverse reactions need to be 
followed until resolution and information returned 
to study coordinators.
o Should a subject decide to withdraw after 
administration of study drug, or should the 
investigator decide to withdraw the subject, all 
efforts should be made to complete and report the 
observations up to the time of withdrawal as 
thoroughly as possible. A final evaluation, the 
reason for, and the date of withdrawal must be 
recorded on the CRF. The last visit for each subject 
will be defined as a study discontinuation/ end-of-
study visit, which will occur 30 (±7 days) days after 
time of study drug withdrawal. 
o Subjects with clinically significant abnormal 
laboratory values as determined by the investigator 
or who have ongoing clinically significant treatment 
related adverse events during their last scheduled 
clinical evaluation will be monitored and treated 
until resolution or stabilization is achieved; or, in 
the event that the subject’s condition is not likely to 
improve because of disease progression, until the 
cause of the abnormal test result or adverse event 
can be determined.
•
Pregnancy during the course of the study for a child-
bearing participant
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•
Death

Study chair reserves the right to temporarily suspend or prematurely 
discontinue this study.  The date and reason for discontinuation must be 
documented. Every effort should be made to complete the appropriate 
assessments. 
6.4
Duration of Follow Up
The evaluation of the primary and secondary endpoints of ORR, CIR, and DOR are 
continuous. If in the judgement of patients and the treating clinical team, patients are 
benefiting from this therapy, the therapy will be continued even after measurement 
of the primary end-point at week 12 but monitoring will continue every 4 weeks or 
more often if clinically indicated. Patients will be considered off-protocol 
monitoring if they develop relapsed or progressive disease. 
 
6.5
Early Stopping Rule for Excessive Toxicity 
Bayesian toxicity monitoring (https://trialdesign.org/one-page-shell.html#BTOX) 
will be used to terminate early for excessive toxicity. The maximum allowable 
probability of Grade ≥ 3 non-hematologic, non-infectious toxicity  related to 
treatment during the induction phase (weeks 1-12) attributed to study treatment,  is 
assumed to be 20% and prior distribution (1,1), then early stopping   will occur if 
the posterior probability that the Grade ≥ 3 non-hematologic toxicity rate exceeds 
this maximum allowable rate is 80% or greater.  The minimum number of patients 
before stopping 3, cohort size 3, then the study will be stopped early for example, 
if 2 out of 3,  4 out 9, 7 out of 18, and 12 out of 33 experience SAEs. 
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7.0
ADVERSE EVENTS AND POTENTIAL RISKS 
7.1              Agent Adverse Events
The most commonly occurring adverse reactions for Decitabine and venetoclax 
are:

Nausea

Reduced red blood count (anemia)

Low blood platelets count (thrombocytopenia)

Vomiting

Raised body temperature; fever

Reduced white blood cell count (leukopenia)

Diarrhea

Weakness

Reddening of the skin at Injection site (erythema)

Constipation

Abnormally low count of white blood cells (neutropenia)

Discoloration of the skin resulting from bleeding underneath 
(ecchymosis)

Round spots that appear on the skin as a result of bleeding (petechia)

Low potassium level (hypokalemia)

Shivering as a result of a high fever (rigors)
Leukopenia is a major toxicity of decitabine and nausea, or vomiting were 
common non-hematologic toxicities. The main side-effect was an increase in the 
platelet count (as opposed to the usual side-effect of thrombocytopenia seen with 
cytotoxic treatments) consistent with a non-cytotoxic mechanism of action. 
Cytotoxicity/DNA damage assays based on bone marrow morphological 
examination, bone marrow DNA content analysis, VDJ recombination assay, 
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erythrocyte micronucleus assay and gamma-H2AX assay were also negative. 
These assays did not reveal evidence of DNA damage or cytotoxicity. The increase 
in the platelet count was not associated with any clinical adverse events, and 
specifically, without evidence by correlative studies for an increase in thrombotic 
tendency. 
7.2
Definitions 
7.2.1
Adverse Event  
An adverse event (AE) is any unfavorable or unintended event, physical or 
psychological, associated with a research study, which causes harm or injury to a 
research participant as a result of the participant’s involvement in a research study. 
The event can include clinically significant abnormal laboratory findings, 
symptoms, or disease associated with the research study. The event does not 
necessarily have to have a causal relationship with the research, any risk associated 
with the research, the research intervention, or the research assessments. 
Adverse events may be the result of the interventions and interactions used in the 
research; the collection of identifiable private information in the research; an 
underlying disease, disorder, or condition of the subject; and/or other circumstances 
unrelated to the research or any underlying disease, disorder, or condition of the 
subject
7.2.2
Serious Adverse Events 
A serious adverse event (SAE) is any adverse experience occurring at any dose that 
results in any of the following outcomes: 

Results in death. 

Is a life-threatening adverse experience.  The term life-threatening in the 
definition of serious refers to an adverse event in which the subject was at risk 
of death at the time of the event.  It does not refer to an adverse event which 
hypothetically might have caused death if it were more severe. 

Requires 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization.  Any adverse event leading to hospitalization or prolongation 
of hospitalization will be considered as Serious, UNLESS at least one of the 
following expectations is met:
o The admission results in a hospital stay of less than 24 hours OR
o The admission is pre-planned (e.g., elective or scheduled surgery 
arranged prior to the start of the study) OR
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care.
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However it should be noted that invasive treatment during any hospitalization may 
fulfill the criteria of “medically important” and as such may be reportable as a 
serious adverse event dependent on clinical judgment.  In addition, where local 
regulatory authorities specifically require a more stringent definition, the local 
regulation takes precedent. 

Results in persistent or significant disability/incapacity.  The definition of 
disability is a substantial disruption of a person’s ability to conduct normal 
life’s functions.

Is a congenital anomaly/birth defect. 

Is an important medical event.  Important medical events that may not result 
death, be life-threatening, or require hospitalization may be considered a 
serious adverse experience when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples 
of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood disease or disorders, or 
convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse. The development of a new cancer is always 
considered an important medical event.
Moreover, grade 3 and 4 hematologic laboratory investigations are common in 
myeloid malignancies and will not be considered SAEs regardless of clinical 
significance.  Grade 3 and 4 laboratory investigations not felt clinically significant 
by the treating physician will not be considered SAEs.  
Patients with hematologic malignancies are known to have high rates of neutropenic 
fever, admission for the administration of IV antibiotics for uncomplicated 
neutropenic fever will not be considered a Serious Adverse Event, but will be 
tabulated as grade 3 or grade 4 toxicity as appropriate.  
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7.2.3
Adverse Event Evaluation 
The investigator or designee is responsible for ensuring that all adverse events (both 
serious and non-serious) observed by the clinical team or reported by the 
subject which occur after the subject has signed the informed consent are 
fully recorded in the subject’s medical records. Source documentation 
must be available to support all adverse events.  
Any grade laboratory investigation abnormality considered clinically significant 
should be reported as an adverse event, with exceptions as noted above.
The investigator or sub-investigator (treating physician if applicable) will provide 
the following for all adverse events (both serious and non-serious):

Event term (as per CTCAE)

Description of the event

Date of onset and resolution

Expectedness of the toxicity

Grade of toxicity 

Attribution of relatedness to the investigational agent - (this must be 
assigned by an investigator, sub-investigator, or treating physician)

Action taken as a result of the event, including but not limited to; no changes, 
dose interrupted, reduced, discontinued, etc. or action taken with regard to the 
event, i.e. no action, received concomitant medication or other intervention, 
etc.

Outcome of event
Descriptions and grading scales found in the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting. 
An expected adverse event is an event previously known or anticipated to result 
from participation in the research study or any underlying disease, 
disorder, or condition of the subject. The event is usually listed in the 
package insert for Decitabine or venetoclax, consent form or research 
protocol. 
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An unexpected adverse event is an adverse event not previously known or 
anticipated to result from the research study or any underlying disease, 
disorder, or condition of the subject. 
Attribution is the relationship between an adverse event or serious adverse event 
and the study drug.  Attribution will be assigned as follows:

Definite – The AE is clearly related to Decitabine/venetoclax.

Probable – The AE is likely related to Decitabine/venetoclax.

Possible – The AE may be related to Decitabine/venetoclax.

Unlikely – The AE is doubtfully related to Decitabine/venetoclax.

Unrelated – The AE is clearly NOT related to Decitabine/venetoclax.
Protocol must specify if attribution is required for individual components of the 
treatment regimen or the treatment regimen as a whole.
7.3
SAE Report Form
SAEs will be recorded in Velos and reported to the DSMC. If needed, the SAE will 
also be reported to Einstein IRB 
7.4
Reporting Procedures for Serious Adverse Events
For the purposes of safety reporting, all adverse events will be reported that occur 
on or after day 1 of cycle 1 through 30 days after the final dose of study drug. 
Adverse events, both serious and non-serious, and deaths that occur during this 
period will be recorded in the source documents. All SAEs should be monitored until 
they are resolved or are clearly determined to be due to a subject’s stable or chronic 
condition or intercurrent illness(es). Related AEs will be followed until resolution to 
baseline or grade 1 or stabilization. 
7.4.1
SAE Reporting Requirements
•
Participating investigators (all sites) must report all serious 
adverse events to the Principal Investigator within 24 hours of 
discovery or notification of the event. The participating investigator 
must also provide follow-up information on the SAE until final 
resolution. 
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o Mendel Goldfinger, MD, E-mail: mgoldfin@montefiore.org, 
718-920-4826 
The Principal Investigator will review the SAE and report the event to 
the DSMC and IRB as applicable.
It is the Principal Investigator’s responsibility to ensure that ALL 
serious adverse events that occur on the study (e.g. ALL SAEs that 
occur at each enrolling institution) are reported to all participating 
sites.
Institutional Review Board Reporting Requirements:
•
Principal investigator will report adverse events to the IRB 
according to the Einstein IRB’s policies and procedures in reporting 
adverse events. 
7.5
SAEs and REDcap

All SAEs will be entered into the REDcap database.  

A copy of the SAE form(s) submitted to the investigator is also uploaded into 
the REDcap database.
7.6
Data Safety and Toxicity Committee
It is the responsibility of the PI to ensure that all SAEs occurring on this trial are 
reported to the Einsteins Cancer Center’s Data and Safety Toxicity Committee. 
This submission is simultaneous with their submission to other regulatory bodies. 
The principal investigator is responsible for submitting an annual report to the 
DSTC as per CCCC Data and Safety Monitoring Plan.

7.7
Data and Safety Monitoring Plan (DSMP)
This protocol will adhere to the policies of the Montefiore/Einstein Cancer Center 
Data and Safety Monitoring Plan in accordance with NCI guidelines. The principal 
investigator will review with his co-investigators the data relevant to the safety 
run-in phase, stopping rules (see sections 6.5 and 6.6) and also for an interim 
analysis. As outlined in sections 6.5 and 6.6, if  3 or more of the first 6 patients 
develop Grade 3 or 4 non-hematologic, non-infectious toxicity possibly, probably 
or definitively related to decitabine or venetoclax , during the induction phase 
(weeks 1-8) of therapy, then the study will be permanently stopped. During the 
course of the clinical trial, an interim analysis will be done to monitor the safety 
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following the accrual of every 3 patients after run-in of 6 patients.  The stopping 
criteria are described for the incidence of Grade 3 or 4 non-hematologic, non-
infectious toxicity (SAE).Using Bayesian toxicity monitoring with maximum 
probability of Grade ≥ 3 non-hematologic toxicity of 0.2, prior distribution (1,1), 
maximum patients 33, minimum number of patients before stopping 3, cohort size 
3, and posterior probability 0.8, we will pause the study for review if 2 out of 3,  4 
out 9, 7 out of 18, and 12 out of 33 experience SAEs.
8.0
PHARMACEUTICAL INFORMATION 
8.1 Investigational Agents
8.1.1 
Name of Agent: Decitabine
Product description: 
Decitabine is manufactured for Otsuka pharmaceuticals and is commercially 
available.  It is supplied as a sterile, lyophilized white to almost white powder, in a 
single-dose vial, packaged in cartons of 1 vial. Each vial contains 50 mg of 
decitabine.
Solution preparation: 
For Administration Within 15 Minutes of Preparation: If Decitabine is intended to 
be administered within 15 minutes from the time of preparation, dilute the 
reconstituted solution with room temperature (20˚C - 25˚C) 0.9% Sodium Chloride 
Injection or 5% Dextrose Injection to a volume of 5mL.
For Delayed Administration:  If Decitabine is intended to be administered after 15 
minutes of preparation, dilute the reconstituted solution with 5mL of cold (2˚C - 
8˚C) 0.9% Sodium Chloride Injection or 5% Dextrose Injection. Store at 2˚C - 8˚C 
for up to 4 hours. Diluted stored solution must be used within 4 hours from the 
time of preparation. Use the diluted, refrigerated solution within 4 hours from the 
time of preparation or discard. Parenteral drug products should be inspected 
visually for particulate matter and discoloration prior to administration, whenever 
solution and container permit. Do not use if there is evidence of particulate matter 
or discoloration.
Storage requirements: 
Store vials at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
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Route of administration: 
To provide a homogeneous suspension, the contents of the syringe must be re-
suspended by inverting the syringe 2–3 times and vigorously rolling the syringe 
between the palms for 30 seconds immediately prior to administration. 
Decitabine is administered subcutaneously. Doses greater than 5 mL should be 
divided equally into 2 syringes and injected into 2 separate sites. Rotate sites for 
each injection (thigh, abdomen, or upper arm). New injections should be given at 
least 1 inch from an old site and never into areas where the site is tender, bruised, 
red, or hard
Drug Procurement: 
Decitabine must be obtained from commercial sources.  Cost of this agent will be 
subject’s responsibility 
8.2.1 Name of Agent: Venetoclax
Product description: 
Venetoclax is manufactured by AbbVie Inc.  and is commercially available.  It is 
supplied as tablets
Route of administration: 
Oral 
Drug Procurement: 
Venetoclax must be obtained from commercial sources.  Cost of this agent will be 
subject’s responsibility 
9.0
CORRELATIVE STUDIES
9.1
Methods
Immuno-detection and quantitation: As part of standard of care, all patients on this 
trial will have a bone marrow biopsy at baseline (pre-treatment), then every three 
months and as clinically indicated. For each bone marrow sample, the paraffin block 
be stored at the pathology department for testing in formalin-fixed paraffin-embed 
embedded tissue. For quantitative analysis of DNMT1, paraffin blocks from 
different time-points will be cut onto the same slide for staining. The Pathology 
department will send 4 micron section slides to the Cleveland Clinic lab of Dr. 
Yogen Sauntharajah where immunostaining will be performed on bone marrow 
biopsy slides (4μm), positive and negative controls. Nuclei positive for the targeted 
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biomarker are identified and quantified in high resolution, large field-of-view 
images per ImageIQ algorithms (Image IQ Inc., Cleveland, OH) after subtraction of 
bone from the original image. DNMT1 quantification is correlated with bone 
marrow morphology parameters and hematologic response as previously described.4 
Peripheral blood or Bone marrow aspirate collection: Peripheral blood or bone 
marrow aspirates for correlate analyses will be collected at three months intervals. 
When patients come in for routine blood draws or bone marrow aspirates done as 
part of their routine clinical care,  an extra  tubes with ~ 8 ml will be collected every 
three months. These samples will be cryopreserved for future analysis and stored at 
the Einstein lab of Dr Amit Verma. Blood or bone marrow will be collected in a one 
8mL (purple or green top) tube at pre-treatment baseline and every three months if 
patient is having blood drawn or a Bone marrow biopsy done at Montefiore cancer 
center or any other site where the protocol is open. These samples will be used for 
flow cytometry analysis of DNMT1 protein levels in non-G0 cells if needed to 
confirm results of DNMT1-protein analyses in the bone marrow biopsies: 
Cryopreserved mononuclear cells from patient blood or marrow are thawed and 
fixed using formaldehyde (1%) and methanol (90%). Fixed cells are stained for 
DNMT1 and cell surface antigens. Cell cycle analysis is performed using DAPI 
staining. The expression of DNMT1 in white blood cells in S-phase is measured as 
mean fluorescent intensity (MFI) normalized to a control as previously described.22 
Samples may also be used for preclinical research analyzing mechanisms of 
resistance to HMA and/or venetoclax treatment. 
9.2      Analytical Laboratory
Specimens will be analyzed in the labs of Dr. Yogen Sauntharajah, Dr Amit 
Vermaand Dr Marina Konopleva.  Delivery will be arranged by the primary 
investigator:
Mendel Goldfinger
Montefiore Medical Center 
111 East 210 street
Bronx, NY 10952
Telephone: 718-920-4826
E-mail: mgoldfin@montefiore.org
10.0
STUDY PARAMETERS AND CALENDAR 
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STUDY CALENDAR
Study Days:
Pre-
study/Screening1
Induction Phase, Day 
1 (+/- 4 days)
Long-term Treatment 
phase – 4-week 
treatment intervals – 
Day 1 (+/- 4 days)
End of Treatment9
REQQUIRED ASSESSMENTS
Informed consent
X
Demographics
X
Medical History
X
Height
X
Weight
X
X
X
Vitals
X
X
X
X
Physical Examination
X
X
X
Concomitant Medications
X
X
Performance status
X
X
Baseline Symptoms
X
X
SAE and > grade 2 AE Assessment
X
X
X2
X
CBC w/diff 
X
X3
X3
X
CMP
X
X4
X4
X
LDH, uric acid
X
X4
Pregnancy test10
X
DISEASE ASSESSMENT
Bone Marrow Biopsy or peripheral 
blood pathology 
X11
X5
X6
TREATMENT
Decitabine/venetoclax 7
X
X
CORRELATIVE STUDIES (Refer 
to section 9 for details)
Peripheral 
blood 
and/or 
Marrow 
Samples8 
X
X
X5
X6
1Pre-study assessments for screening should be completed within 21 days of registration.  All other assessments are ± 3 days unless otherwise noted.
Pre-study/screening starts from when patient signs the consent.  
2.May be captured continuously 
3During induction phase weeks 1-12, CBC needs to be checked a minimum of weekly.  Study only requires CBC to be collected at start of each 
treatment interval to evaluate toxicity and hematologic response in the long-term phase and beyond; however, treating physicians should assess 
CBC as clinically indicated depending on disease status and need for potential transfusion support or other supportive care, as per their judgement 
and standard clinical practice.  Any CBC results collected should be considered data for efficacy analysis.  See section 6.2.
4During induction phase weeks 1-12, CMP,  LDH, uric acid are required a minimum of every 3 weeks.  During the long-term treatment phase, 
CMP, LDH, uric acid are only required at day 1 of treatment.  Treating physicians should consider increased frequency as clinically indicated for 
supportive as per their judgement and standard clinical practice.  
5Marrow should be obtained at the end of cycle 3 and every three months for the first two years. After two years BM biopsy every six months. 
Marrow timing may be considered ± 14 days.   IHC will be completed from core biopsy samples processed in the department of pathology per 
standard of care..  Peripheral blood samples should be sent the same day as any marrow samples when able.
6If feasible but not mandated, but especially in cases where EOT is due to progressive disease.
7See Treatment Schema and section 6 for details. 
8 Correlative samples are not mandatory and are obtained when able 
9 End-of-treatment evaluations should be done when able but is not mandatory 
10 For women of childbearing age 
11 Bone marrow biopsy done before enrolling in the study done within 28-days of study therapy is acceptable.
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11.0
MEASUREMENT OF EFFECT 
Responses for CR, PR and HI will be described per IWG criteria for MDS and 
MPN23,24. For AML will use ELN response criteria. Additionally, in order to focus 
the most objective outcomes, additional MDS/MPN response criteria of spleen 
response and symptoms response will not be part of the measurement of effect of 
response, although will be collected as available for descriptive purposes.  
Table 2: Criteria for Hematologic Improvement (HI)
Hematologic Improvement (HI)
Response Criteria (Must last at least 8 weeks)
Erythroid Response (pretreatment 
< 11g/dL
Hgb increase by ≥ g/dL
Relevant reduction of units of RBC transfusions by an 
absolute number of at least 4 RBC transfusions/8 weeks 
comparted with the pretreatment transfusion number in the 
previous 8 weeks.  
Platelet response (pretreatment, < 
100 109/L)
Absolute increase of ≥ 30109/L for patients with > 
20109/L platelets
Increase from < 20109/L to > 20109/L and by at least 
100%
Neutrophil 
response 
(pretreatment < 1.0109/L)
At least 100% increase and an absolute increase > 
0.5109/L
*Pretreatment values should not be influenced by transfusion, if they are considered transfusion dependent
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Table 3: Response criteria for patients with primary diagnosis of MDS23
Category
Response Criteria (response must last at least 4 weeks) 
Complete Remission
Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines.  
(Note persistence of dysplasia)
Peripheral Blood
o
Hgb ≥ 11g/dL
o
Platelets ≥ 100109/L
o
Neutrophils ≥ 1.0109/L
o
Blasts 0%
Partial Remission
All CR criteria if abnormal before treatment except:
o
Bone marrow blasts decreased by ≥ 50% over pretreatment but 
still > 5%
o
Cellularity and morphology no relevant
Marrow CR
Bone marrow: ≤ 5% myeloblasts and decrease by ≥ 50% over 
pretreatment
Peripheral blood: if HI responses, should be noted in addition to marrow 
CR.  (for this protocol, marrow CR absent HI is NOT considered a 
response)
Stable Disease
Failure to achieve at least PR, but no evidence of progression for > 8 
weeks
Failure
Death during treatment or disease progression characterized by 
worsening of cytopenias, increase in percentage of bone marrow blasts, 
or progression to a more advanced MDS subtype than pretreatment
Relapse after CR or PR
At least one of the following:
o
Return to pretreatment bone marrow blast percentage
o
Decrement of ≥ 50% from maximum remission/response levels 
in granulocytes or platelets
o
Reduction in Hgb concentration by ≥ 1.5g/dL or transfusion 
dependence
Cytogenetic response
Complete: Disappearance of the chromosomal abnormality without 
appearance of the new ones
Partial: at least 50% reduction of the chromosomal abnormality
Disease Progression
For patients with:
o
Less than 5% blasts: ≥ 50% increase to > 5% blasts
o
5%-10% blasts: ≥ 50% increase to > 10% blasts
o
10-20% blasts: : ≥ 50% increase to > 20% blasts
Any of the following:
o
At least 50% decrement from maximum remission/response in 
granulocytes or platelets
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o
Reduction in hgb by ≥ 2g/dL
o
Transfusion dependence
In general, all reductions in to define progression counts must not be attributable to treatment.  If treatment causes transient reductions 
in counts, response should be considered durable through therapy.  Other concomitant causes such as infection or bleeding need to 
be considered to ensure there is not concomitant causes.  
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Table 4: Response Criteria for patient with a primary diagnosis of MDS/MPN24
Category
Response Criteria (response must last at least 4 weeks) 
Complete 
Remission 
(presence of all of the 
following)
Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines, 
and return to normal cellularity  
Osteomyelofibrosis absent or equal to “mild reticulin fibrosis” (≤ grade 1 
fibrosis)
Peripheral Blood
o
WBC ≤ 10109/L
o
Hgb ≥ 11g/dL
o
Platelets ≥ 100109/L; ≤ 450109/L
o
Neutrophils ≥ 1.0109/L
o
Blasts 0%
o
Neutrophil precursors reduced to ≤ 2%
o
Monocytes ≤ 1109/L
Extramedullary disease: complete resolution of extramedullary disease 
present before therapy (e.g. cutaneous disease, disease-related serous 
effusions) including palpable splenomegaly
Persistent low-level dysplasia is permitted given subjectivity of 
assignment of dysplasia
Complete 
cytogenetic 
remission
Resolution of previously present chromosomal abnormality (known to 
be associated with MDS, MPN, or MDS/MPN) as seen on classic 
karyotyping with minimal of 20 metaphases or FISH
Partial Remission
Normalization of peripheral counts and hepatosplenomegaly with bone 
marrow blasts (and blasts equivalents) reduced by 50%, but remaining 
> 5% of cellularty, except in cases of MDS/MPN with ≤ bone marrow 
blasts at baseline
Marrow response
Optimal marrow response: presence of all marrow criteria for CR without 
normalization of peripheral blood indices as per CR
Partial marrow response: bone marrow blasts (and blast equivalents) 
reduced by 50%, but remaining > 5% of cellularity, or reduction in 
grading of reticulin fibrosis from baseline on at least 2 bone marrow 
evaluations spaced at least 2 months apart.  
Stable Disease
Failure to achieve at least PR, but no evidence of progression for > 8 
weeks
Failure
Death during treatment or disease progression characterized by 
worsening of cytopenias, increase in percentage of bone marrow blasts, 
or progression to a more advanced MDS subtype than pretreatment
Relapse after CR or PR
At least one of the following:
o
Return to pretreatment bone marrow blast percentage
o
Decrement of ≥ 50% from maximum remission/response levels 
in granulocytes or platelets
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o
Reduction in Hgb concentration by ≥ 1.5g/dL or transfusion 
dependence
Cytogenetic response
Complete: Disappearance of the chromosomal abnormality without 
appearance of the new ones
Partial: at least 50% reduction of the chromosomal abnormality
Disease 
Progression: 
(Combination of 2 major 
criteria, 1 major and 2 
minor 
criteria, 
or 
3 
minor criteria
Major Criteria:
o
Increase in marrow blast count

Less than 5% blasts: ≥ 50% increase to > 5% blasts

5%-10% blasts: ≥ 50% increase to > 10% blasts

10-20% blasts: : ≥ 50% increase to > 20% blasts
o
New extramedullary disease

worsening splenomegaly

Extramedullary 
disease 
outside 
the 
spleen 
(new 
hepatomegaly 
Minor Criteria
o
Transfusion dependence (at least 2 units of red blood cell 
transfusion in past month for hgb < 8.5g/dL not associated with 
clinically overt bleeding nor secondary to therapy)
o
Significant loss of maximal response on cytopenias ≥ 50% 
decrement from maximum remission/response in granulocytes or 
platelets 
o
Reduction in Hgb by ≥ 1.5g/dL from best response or from 
baseline as noted on complete blood count
Table 5: Response Criteria for patient with AML
Category
Definition 
Comment 
Response
CR 
without 
minimal 
residual 
disease (CRMRD) 
If 
studied 
pretreatment, 
CR 
with 
negativity for a genetic marker by RT–
qPCR, or CR with negativity by MFC 
Sensitivities vary by marker tested, and 
by method used; therefore, test used 
and sensitivity of the assay should be 
reported; analyses should be done in 
experienced laboratories (centralized 
diagnostics)
Complete 
remission (CR) 
Bone marrow blasts <5%; absence of 
circulating blasts and blasts with Auer 
rods; 
absence 
of 
extramedullary 
disease; 
ANC 
≥1.0 
× 
109/L 
(1000/microL); platelet count ≥100 × 
109/L (100,000/microL)
MRD+ or unknown
CR 
with 
incomplete 
 All CR criteria except for residual 
neutropenia 
(<1.0 
× 
109/L 

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hematologic 
recovery (CRi) 
[1000/microL]) 
or 
thrombocytopenia 
(<100 × 109/L [100,000/microL])
Morphologic 
leukemia-free 
state (MLFS) 
Bone marrow blasts <5%; absence of 
blasts with Auer rods; absence of 
extramedullary disease; no hematologic 
recovery required
Marrow should not merely be "aplastic"; at 
least 200 cells should be enumerated or 
cellularity should be at least 10%
Partial remission 
(PR) 
All hematologic criteria of CR; decrease 
of bone marrow blast percentage to 5 to 
25%; and decrease of pretreatment 
bone marrow blast percentage by at 
least 50%
Especially important in the context of 
phase 1/2 clinical trials
Treatment Failure
Primary-refractory 
disease 
No CR or CRi after 2 courses of 
intensive induction treatment; excluding 
patients with death in aplasia or death 
due to indeterminate cause

Regimens containing higher 
doses 
of 
cytarabine 
are 
generally considered as the 
best option for patients not 
responding to a first cycle of 
7+3; 
the 
likelihood 
of 
responding to such regimens is 
lower after failure of a first
Death in aplasia 

Deaths 
occurring 
≥7 
days 
following completion of initial 
treatment while cytopenic; with 
an aplastic or hypoplastic bone 
marrow obtained within 7 days of 
death, 
without 
evidence 
of 
persistent leukemia
Death from 
indeterminate 
cause 

Deaths 
occurring 
before 
completion of therapy, or <7 
days following its completion; or 
deaths 
occurring 
≥7 
days 
following completion of initial 
therapy with no blasts in the 
blood, but no bone marrow 
examination available
Response criteria for clinical trials only
Stable disease 

Absence of CRMRD–, CR, CRi, 
PR, MLFS; and criteria for PD 
not met 

Period of stable disease should 
last at least 3 months
Progressive 
disease (PD)*¶
Evidence for an increase in bone marrow 
blast percentage and/or increase of absolute 
blast counts in the blood: 

>50% increase in marrow blasts 
over baseline (a minimum 15% point 
increase is required in cases with 
<30% blasts at baseline; or 
persistent marrow blast percentage 
of >70% over at least 3 months; 
without at least a 100% 
improvement in ANC to an absolute 
Category mainly applies for older patient 
given low-intensity or single-agent "targeted 
therapies" in clinical trials
In general, at least 2 cycles of a novel agent 
should be administered
Some protocols may require blast increase 
in 2 consecutive marrow assessments at 
least 4 weeks apart; the date of progression 
should then be defined as of the first 
observation date
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level (>0.5 × 109/L [500/microL], 
and/or platelet count to >50 × 109/L 
[50,000/microL] nontransfused); or 

>50% increase in peripheral blasts 
(WBC × % blasts) to >25 × 109/L 
(>25,000/microL) (in the absence of 
differentiation syndrome)¶; or 

New extramedullary disease 
Some protocols may allow transient addition 
of hydroxyurea to lower blast counts
"Progressive disease" is usually 
accompanied by a decline in ANC and 
platelets and increased transfusion 
requirement and decline in performance 
status or increase in symptoms 
Relapse
Hematologic 
relapse (after 
CRMRD–, CR, CRi)
Bone marrow blasts ≥5%; or reappearance of 
blasts in the blood; or development of 
extramedullary disease
Molecular relapse 
(after CRMRD–)
If studied pretreatment, reoccurrence of MRD 
as assessed by RT–qPCR or by MFC
Test applied, sensitivity of the assay, and 
cutoff values used must be reported; 
analyses should be done in experienced 
laboratories (centralized diagnostics)
CR: complete response; MRD: measurable residual disease (also known as minimal residual 
disease); ANC: absolute neutrophil count; MLFS: morphologic leukemia-free state; WBC: white 
blood cell; IDH: isocitrate dehydrogenase; RT-qPCR: real-time quantitative polymerase chain 
reaction; MFC: multiparameter flow cytometry.
* The authors acknowledge that this new provisional category is arbitrarily defined; the category 
aims at harmonizing the various definitions used in different clinical trials.
¶ Certain targeted therapies, for example, those inhibiting mutant IDH proteins, may cause a 
differentiation syndrome, that is, a transient increase in the percentage of bone marrow blasts and 
an absolute increase in blood blasts; in the setting of therapy with such compounds, an increase in 
blasts may not necessarily indicate PD.
12.0
DATA REPORTING / REGULATORY CONSIDERATIONS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events and potential risks).
12.1
Data Reporting 
The REDCap database will be utilized, as required by the Montefiore/Einstein 
Cancer Center, to provide data collection for both accrual entry and trial data 
management. REDCap is a Clinical Trials Management System housed on secure 
servers. Access to data through REDCap is restricted by user accounts and assigned 
roles. Once logged into the REDCap systems with a user ID and password, defined 
roles for each user limit access to appropriate data. User information and password 
can be obtained by contacting the REDCap administrator. REDCap is designed with 
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the capability for study setup, activation, tracking, reporting, data monitoring and 
review, and eligibility verification. This study will utilize electronic Case Report 
Forms. A calendar of events and required forms will be available on REDCaps. 
12.2
Regulatory Considerations
The study will be conducted in compliance with ICH guidelines and with all 
applicable federal state or local laws.
12.2.1
Written Informed consent
Provision of written informed consent must be obtained prior to any study-related 
procedures. The Principal Investigator will ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, possible risks and 
benefits of the study as well as the subject’s financial responsibility. Subjects must 
also be notified that they are free to discontinue from the study at any time. The 
subject should be given the opportunity to ask questions and be allowed time to 
consider the information provided. 
The original, signed written Informed Consent Form must be kept with the Research 
Chart in conformance with the institution’s standard operating procedures. A copy 
of the signed written Informed Consent Form must be given to the subject. 
Additionally, documentation of the consenting process should be located in the 
research chart.
12.2.2
Subject Data Protection
In accordance with the Health Information Portability and Accountability Act 
(HIPAA), a subject must sign an authorization to release medical information to the 
regulatory authority, or Institutional Review Board access to subject’s medical 
information that includes all hospital records relevant to the study, including 
subjects’ medical history. 
12.2.3
Retention of records
The Principal Investigator will supervise the retention of all documentation of 
adverse events, records of study drug receipt and dispensation, and all IRB 
correspondence for as long as needed to comply with local, national and 
international regulations. No records will be destroyed until the Principal 
Investigator confirms destruction is permitted. Records will be retained for 5 years 
after the last accrual. 
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12.2.4 
Audits and inspections 
The Montefiore Einstein Cancer Center Cancer Clinical Trials Office (MECC 
CCTO) quality assurance team will perform monitoring visits and audits of 
regulatory documents and participant charts either in person or remotely for all sites 
which  includes but is not limited to eligibility verification, drug accountability, and 
source data verification. The MECC quality assurance team will follow the MECC 
DSMP timeline of quality assurance program monitoring and audit frequency based 
on the protocol risk category. 
The purpose of an audit or inspection is to systematically and independently examine 
all study-related activities and documents to determine whether these activities were 
conducted, and data were recorded, analysed, and accurately reported according to 
the protocol, Good Clinical Practice (GCP), guidelines of the International 
Conference on Harmonization (ICH), and any applicable regulatory requirements.  
13.0
STATISTICAL CONSIDERATIONS 
The combination of HMA (decitabine or azacytidine) and Venetoclax are approved 
to treat elderly patients with AML. The FDA-approved regimens of 
HMA/venetoclax is with pulse-cycle drug administration of HMA and venetoclax 
requires continuous dosing. However, with this approach the myelosuppression from 
treatment leads to frequent dose-reductions, and/or cycle delays especially for many 
older patients and patients who have poor bone marrow reserve. In addition, some 
subgroups of myeloid malignancies have not been shown to benefit from standard 
dosing of decitabine/venetoclax as outlined above in section 1 study rationale. The 
registration trial which lead to FDA approval of Azacitidine in combination with 
venetoclax (VIALE-A) used standard dosing (Aza 75 mg/m2 days 1-7, venetoclax 
400 mg days 1-28 of a 28 days cycle). In this trial 24% of patients had to discontinue 
azacitidine–venetoclax due to adverse events and more importantly the dose 
interruption of azacitidine–venetoclax between cycles owing to adverse events 
occurred in 72% of patients. 
While venetoclax enhances the activity of HMA, the inability to get the required 
doses due to myelosuppression limits the benefits. Our hypothesis is that the weekly 
low dose venetoclax/decitabie regimen avoids severe myelosuppression by 
preserving functional hematopoietic cells, while maximizing suppression of clonal 
cell population by decitabine’s S-phase dependent DNMT1-targeting while the 
venetoclax priming inhibits de novo pyrimidine synthesis which counters a major 
mechanism of resistance to decitabine in myeloid malignancies. This regimen will 
allow for continuous dosing without interruptions due to myelosuppression and may 
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lead 
to 
more 
durable 
responses. 
The 
doses 
and 
total 
amounts 
of 
decitabine/venetoclax administered int this trial  are known to be safe and effective 
in this patient population based on our experience at Montefiore medical center using 
this regimen. Therefore, in this proof-of-concept study, the primary end-point relates 
to the ability to administer the treatment continuously without interruptions 
compared to standard dosing used in VIALE-A trial 
Considerations in choice of primary end-point:  The primary end-point is the 
overall percent of patients who can receive weekly low dose decitabine/ven during 
the induction period (weeks 1-12) without dose interruptions. The reason for the 12-
week time period was used is because responses to HMA/ven are gradual and more 
so with the low dose regimen. For example, in VILAE-A, the median time to first 
response (either complete remission or complete remission with incomplete 
hematologic recovery) was 1.3 months (range, 0.6 to 9.9) and 2.8 months (range, 0.8 
to 13.2), respectively. 
Considerations in sample-size calculations:  As mentioned above, in VIALE-A 
dose interruptions were required in 72% of patients receiving standard currently 
approved dosing of Aza/ven . Therefore, the sample size has been calculated to 
detect a 50% reduction in treatment interruptions, which would suggest that the 
proposed regimen has a high likelihood of being an advance over the current FDA 
approved regimen.
Sample size calculations:  A  Simon 2-stage Optimal design is used to test the null 
hypothesis of 60% or more  patients requiring a dose reduction versus the alternative 
hypothesis of  36% or less of patients requiring dose interruptions with a one-sided 
alpha of 5%, power of 80%, and a probability of early termination of 0.77.  After 
assessing dosing of decitabine/ven in 13 patients in the first stage, the trial will be 
terminated if 7 or more patients require dose reduction. If the trial goes on to the 
second stage, a total of 33 patients will be studied. If the total number of dose 
reduction is greater than or equal to 16, the treatment regimen is rejected. 
After the 19 patients were enrolled into the study and 17 patients were evaluable 
after a 12-week induction, there were with no safety concerns. If after a total of 33 
patients have been evaluated after the 12-week induction period and show 
satisfactory results (i.e., fewer than 16 dose reductions during the induction period, 
so the treatment was not rejected), the proposed amendment for an expansion phase 
will be implemented in which additional patients will be enrolled to gather more data 
on the secondary endpoints of efficacy using this regimen in MDS and AML.  
Background for the rationale for this amendment is outlined in section 1.4. Given 
the early efficacy seen in the first 11 evaluable patients with AML (64% response 
rate) and very low toxicity, more subjects will be required to establish the secondary 
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endpoints of efficacy in MDS and AML. This additional data may help in the design 
subsequent studies which will require  adding an additional agent to this regimen as 
a backbone as it’s becoming increasingly clear the HMA/VEN does not  have a cure 
rate25 and the way forward will requires a third effective agent with multiple trials 
now evaluating triplets and using HMA/VEN as a backbone. The comparator arm 
for HMA/VEN in all trials is the current standard of single agent HMA (Azacitidine 
or Decitabine). 
The expansion phase will be stratified by disease type, i.e., MDS and AML. 
Single agent HMA has a 16% CR rate in MDS. 26  The CR rate with HAM/VEN is 
expected to be at least 36%. The target sample size for the MDS group will be a total 
of 32 patients (from both initial and expansion phases). With this sample size, we 
can  estimate the CR rate with standard error no greater than 9%. 
In AML, single agent HMA has a CR rate of 17.9%. 1 The CR rate with HAM/VEN 
is expected to be at least 38%. With a total of 38 AML patients from both phases, 
we can estimate the CR rate with standard error no greater than 8%. 
In summary, an amendment will be added for additional 42 patients (above the 
originally planned 33 patients) with either MDS or AML after accounting for drop-
outs. For example, if we assume among the first stage of 33 patients, we have 16 
MDS, 17 AML, then the study needs enroll additional 16 MDS and 21 AML, a total 
of 37 patients.  Allowing up to 5 patients to drop out from the study and the study 
may also enroll approximately 10 patients with other rare myeloid malignancies such 
as CMML and MDS/MPN.  We therefore expect the total number of patients needed 
to be enrolled in the study to be not more than 85 (33+37+5+10) patients. 
Safety: Incidence of treatment-emergent adverse events will be tabulated 
severity/grade, and whether the AE resulted in death or discontinuation of treatment.
Early Stopping Rule for Excessive Toxicity in Expansion Phase: We will 
continue using Bayesian toxicity monitoring in the expansion phase, similar to what 
was described in the initial stage of the study (Sec 6.6), to allow for early stopping 
due to excessive toxicity.  
Laboratory data will be summarized in tables that show changes from pre-treatment 
values and frequencies of abnormal values.  Descriptive statistics will also be 
provided.
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Efficacy:  The primary end-point of a decrease in dose interruptions will be 
described as proportion of patients point-estimates, together with the corresponding 
95% confidence interval.  Kaplan-Meier method will be used to summarize time to 
event variables.
Secondary end-points and scientific correlative studies:  For the secondary end-
points and scientific correlates (secondary objectives), either logistic regression or 
correlation analysis will be utilized to examine and assess the relationships and 
predictive nature of these biological parameters on hematologic improvement and 
ability of decitabine/ven to deplete DNMT1 in malignant cells, and the alteration of 
pyrimidine metabolism.  Descriptive summaries of the data will be provided.  
Accrual rate: Estimated accrual rate of 1-3 patients per month with approximately 
18-24 months to meet total accrual goals, and additional 3 months to observe primary 
outcome measures.  DOR of response will be followed for up to two years, thus a 
total of three to four years is anticipated to meet all study endpoints. 
14.0  FUNDING
Study expenditures for research correlatives and in cases where patients need 
assistance with treatment, will be supported by research grants, department funds 
and philanthropic donations. 
1.
DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in Previously Untreated Acute 
Myeloid Leukemia. N Engl J Med. Aug 13 2020;383(7):617-629. doi:10.1056/NEJMoa2012971
2.
DiNardo CD, Tiong IS, Quaglieri A, et al. Molecular patterns of response and treatment failure after 
frontline venetoclax combinations in older patients with AML. Blood. Mar 12 2020;135(11):791-803. 
doi:10.1182/blood.2019003988
3.
Velcheti V, Schrump D, Saunthararajah Y. Ultimate Precision: Targeting Cancer but Not Normal 
Self-replication. Am Soc Clin Oncol Educ Book. May 23 2018;38:950-963. doi:10.1200/edbk_199753
4.
Saunthararajah Y, Sekeres M, Advani A, et al. Evaluation of noncytotoxic DNMT1-depleting 
therapy in patients with myelodysplastic syndromes. J Clin Invest. Mar 2 2015;125(3):1043-55. 
doi:10.1172/jci78789
5.
Awada H, Mahfouz RZ, Kishtagari A, et al. Extended experience with a non-cytotoxic DNMT1-
targeting regimen of decitabine to treat myeloid malignancies. Br J Haematol. Mar 2020;188(6):924-929. 
doi:10.1111/bjh.16281
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6.
Gu X, Tohme R, Tomlinson B, et al. Decitabine- and 5-azacytidine resistance emerges from 
adaptive responses of the pyrimidine metabolism network. Leukemia. Apr 2021;35(4):1023-1036. 
doi:10.1038/s41375-020-1003-x
7.
Gu XT, R.  Goldfinger, M et al. Venetoclax Inhibition of Pyrimidine Synthesis Guides Methods for 
Integration with Decitabine or 5-Azacytidine That Are Non-Myelosuppressive. ASH meeting poster 2020;
8.
Jonas BA, Pollyea DA. How we use venetoclax with hypomethylating agents for the treatment of 
newly diagnosed patients with acute myeloid leukemia. Leukemia. Dec 2019;33(12):2795-2804. 
doi:10.1038/s41375-019-0612-8
9.
Winters AC, Gutman JA, Purev E, et al. Real-world experience of venetoclax with azacitidine for 
untreated patients with acute myeloid leukemia. Blood Adv. Oct 22 2019;3(20):2911-2919. 
doi:10.1182/bloodadvances.2019000243
10.
Tremblay D, Feld J, Dougherty M, et al. Venetoclax and hypomethylating agent combination 
therapy in acute myeloid leukemia secondary to a myeloproliferative neoplasm. Leuk Res. Nov 
2020;98:106456. doi:10.1016/j.leukres.2020.106456
11.
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of 
conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, 
open-label, phase III study. Lancet Oncol. Mar 2009;10(3):223-32. doi:10.1016/s1470-2045(09)70003-8
12.
Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic 
syndromes: results of a phase III randomized study. Cancer. Apr 15 2006;106(8):1794-803. 
doi:10.1002/cncr.21792
13.
Prébet T, Gore SD, Thépot S, et al. Outcome of acute myeloid leukaemia following myelodysplastic 
syndrome after azacitidine treatment failure. Br J Haematol. Jun 2012;157(6):764-6. doi:10.1111/j.1365-
2141.2012.09076.x
14.
Jabbour E, Garcia-Manero G, Batty N, et al. Outcome of patients with myelodysplastic syndrome 
after failure of decitabine therapy. Cancer. Aug 15 2010;116(16):3830-4. doi:10.1002/cncr.25247
15.
Pollyea D GJ, Brunner AM et al. Phase 1b Study Evaluating the Safety and Efficacy of Venetoclax 
in Combination with Azacitidine for the Treatment of Relapsed/Refractory Myelodysplastic Syndrome. 
ASH 2020.
16.
Ball BJ, Famulare CA, Stein EM, et al. Venetoclax and hypomethylating agents (HMAs) induce high 
response rates in MDS, including patients after HMA therapy failure. Blood Adv. Jul 14 2020;4(13):2866-
2870. doi:10.1182/bloodadvances.2020001482
17.
Koenig KL, Sahasrabudhe KD, Sigmund AM, Bhatnagar B. AML with Myelodysplasia-Related 
Changes: 
Development, 
Challenges, 
and 
Treatment 
Advances. 
Genes 
(Basel). 
Jul 
24 
2020;11(8)doi:10.3390/genes11080845
18.
Batty GN, Kantarjian H, Issa JP, et al. Feasibility of therapy with hypomethylating agents in patients 
with 
renal 
insufficiency. 
Clin 
Lymphoma 
Myeloma 
Leuk. 
Jun 
2010;10(3):205-10. 
doi:10.3816/CLML.2010.n.032
19.
Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute 
myeloid leukemia. Blood. 04/13/received
05/19/accepted 2017;130(6):722-731. doi:10.1182/blood-2017-04-779405
20.
DiNardo CD, De Botton S, Stein EM, et al. Ivosidenib (AG-120) in Mutant IDH1 AML and Advanced 
Hematologic Malignancies: Results of a Phase 1 Dose Escalation and Expansion Study. Blood. 
2017;130(Suppl 1):725. 
21.
Laufer CB, Roberts O. Differentiation syndrome in acute myeloid leukemia after treatment with 
azacitidine. European journal of haematology. 2015;95(5):484-485. doi:10.1111/ejh.12598
22.
Ueda M, El-Jurdi N, Cooper B, et al. Low-Dose Azacitidine with DNMT1 Level Monitoring to Treat 
Post-Transplantation Acute Myelogenous Leukemia or Myelodysplastic Syndrome Relapse. Biol Blood 
Marrow Transplant. Jun 2019;25(6):1122-1127. doi:10.1016/j.bbmt.2018.12.764
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23.
Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of 
the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108(2):419. 
doi:10.1182/blood-2005-10-4149
24.
Savona MR, Malcovati L, Komrokji R, et al. An international consortium proposal of uniform 
response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood. Mar 19 
2015;125(12):1857-65. doi:10.1182/blood-2014-10-607341
25.
Pratz KW. Long-Term Follow-up of the Phase 3 Viale-a Clinical Trial of Venetoclax Plus Azacitidine 
for Patients with Untreated Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy. Abstract, ASH 
annual Meeting 2022. 
26.
Hasegawa K, Wei AH, Garcia-Manero G, et al. Azacitidine Monotherapy in Patients With 
Treatment-Naïve Higher-risk Myelodysplastic Syndrome: A Systematic Literature Review and Meta-
analysis. Clin Lymphoma Myeloma Leuk. Feb 2023;23(2):127-137. doi:10.1016/j.clml.2022.11.002
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