Salsalate + Venetoclax/Decitabine for Patients With Acute Myelogenous Leukemia or Advanced Myelodysplasia/Myeloproliferative Disease
Phase: PHASE2
Conditions: Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myeloblasts 10 Percent or More of Bone Marrow Nucleated Cells, Myelodysplastic Syndrome, Myeloproliferative Neoplasm, Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia
Sponsor: Rutgers, The State University of New Jersey

 
 
Official Title: 
Salsalate, Venetoclax, and Decitabine or Azacitidine for the 
Treatment of Acute Myeloid Leukemia or Advanced 
Myelodysplasia/Myeloproliferative Disease 
NCT number: 
NCT04146038 
Document Type:  
Protocol and SAP 
Date of the 
Document: 
12/29/2020 
 
 

1
1.0
Research Design
1.1
Purpose/Specific Aims
1.2
Research Significance
1.3
Research Design and Methods
1.4
Preliminary Data
1.5
Sample Size Justification
1.6
Study Variables
1.7
Drugs/Devices/Biologics
1.8
Primary Specimen Collection
1.9
Interviews, Focus Groups, or Surveys
1.10
Timetable/Schedule of Events
2.0
Project Management
2.1
Research Staff and Qualifications
2.2
Resources Available
2.3
Research Sites
3.0
Multi-Site Research Communication & Coordination
3.1
Outside Research
4.0
Research Data Source/s
4.1
Primary Data – Subjects and Specimens
4.2
Subject Selection and Enrollment Considerations
4.3
Subject Randomization
4.4
Secondary Subjects
4.5
Number of Subjects
4.6
Consent Procedures
4.7
Special Consent Populations
4.8
Economic Burden and/or Compensation For Subjects
4.9
Risks to Subjects
4.10
Secondary Data – Record/Chart Reviews, Databases, Tissue Banks, Etc.
4.11
Chart/Record Review Selection
4.12
Secondary Specimen Collection
5.0
Special Considerations
5.1
Health Insurance Portability and Accountability Act (HIPAA)
5.2
Family Educational Rights and Privacy Act (FERPA)
5.3
NJ Access to Medical Research Act
5.4
Code of Federal Regulations Title 45 Part 46 (Vulnerable Populations)
6.0
Research Data Protection and Reporting
6.1
Data Management and Confidentiality
6.2
Data Security
6.3
Data Safety And Monitoring
6.4
Reporting Results
6.5
Data Sharing
7.0
Data and/or Specimen Banking
8.0
Other Approvals/Authorizations
9.0
Bibliography

2
1.0 Research Design
1.1 Purpose/Specific Aims
To determine if the novel combination of salicylic-salicylic acid (Salsalate), venetoclax and decitabine 
(or alternate hypomethylating agent [HMA], 5-azacytidine] should be developed as a therapy for 
patients with advanced myeloid malignancies [acute myelogenous leukemia (AML); high risk 
myelodysplasia (MDS); or high risk chronic myeloproliferative disease] who are not candidates for 
standard induction chemotherapy with anthracycline + cytarabine. This is a phase 2 study to 
determine if the novel combination therapy is tolerated well and if biological endpoints are met. There 
is no control group.
A.  Objectives 
Primary Objective: Determine the tolerability of the addition of standard dose Salsalate to the 
standard treatment combination of venetoclax + HMA (decitabine or 5-azacytidine).  
Secondary Objective: Determine the remission rate and, when feasible, perform exploratory 
studies of: (i) patterns of mutation clearance; and (ii) distribution of cells with low and high 
reactive oxygen species (ROS) content at various points during therapy.
B.  Hypotheses / Research Question(s)
Salicylate has been studied at 
 as an adjunct to standard AML induction 
chemotherapy.  In those studies, salicylate, administered as choline magnesium trisalicylate was 
shown to inhibit the expression of the transcription factor nuclear factor kappa-B (NF-kB) in the 
nucleus of AML cells.  The salicylate was also shown to modulate the expression of NF-kB 
modulated genes, including XIAP, an inhibitor of apoptosis. (1,2).  Salicylates are also known to 
inhibit mitochondrial oxidative phosphorylation, an effect that is anticipated to enhance the anti-
leukemic effect of venetoclax (3,5,6,7,9,10). There were no adverse effects associated with 
choline magnesium trisalicylate in our studies when administered with standard induction 
chemotherapy (1,2). Other forms of non-acetylated salicylates have also been administered to 
patients with myeloid malignancies (8).  The safety of salicylates in combination with the induction 
of enhanced expression of anti-apoptotic genes and the uncoupling of oxidative phosphorylation 
make them an excellent candidate for study in combination with venetoclax + decitabine or 5-
azacytidine, a newly approved therapy for patients with AML who are not candidates for standard 
induction chemotherapy. Our primary hypothesis is that the combination of a salicylate + 
venetoclax + decitabine (or in selected patients previously treated with decitabine, 5-azacytidine) 
will be well tolerated and, if so, should be studied further as therapy for advanced myeloid 
malignancies.  We propose to use salicylic-salicylic acid (Salsalate) in this study because our 
previously performed study used a salicylate, choline magnesium trisalicylate, which is no longer 
commercially available.  Salsalate (salicylsalicylic acid) is composed of two molecules of salicylic 
acid joined by an ester link. The ester bond of salsalate occurs at the carboxyl group of one salicylic 
acid molecule and the hydroxyl group of another. Salsalate is non-acetylated so has no effect on 
platelet function 8). It is used in the treatment of osteoarthritis, rheumatoid arthritis, and other 

4
Another clinical trial of combination decitabine + venetoclax was presented recently at the 2018 
American Society of Hematology Meeting (abstract 286 Maiti et al. Interim Analysis of Phase II Study 
of Venetoclax with 10-Day Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndrome. 
American Society of Hematology 2018). In that study, a prolonged course of decitabine (10 
days/cycle as opposed to the standard 5 days/course) was used in combination with venetoclax.   
Treated patients included elderly patients with newly diagnosed or relapsed/refractory AML   CR + 
CRi rates for de novo AML, secondary AML and relapsed/refractory AML patients were 91%, 72% 
and 44% respectively.  Patients with relapsed/refractory AML had a median duration of response of 
only ~3 months; patients with de novo or secondary AML had median durations of response that 
exceeded the 12 month period of monitoring.  
Both of these studies indicated rapid response rates with best response usually seen by 1-2 cycles of 
treatment.  Both studies also tested for measurable residual disease (MRD).  As seen with standard 
AML therapy, there appeared to be improved response duration in the subset of patients reaching a 
state of undetectable MRD. In patients treated at the University of Colorado, 22 patients had 
molecular determination of MRD and 4 had no detectable MRD; none of the 4 with no MRD had 
relapsed at median f/u > 2 years (5).
These and other studies of older patients with AML indicate that treatment with a HMA in 
combination with venetoclax can be very effective.  Comparison to historic controls treated with 
standard chemotherapy or single agent hypomethylating agent much improved CR rates and 
duration of response compared were seen. Even those with traditionally high-risk mutation profiles, 
secondary AML or age > 75 years old seem to benefit greatly compared to historic controls.  
However, elderly AML patients with high-risk cytogenetics, relapsed/refractory disease, or prior 
HMA exposure will have lower CR + CRi rates and durations of response.   Even those with newly 
diagnosed disease who respond are likely to relapse within 2 years.  Therefore, modifications of this 
regimen need to be tested.
Mechanistic studies indicate that leukemic stem cells (the self-renewing population of AML cells) 
are very dependent on oxidative phosphorylation.   It has also been shown that the beneficial effect 
of venetoclax may in part be based upon this dependence.  Well-tolerated drugs known to impact 
oxidative phosphorylation and/or apoptosis are logical choices for addition to HMAs + venetoclax 
(3,5,10).
Salsalate is our choice to test in combination with a hypomethylating agent + venetoclax.  
Salicylates are known to inhibit oxidative phosphorylation and previous clinical trials at Rutgers-CINJ 
have utilized a salicylate as part of anti-leukemic therapy (1,2,6,7).  Choline magnesium trisalicylate 
used in prior studies is no longer available commercially.  In this study we will utilize saliclicsalicylic 
acid (Salsalate) at a standard dose.  The dose has been shown to result in therapeutic salicylate 
levels and like the choline magnesium trisalicylate is not acetylated and will not result in platelet 
dysfunction.  This medication is often used as part of supportive care (anti-pyretic) during AML 
induction chemotherapy. We have shown previously that salicylate modulates the expression of 
many genes in the WNT and NF-kB pathways, including XIAP, an inhibitor of apoptosis (2).  It has 
also been shown by others that salicylates have a direct mitochondrial effect that impedes oxidative 
phosphorylation (6,7).  In this context, we will study Salsalate in combination with decitabine and 

5
venetoclax as induction therapy for selected elderly patients with advanced myeloid malignancies 
such as AML, myelodysplasia (MDS) or myeloproliferative diseases with > 10% blast or blast 
equivalents.  Patients who have received decitabine previously will be treated with 5-azacytidine as 
the HMA.  Morphology, standard flow cytometry and next generation sequencing will be used as 
markers of MRD.  When available, single cell DNA sequencing will be used to determine the 
sensitivity of individual leukemia clones to treatment.  Oxidative phosphorylation status of cells will 
be profiled by flow cytometry to determine if response rates correspond with changes in the profile 
of oxidative phosphorylation and if Salsalate has independent effects on the profile.
1.3 Research Design and Methods
A. Research Procedures
In this study we will treat patients with AML, MDS and advanced myeloproliferative disorders with 
decitabine, venetoclax and salsalte.  5-azacytidine may be substituted for decitabine if the patient 
has been previously treated with decitabine. Patients will be hospitalized for initiation of therapy 
(for at least 4 days). Venetoclax dose escalation in cycle 1 will follow the recommended “ramp 
up” to minimize the risk of tumor lysis. Salsalate will be added on day 5 of decitabine + venetoclax 
(or 5-azacytidine).  There will be only one cycles of treatment with salsalate. The next treatment 
cycle will be administered under the direction of the treating physician.  
Cycle 1:
i.
Venetoclax and decitabine (or 5-azacytidine) will initiate concurrently on d1; 
salsalate will be start on d5. 
1.
Decitabine 20 mg/m2/d IV will be administered d1-10.  If 5-azacytidine 
is being used (if the patient has previously been exposed to decitabine) 
it will be administered at 75 mg/m2/d SC or IV d1-7.
2.
Venetoclax will be dose escalated per package insert - 100 mg d1; 200 
mg d2; and 400 mg d3-28.  
3.
Salsalate 1500 mg PO bid will start on day 5 of decitabine (or 5-
azacytidine) and be administered until and including the day of 
completion of the decitabine or 5-azacytidine.  
Patients with WBC greater than 25,000/uL will be treated with hydroxyurea 2-3g PO bid per treating 
physician to obtain a WBC<15,000/uL. Once WBC is in target range the protocol treatment can  be 
started. Hydroxyurea may be continued to sustain WBC < 15,000/uL as needed. Standard tumor lysis 
monitoring and prophylaxis will be used.  Allopurinol (or alternate hypouricemic agent) will be 
started >24 h prior to starting venetoclax and continued through dose escalation of venetoclax, or 
longer, as clinically indicated. During dose escalation of venetoclax  patients will receive IV fluids, 
and tumor lysis laboratory studies (basic chemistry profile including calcium, phosphate, uric acid 
and lactate dehydrogenase) will be obtained every 8 hours. 

6
Infectious disease prophylaxis may be used at the discretion of the patients treating physician. If 
anti-fungal prophylaxis is used the dose of venetoclax will be modified as outlined below. Proton  
pump inhibitors are mandated unless there is a contraindication. Venetoclax dosing will be 
adjusted if concurrent anti-infectives are CYP3A4 or Pgp inhibitors (see below).
Venetoclax dosing will be modified in the context of concurrent use of CYP3A4 or Pgp inhibitors.  
Venetoclax will be dosed at 70mg /d (if concurrent posaconazole) or 100 mg/d if there is concurrent 
use of other strong CYP3A4 inhibitors or 200 mg/d if use of moderate CYP3A4 inhibitors. Venetoclax 
will be dosed at 200 mg/d in the setting of concurrent use of moderate CYP3A4 inhibitors.  Dosage 
should be modified and timing of dose adjusted if concurrent Pgtp inhibitors are used.  All concurrent 
meds will be reviewed and dosing schedules approved by a research pharmacist.
If the patient has profound thrombocytopenia (< 10,000/uL at day 21 – 28 in the first cycle) a BM asp 
and biopsy may be performed at the discretion of the treating physician with the option to hold 
venetoclax. The start of the second cycle is at the discretion of the treating physician and may include 
modifications of decitabine/5-azacytidine or venetoclax dosing as per standard recommendations. 
These additional cycles (starting at cycle 2 are not considered part of this clinical trial).
Any Grade 3 or 4 non-hematologic adverse event thought to be Salsalate-related will require the 
dose to be held until the event recovers to Grade 2 or less. If the adverse event does not resolve 
within 1 week, the patient will be removed from the study.  For Salsalate these events include renal 
insufficiency, gastritis, tinnitus, vertigo and unanticipated GI bleeding as common toxicities; the 
Salsalate-relatedness of other toxicities will be assessed by the research team in real time.
Patients will receive full supportive care therapies per Leukemia Tumor Study Group practices 
concomitantly during the study. No other chemotherapy, immunotherapy, hormonal cancer 
therapy, radiation therapy, surgery for cancer, or experimental medications will be permitted 
while the patients are participating in the treatment component of this study (first 2 cycles).

7
CSFs are not permitted as primary prophylactics. If, in the investigator’s opinion, it is required in 
the presence of severe neutropenia (ANC <500/µl for at least 3 days or concurrent neutropenia 
and infection) then use of CSFs is allowed per treatment plan described above.  
Patients that are not hospitalized will be asked to keep a medication diary and instructed to record 
the number of capsules taken and the time taken. At the end of each cycle of treatment, the actual 
amount of unused drug will be compared to the amount taken as recorded on the subject’s 
medication diary.
All patients who receive one dose of protocol therapy will be evaluable for assessment of toxicity.  
Prior to each cycle the treating physician will fully assess the patient’s condition with respect to 
possible treatment related toxicities.  All adverse events, whether observed by the physician or 
reported by the patient, occurring during the active portion of therapy, or up to 30 days after the 
last dose of treatment will be graded by a numerical score according to the NCI’s Common 
Terminology 
Criteria 
for 
Adverse 
Events 
(CTCAE), 
Version 
5.0 
(http://ctep.cancer.gov/reporting/ctc.html) and recorded in the patient’s medical record. For the 
purposes of reporting laboratory abnormalities, only Grade 3-4 adverse events will be recorded 
on the adverse event CRF pages.  Grade 1-2 laboratory abnormalities will not be recorded on the 
adverse event CRF pages.  Information entered on the adverse event CRF pages will include: 

Specific type and duration of reaction (i.e., start and stop dates, resolution).

Severity/grade. 

Relationship to study drug (causality, attribution).

Management of the event, if treated with medication and other actions taken to alleviate 
the clinical event.

Whether or not it was considered a SAE. 
A preexisting condition is one that is present at the start of the study.  A preexisting condition will be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens 
during the study period.
An adverse experience is defined as any unintended or abnormal clinical observation that is not of 
benefit to the patient.  Either the condition was not present prior to exposure to the study therapy, 
or it has worsened in intensity or frequency following exposure to the study therapy.  
All “unexpected” (defined below) and/or “serious” experimental drug related adverse events 
occurring during the active portion of therapy, or up to 30 days after the last dose of treatment, will 
be reported to the Office of Human Research Services at (732) 235-7577 or (732) 235-2465. Events 
will be promptly reported, in writing, to the local IRB in accordance with IRB policy.  If a death occurs 
the IRB will be notified within 24-hours of initial receipt of information.  All other SAEs must be 
reported to the IRB within three to ten days of initial receipt of information. Written follow-up reports 
are required when additional information is needed to fully characterize the event. Copies of each 
report sent to the IRB will be kept in the study regulatory file.
In addition to reporting to the local IRB, reporting to external bodies such as industry and/or the FDA 
may be necessary 

8
In the absence of treatment delays due to adverse events, treatment may continue until one of the 
following criteria applies:
a)
Disease progression/relapse during active treatment,
b)
Intercurrent illness that prevents further administration of treatment,
c)
Unacceptable adverse event(s).  
d)
In the event of any drug-related life-threatening toxicity or laboratory abnormality the patient 
will be withdrawn from further treatment,
e)
Patient decides to withdraw from the study,
f)
Noncompliance with treatment plan,
g)
General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator, or
h)
Protocol violation - any patient found to have entered this study in violation of the protocol might 
be discontinued from the study at the discretion of the Principal Investigator.
i)
The desired level of compliance is  75%.  Patients who cannot maintain this level of compliance 
may be removed from the study. 
Evaluations
Pre-
Study 
(within 2 
weeks)
Daily during 
treatment 
with 
decitabine or 
5-azacytidine 
Prior 
to 
Next 
Treat
met12
Initial History & Physical
X
Interim History & Physical
X while 
hospitalized
X
Toxicity Assessment
X
X
Concomitant Medications
X
X
X
ECOG Performance Status
X
X

9
CBC, differential, platelets
X1
X while 
hospitalized
X
Serum Chemistries2
X
X  while 
hospitalized
X
Tumor lysis monitoring and 
treatment)
X (q8h during 
ramp up and q 
d while 
hospitalized) 
Liver Enzymes3
X
X while 
hospitalized
X
EKG
X
Pregnancy Test4
X
X
Radiographic Assessments5
X
REDOX Blood Studies6
(during first week of 
treatment)
X
X (pre first 
dose of 
salsalate and 
after 4-8 doses 
salsalate based 
on blood 
counts) 
BM asp and biopsy
X
X11
Blood flow cytometry/NGS 
(next generation 
sequencing)7
X
X
Compliance Assessment
X
Survival8

10
1.
Within 1 week of enrollment.
2.
Includes: Electrolytes, Calcium, BUN, Creatinine, Total Protein, Glucose, Albumin, Total Bilirubin, Alk. 
Phosphatase, SGOT/SGPT.
3.
Includes: Total and Direct. Bilirubin, AST/ALT, Alkaline Phosphatase, Albumin, Total Protein.
4.
Women of childbearing potential must have pregnancy test verified by BHCG within 1 week of enrollment.
5.
Radiographic assessments will be selected by the attending physician as clinically indicated and in accordance 
with the criteria for tumor measurement assessments.
6.
REDOX analysis (Dr. Herranz lab) will be done on blood samples with CD34 selected blasts at baseline, after 1-5 
days of treatment and following administration of of Salsalate with exact timing determined by numbers of 
leukemic blasts in the blood 
7.
NGS from BM will be done at baseline and after the second cycle or on any BM with leukemic cells detected as 
performed for clinical reasons. NGS or Single cell DNA sequencing may also be done by Dr. Khiabanian as feasible 
from blood based upon disease status and resources.
8.     Subjects will be tracked until relapse or change of therapy.
9.     Disease status and survival status will be documented every 2 months until disease progression or start of new 
treatment.
10.   End of Treatment = 45 days after the last dose of Salsalate.
11.   Bone marrow aspirate can be performed within 14 days of anticipated next treatment cycle.
B.
Data Points
Please see above for data points for REDOX analysis, DNA sequencing and disease assessment by 
bone marrow analysis.
C.
Study Duration
Eligible patients will be treated with experimental drug Salsalate + standard venetoclax + 
decitabine (or 5-azacytidine) for 1 cycles of therapy.  Responding patients will then continue on 
standard of care venetoclax + decitabine (or 5-azacytidine) in the observation phase of the study 
under supervision of their physician. 
D. Endpoints
Primary endpoint: For testing the primary hypothesis, the toxicity of salicylate + venetoclax + 
decitabine during the first two cycles will be collected as primary endpoints.
Secondary endpoint: We will correspond response rates with the pattern of survival of low oxygen 
reactive species cells. The administration of drugs will be timed to determine if there is a 
measurable added effect of salicylate on the oxidative state of cells when used in combination 
with venetoclax + decitabine. Next generation sequencing will determine also if there is a 
correspondence of remission with patterns of mutation clearance and/or effects of treatment on 
the oxidative state of the leukemia cells.
1.4 Preliminary Data
See above (Hypotheses, Research Question). Salicylates have been shown to modulate NF-kB gene 
expression (studies performed at Rutgers/CINJ) (1,2).  Salicylates are known to uncouple oxidative 
phosphorylation (6,7). In combination these effects are hypothesized to enhance the anti-leukemic 
effects of combined hypomethylating agent + venetoclax therapy of AML.

11
1.5 Sample Size Justification
We propose 20 patients over the course of 3 years to assess toxicity, as outlined above. We anticipate 
also the use of data to support development of a larger multi-instutional randomized phase 2 trial.
1.6 Study Variables
A.   Independent Variables, Interventions, or Predictor Variables 
Decitabine (or 5-azacytidine, in patients previously treated with decitabine) in combination with 
venetoclax is a frequently used AML therapy.  This study will introduce salicylic-salicyclic acid 
(Salsalate) as the experimental agent.  Standard doses of decitabine (20 mg/m2/d IV x 10d for the 
first cycle and 5d for cycle 2) or 5-azacytidine (75 mg/m2/d x 7d SC or IV for 1 cycle). Ramp up 
dosing of venetoclax and standard dose salsalate will be used.
B.  Dependent Variables or Outcome Measures 
Remission rate, biochemical response
1.7 Drugs/Devices/Biologics 
Product description: Salsalate (salicylic-salicylic acid is commercially available
Preparation (how the dose is to be prepared): The dose will be administered as 3 x 500 mg or 2 x 
750 mg bid for a total of 3000 mg/d orally as indicated in the treatment plan. 
Storage requirements: The tablets are stored at room temperature. 
Route of administration: Oral tablet
1.
Expected toxicities: Constipation, diarrhea, heartburn, tinnitus, nephrotoxicity, liver function test 
abnormalities, GI intolerance including abdominal pain, nausea & diarrhea, peripheral edema 
and somnolence.
Drug Interactions: no known interactions with hypomethylating agents or venetoclax; Salsalate is 
metabolized by conjugation to glycine and glucuronide metabolites 
A. Drug/Device Accountability and Storage Methods
The investigator is required to maintain adequate records of receipt, dispensing and final 
disposition of study drug.  This responsibility has been delegated to the pharmacy.  Include on 
receipt record (e.g. packing slip) from and to whom study drug was shipped, date, quantity, and 
batch or lot number.  On dispensing record, note quantities and dates study drug was dispensed 
to and returned by each subject.  Empty and partially empty containers of study drug will be 
disposed of in accordance with institutional policies and procedures.  
1.8 Specimen Collection
Exploratory studies include: (i) flow cytometric characterization of malignant cells by reactive oxygen 
species content using labeling with CELLRox; and (ii) next generation sequencing of malignant cells.  
The timing of these studies will be determined by the percentage (and total number of malignant 
cells/uL at the following time points: (i) pretreatment; (ii) after the ramp-up of venetoclax; and (iii) 
after the initiation of salsalte.  These studies are exploratory and logistics regarding cell number and 
purity are likely to determine the specific timing of studies (based on each individual patient’s blood 

13
Liver Enzymes3
X
X
X
EKG
X
Pregnancy Test4
X
X
Radiographic Assessments5
X
REDOX Blood Studies6
X (during 
first week of 
treatment)
BM asp and biopsy
X
X
Blood flow cytometry/NGS (next 
generation sequencing)7
X
X
Compliance Assessment
X
Survival8
1.
Within 1 week of enrollment.
2.
Includes: Electrolytes, Calcium, BUN, Creatinine, Total Protein, Glucose, Albumin, Total Bilirubin, Alk. 
Phosphatase, SGOT/SGPT, Uric Acid.
3.
Includes: Total and Direct. Bilirubin, AST/ALT, Alkaline Phosphatase, Albumin, Total Protein.
4.
Women of childbearing potential must have pregnancy test verified by BHCG within 1 week of 
enrollment.
5.
Radiographic assessments will be selected by the attending physician as clinically indicated and in 
accordance with the criteria for tumor measurement assessments.
6.
REDOX analysis (Dr. Herranz lab) will be done on blood samples with CD34 selected blasts at 
baseline, after ramp-up of venetoclax and after 1-2 days of SALSALATE as feasible based upon blood 
counts (leukemia cells in blood)  during first cycle
7.
NGS from BM will be done at baseline and after the second cycle or on any BM performed for clinical 
reasons. NGS or Single cell DNA sequencing may also be done by Dr. Khiabanian as feasible from 
blood based upon disease status and resources.
8.    Disease status and survival status will documented every 2 months until disease progression or start 
of new treatment.
2.0 Project Management
2.1 Research Staff and Qualifications
Study personnel are experts in designing and running clinical trials and do so as part of their positions 
at Rutgers
2.2 Research Staff Training

15
Patients must have an ECOG performance status ≤2 (Appendix A).
Patients must have normal organ function as defined below:
o
Total bilirubin < 2 x ULN
o
AST(SGOT)/ALT(SGPT) <2.5 X institutional ULN
o
Creatinine clearance > 30 ml/min 
Exclusion Criteria
A patient /subject will not be eligible for this study if any of the following exclusion criteria 
are met.
WBC uncontrolled (>15,000/uL) despite hydroxyurea x 5 days (see below).
Known CNS AML.
Serious concomitant systemic disorders (including active infections) that would 
compromise the safety of the patient or compromise the patient’s ability to complete the 
study, at the discretion of the investigator. Pregnant patients are excluded.
Age <18 years.  Because no dosing or adverse event data are currently available on the 
use of Salsalate in combination with venetoclax and decitabine in patients <18 years of 
age, children are excluded from this study.  Salicylates have also been associated with 
Reyes syndrome in pediatric patients. 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to Salsalate or other agents used in the study.  Examples include aspirin.
The effects of venetoclax and decitabine or 5-azacytidine on the developing human fetus 
at the recommended therapeutic dose are unknown.  For this reason and because 
therapeutic agents used in this trial are known to be teratogenic, women of child-bearing 
potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry, for the duration of study 
participation and for 24 weeks after.  Should a woman become pregnant or suspect she 
is pregnant while participating in this study, she should inform her treating physician 
immediately.
Patients with immune deficiency are at increased risk of lethal infections when treated 
with marrow-suppressive therapy, therefore, known HIV-positive patients receiving 
combination anti-retroviral therapy are excluded from the study because of possible 
pharmacokinetic interactions with treatment medications or other agents administered 
during the study.  
4.3 Number of Subjects
A. Total Number of Subjects
Twenty at Rutgers CINJ. Total = 20 patients.
C. Feasibility

16
Based on the number of patients seen at CINJ/RWJUH with AML, MPN, or MDS meeting recruitment 
goals within the timeframe is expected. 
4.4 Consent Procedures
A. Consent Process
Informed consent will be obtained prior to commencing any research procedures.  The investigators 
will seek consent only under circumstances that provide the prospective patient opportunity to 
consider whether or not to participate and that minimizes the possibility of coercion or undue 
influence.  The information given to the patient, or the representative, shall be in a language 
understandable to the subject or representative.  The informed consent document may not include 
any exculpatory language through which the subject or representative is made to waive any of the 
subject’s legal rights or releases, or appears to release the investigator, the sponsor or the institution 
from liability for negligence
C.
Documentation of Consent

Documenting Consent
Individuals will be asked to sign an informed consent document
Waiver of Documentation Of Consent (i.e., will not obtain subject’s signature)
N/A
4.5 Special Consent/Populations
A. Minors-Subjects Who Are Not Yet Adults 
No dosing or adverse event data are currently available on the use of Salsalate in 
combination with venetoclax and decitabine in patients <18 years of age. Pediatric patients 
who receive salicylates are also at risk for Reyes syndrome. Therefore, minors will not 
participate in this study
B.
Wards of the State
N/A
C.
Non-English-Speaking Subjects

Process for Non-English-Speaking Subjects
Non English speakers will not be enrolled because this is an investigator-initiated study 
without funding source. 

Short Form Consent for Non-English Speakers
This will not be used. 
D. Adults Unable to Consent / Cognitively Impaired Adults (for interventional studies)
Those unable to consent or cognitively impaired will not be asked to enroll in this trial.
4.6 Economic Burden and/or Compensation for Subjects

17
The study is an investigator-initiated clinical trial with no financial support. Philantropic funds will be 
used to pay for study drug (SALSALATE). The additional medications are standard of care and will be 
financed based upon the patients insurance.
 
4.7 Risks of Harm/Potential for Benefits to Subjects
A. Description of Risks of Harm to Subjects
MDS, AML and related advanced myeloid disorders are life-threatening diseases.  Risks of the disease 
include bleeding, infection and organ dysfunction.  The disease is fatal with standard chemotherapy 
in > 80% patients eligible for this study over a 2 years.  The combination of venetoclax + 
hypomethylating agent therapy is a breakthrough – greatly improving response rates and, likely, also 
survival.  The potential risks of this study are that there will be toxicity from the study drug related to 
known SALSALATE toxicities (e.g tinnitus, renal insufficiency) or that it will interfere with the anti-
leukemic effect of venetoclax + hypomethylating agent.  To protect against or minimize potential risks, 
we will monitor toxicity real time and have imposed very strict stopping rules.  
B.
Potential Benefits to Subjects
SALSALATE has been safely administered to patients undergoing intense AML induction therapy.  
It is also routinely used as a supportive care medication during AML therapy. We believe it has 
the potential to enhance the anti-leukemic effects of standard venetoclax + hypomethylating 
agent therapy and improve response rates and duration of remission.  
5.0 Special Considerations
N/A
6.0 Data Management Plan
6.1 Data Analysis
1.
An unacceptable adverse event is defined as a Grade 3 study drug (SALSALATE) related or 
possibly related irreversible (i.e. doesn’t reverse within one week) event with the exception of:
a.
 Grade 3 fever, asthenia or constipation. 
b.
Grade 3 nausea, vomiting, diarrhea (not requiring tube feeding, total parenteral 
nutrition, or prolonged hospitalization; 
c.
Grade 3 infection, bleeding or expected complications of cytopenias due to leukemia or 
decitabine + venetoclax treatment; 
d.
Grade 3 or 4 tumor lysis syndrome successfully managed clinically that resolves within 7 
days without end organ damage; or
e.
Grade 3 or 4 isolated electrolyte abnormalities that last < 72 hours. 

18
We consider an adverse event rate of 7% or higher to be unacceptably high, so we will stop the trial if, at 
any point, we are 80% certain that the rate is 7% or higher.  In the following table, the shaded cells in 
the table indicate the region where we are 80% certain that the rate exceeds 7%.  
According to this table, if there is 1 unacceptable (grade 3) SALSALATE related or possibly related 
adverse event (defined above) among the first 10 patients, or if there are 2 unacceptable adverse events 
among the first 20 patients, the trial will be stopped for unacceptable toxicity.
This table was calculated using a Bayesian posterior beta distribution, assuming a uniform prior.
N patients
k: number of unacceptable toxicities
 
0
1
2
3
3
0.748052
0.973272
0.9987
0.999976
4
0.695688
0.957507
0.99692
0.999887
5
0.64699
0.939179
0.994161
0.999679
6
0.601701
0.918726
0.990312
0.999293
7
0.559582
0.896534
0.985301
0.998664
8
0.520411
0.872948
0.979088
0.997729
9
0.483982
0.84827
0.971658
0.996424
10
0.450104
0.82277
0.963021
0.99469
11
0.418596
0.796683
0.953203
0.992473
12
0.389295
0.770217
0.942247
0.989724
13
0.362044
0.743553
0.930205
0.986401
14
0.336701
0.716847
0.917139
0.982467
15
0.313132
0.690237
0.903119
0.977894
16
0.291213
0.663839
0.888217
0.97266
17
0.270828
0.637756
0.87251
0.966749
18
0.25187
0.612071
0.856078
0.960152
19
0.234239
0.586857
0.838997
0.952867
20
0.217842
0.562173
0.821347
0.944896

19
6.2 Data Security
Monitoring of this study will occur in accordance with the Cancer Institute of New Jersey’s NCI 
approved Data and Safety Monitoring Plan (DSMP).  An “initiation audit” will be conducted at the 
Cancer Institute of New Jersey in accordance with the DSMP following enrollment of the first two (2) 
or three (3) patients.  Subsequent audits will occur on an annual basis prior to annual IRB continuing 
review, if the findings from the initiation audit were satisfactory.  More frequent audits of patient 
data and study conduct will occur if necessary.  Prior audit findings and/or situations that may arise 
during the course of the study will determine the need for more frequent auditing.  All audit findings 
will be discussed with the principal investigator and reported to the Cancer Institute of New Jersey’s 
Human Research Oversight Committee and the Rutgers University Institutional Review Board. 
 
6.3 Data and Safety Monitoring
A. Data/Safety Monitoring Plan
A subset of the National Cancer Institute (NCI) CRFs, in electronic format, will be utilized.   Completion 
of the electronic CRFs (eCRFs) will be done in accordance with the instructions in a study specific data 
capture plan.  All eCRFs will be completed by clinical research coordinators of the   Office of Human 
Research Services (OHRS) at the Cancer Institute of New Jersey. The eCRFs will be maintained in a 
confidential format in a secure database.
Completion of eCRFs will occur in accordance with NCI guidelines.  Baseline (pre-study) eCRFs (e.g., 
enrollment, medical history, concomitant medications, disease assessment, etc.) will be completed 
no later than 14 days after the start of treatment.   Treatment eCRFs (e.g., drug administration, 
adverse events, chemistries, etc.) will be completed no later than 14 days following each cycle of 
treatment.  Off-treatment information (e.g., follow-up, best response, etc.) will be completed no later 
than 14 days after the end of protocol treatment.
A research chart (i.e., shadow chart) is maintained at OHRS for each patient enrolled.  Copies of 
significant study source documents will be maintained in the research chart.  Examples of source 
document copies that will be maintained in the research chart include: signed informed consent form, 
documents that verify eligibility and treatment and documents that verify Grade 3-4 adverse events 
and response. This information will be updated on a prospective basis and will be confidentially 
maintained at the Cancer Institute of New Jersey, OHRS.
Data will be analyzed weekly by the PI with review at weekly tumor study group meetings including 
research nurses assigned to the study. 
B.
Data/Safety Monitoring Board Details
 
. 
6.4 Reporting Results
A. Individual Subjects’ Results 

20
Results of investigational diagnostic tests, genetic tests, or incidental findings will not be shared 
with study participants unless that information is the same as would be shared if the patient was 
not enrolled in this trial. 
B.
Aggregate Results
Aggregate research results will not be shared with the study participants.  
C.
Professional Reporting
The policies and procedures of Rutgers University’s legal department (see: Investigator’s 
Handbook) will govern publication of the trial.  It is expected that the results of this trial will be 
submitted for publication in a timely manner following the conclusion.  The Cancer Institute of 
New Jersey PI, and all co-authors prior to submission or use, must review any abstract or 
manuscript. 
D. Clinical Trials Registration, Results Reporting and Consent Posting
This research qualifies as a clinical trial
6.5 Secondary Use of the Data   
There will be no secondary use of the data. 
7.0 Research Repositories – Specimens and/or Data
Specimens will not be stored for use other than outlined in the study.
8.0 Approvals/Authorizations
N/A
9.0 Bibliography
1.
Strair, R.K., et al., Nuclear factor-kappaB modulation in patients undergoing induction 
chemotherapy for acute myelogenous leukemia. Clin Cancer Res, 2008. 14(22): p. 7564-8.
2.
Medina, D., et al., Choline-magnesium trisalicylate modulates acute myelogenous leukemia gene 
expression during induction chemotherapy. Leuk Lymphoma, 2017. 58(5): p. 1227-1230.
3.
Sharma, P. and D.A. Pollyea, Shutting Down Acute Myeloid Leukemia and Myelodysplastic 
Syndrome with BCL-2 Family Protein Inhibition. Curr Hematol Malig Rep, 2018. 13(4): p. 256-264.
4.
Scheffold, A., B.M.C. Jebaraj, and S. Stilgenbauer, Venetoclax: Targeting BCL2 in Hematological 
Cancers. Recent Results Cancer Res, 2018. 212: p. 215-242.
5.
Pollyea, D.A., et al., Venetoclax with azacitidine disrupts energy metabolism and targets 
leukemia stem cells in patients with acute myeloid leukemia. Nat Med, 2018. 24(12): p. 1859-
1866.
6.
Battaglia, V., M. Salvi, and A. Toninello, Oxidative stress is responsible for mitochondrial 
permeability transition induction by salicylate in liver mitochondria. J Biol Chem, 2005. 280(40): 
p. 33864-72.
7.
Smith, B.K., et al., Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, 
and Reduces Liver Lipids Independent of AMPK-beta1. Diabetes, 2016. 65(11): p. 3352-3361.

21
8.
Klimek, V.M., et al., Phase I trial of sodium salicylate in patients with myelodysplastic syndromes 
and acute myelogenous leukemia. Leuk Res, 2012. 36(5): p. 570-4.
9.
Trost, L.C. and J.J. Lemasters, Role of the mitochondrial permeability transition in salicylate 
toxicity to cultured rat hepatocytes: implications for the pathogenesis of Reye's syndrome. 
Toxicol Appl Pharmacol, 1997. 147(2): p. 431-41.
10.
Pollyea, D.A. and C.T. Jordan, Why are hypomethylating agents or low-dose cytarabine and 
venetoclax so effective? Curr Opin Hematol, 2019. 26(2): p. 71-76.
11.
Choi, E.J., et al., Decitabine Versus Intensive Chemotherapy for Elderly Patients With Newly 
Diagnosed Acute Myeloid Leukemia. Clin Lymphoma Myeloma Leuk, 2019.
12.
Cerrano, M. and R. Itzykson, New Treatment Options for Acute Myeloid Leukemia in 2019. Curr 
Oncol Rep, 2019. 21(2): p. 16.
13.
Huang, L.W., et al., Updates on Hematologic Malignancies in the Older Adult: Focus on Acute 
Myeloid Leukemia, Chronic Lymphocytic Leukemia, and Multiple Myeloma. Curr Oncol Rep, 
2019. 21(4): p. 35.
14.
Rowe, J.M., Progress and predictions: AML in 2018. Best Pract Res Clin Haematol, 2018. 31(4): p. 
337-340.
15.
Nakada, D., Venetolax with Azacitidine Drains Fuel from AML Stem Cells. Cell Stem Cell, 2019. 
24(1): p. 7-8.
16.
Aldoss, I., et al., Efficacy of the combination of venetoclax and hypomethylating agents in 
relapsed/refractory acute myeloid leukemia. Haematologica, 2018. 103(9): p. e404-e407.
17.
Andreani, G., et al., Venetoclax plus decitabine induced complete remission with molecular 
response in acute myeloid leukemia relapsed after hematopoietic stem cell transplantation. Am J 
Hematol, 2019. 94(2): p. E48-e50.
18.
Bogenberger, J., et al., Combined venetoclax and alvocidib in acute myeloid leukemia. 
Oncotarget, 2017. 8(63): p. 107206-107222.
19.
DiNardo, C.D., et al., Venetoclax combined with decitabine or azacitidine in treatment-naive, 
elderly patients with acute myeloid leukemia. Blood, 2019. 133(1): p. 7-17.
20.
DiNardo, C.D., et al., Safety and preliminary efficacy of venetoclax with decitabine or azacitidine 
in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-
label, phase 1b study. Lancet Oncol, 2018. 19(2): p. 216-228.
21.
DiNardo, C.D., et al., Clinical experience with the BCL2-inhibitor venetoclax in combination 
therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies. 
Am J Hematol, 2018. 93(3): p. 401-407.
22.
El-Cheikh, J., et al., Feasibility of the Combination of Venetoclax and Asparaginase-based 
Chemotherapy for Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. Clin 
Lymphoma Myeloma Leuk, 2018. 18(10): p. e441-e444.
23.
Konopleva, M. and A. Letai, BCL-2 inhibition in AML: an unexpected bonus? Blood, 2018. 132(10): 
p. 1007-1012.
24.
Liu, B., et al., Venetoclax and low-dose cytarabine induced complete remission in a patient with 
high-risk acute myeloid leukemia: a case report. Front Med, 2018. 12(5): p. 593-599.
25.
Moukalled, N.M., et al., Feasibility of Venetoclax-based combinations for adult patients with 
acute myeloid leukemia relapsing after allogenic stem cell transplantation. Bone Marrow 
Transplant, 2018.
26.
Rahmat, L.T., et al., Venetoclax in Combination with Decitabine for Relapsed T-Cell Acute 
Lymphoblastic Leukemia after Allogeneic Hematopoietic Cell Transplant. Case Rep Hematol, 
2018. 2018: p. 6092646.

22
27.
Yogarajah, M. and R.M. Stone, A concise review of BCL-2 inhibition in acute myeloid leukemia. 
Expert Rev Hematol, 2018. 11(2): p. 145-154.
28.
Nguyen, L.X.T., et al., The Bcl-2 inhibitor venetoclax inhibits Nrf2 antioxidant pathway activation 
induced by hypomethylating agents in AML. J Cell Physiol, 2019.
29.
Mei, M., et al., Hypomethylating agents in combination with venetoclax for acute myeloid 
leukemia: Update on clinical trial data and practical considerations for use. Am J Hematol, 2019. 
94(3): p. 358-362.
1.1
Appendix A
Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
100
Normal, no complaints, no evidence 
of disease.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
80
Normal activity with effort; some 
signs or symptoms of disease.
70
Cares for self, unable to carry on 
normal activity or to do active work.

23
2
In bed <50% of the time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about 
more than 50% of waking hours.
60
Requires occasional assistance, but is 
able to care for most of his/her 
needs.
50
Requires considerable assistance and 
frequent medical care.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
40
Disabled, requires special care and 
assistance.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
20
Very sick, hospitalization indicated. 
Death not imminent.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.