Phase 2 Study of Decitabine and Cedazuridine in Combination With Venetoclax for AML Relapse After Allogeneic Hematopoietic Cell Transplantation
Phase: PHASE2
Conditions: Recurrent Acute Myeloid Leukemia
Sponsor: Sanjay Mohan

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Clinical Study Protocol 
 
VICC HEM2163 
 
Study Title: Phase 2 study of decitabine and cedazuridine in combination with 
venetoclax for AML relapse after allogeneic hematopoietic cell transplantation 
 
Study Phase: II 
 
IND Number: 157074 
 
Indication: Post-transplant acute myeloid leukemia 
 
Funding source: Funding provided by the National Comprehensive Cancer 
Network (NCCN) through a grant provided by Taiho Oncology, Inc. (Taiho). 
Neither NCCN or Taiho are sponsors of this study. 
 
Protocol Date and Version: 26 NOV 2022 Version 1.6 
 
Principal Investigator:  
Sanjay Mohan, MD 
 
 
 
 
Vanderbilt-Ingram Cancer Center  
 
 
 
 
2220 Pierce Avenue 
 
 
 
 
Preston Research Building 777 
 
 
 
 
Nashville, TN 37232 
 
 
Other Investigator(s): 
Asmita Misha, MD 
 
 
 
 
12902 Magnolia Drive 
 
 
 
 
Moffitt Cancer Center 
Tampa, FL 33612 
 
 
 

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Protocol Synopsis: 
 
Title of study: Phase 2 study of decitabine and cedazuridine in combination with 
venetoclax for AML relapse after allogeneic hematopoietic cell transplantation 
 
Indication: Post-transplant acute myeloid leukemia 
 
Study Phase: II  
 
Objectives: 
 
Primary objective: 
1. To assess the effect of DEC-C/venetoclax on the investigator-assessed 
composite CR rate (CR/CRh/CRi) 
 
Secondary objectives: 
1. To assess the rate of partial response (PR) and morphologic leukemia free 
state (MLFS) following treatment with DEC-C/venetoclax 
2. To assess the relapse free survival of patients treated with DEC-C/venetoclax 
3. To assess overall survival of patients treated with DEC-C/venetoclax 
4. To assess the safety and tolerability of DEC-C/venetoclax in the post-HCT 
setting 
5. To assess the rates of measurable residual disease negativity in patients 
achieving a CR. 
 
Background and Study Rationale: 
Acute myeloid leukemia, excluding acute promyelocytic leukemia, is generally 
associated with poor clinical outcomes. Patients with poor-risk clinical and molecular 
features experience a shortened survival with a minority surviving beyond 5 years.1,2,3,4 
Similarly, patients with high-grade myeloid malignancies, including myelodysplastic 
syndrome (MDS) and chronic myelomonocytic leukemia (CMML), are at risk for 
leukemic transformation with rates approaching 40%.5 For poor-risk patients, allogeneic 
HCT is the only potentially curative therapy, however, post-HCT relapse is common and 
as many 85% of poor-risk AML patients will experience recurrence of their underlying 
disease.6 In a registry analysis, 15% of post-HCT relapsed AML patients achieved a 
subsequent complete remission (CR). Less than 5% of patients who relapsed within 6 
months, and 12% of patients who relapsed 6-24 months after HCT were alive at 3 
years.7 
 
Dysregulation of anti-apoptotic proteins, including BCL2, is responsible for tumor 
maintenance and survival. Venetoclax is a selective BCL2 inhibitor that increases cell 
death/apoptosis in hematologic malignancies. In chronic lymphoid leukemia, a disease 
heavily reliant on the loss of apoptosis, overall response rates (ORR) exceed 80% with 
venetoclax.8 In AML, anti-apoptotic pathways are more heterogeneous. Venetoclax, in 
combination with DNMTis or low dose cytarabine, results in CR/CRi rates of 60-75% in 
the treatment naïve (TN) setting.9,10 Off-label use in the relapsed/refractory (R/R) 

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disease is an emerging treatment paradigm with an ORR of 12-51%. In a series of post-
HCT AML patients treated with venetoclax-based salvage therapies at Vanderbilt 
University Medical Center (16/21 with a DNMTi partner), we found the combination is 
safe and effective with an ORR of 42.1%.11 Interrupting therapy in patients with a 
treatment response was associated with improved safety and reduced toxicity after 
HCT. 
 
Based on our published experience, and other retrospective data in R/R AML, we plan a 
phase 2 trial to prospectively assess the ORR of venetoclax/DNMTi salvage therapy 
after allogeneic HCT.11,12,13 Partnering venetoclax with DEC-C is an intuitive extension 
of our prior work and combines the efficacy of venetoclax/DNMTi therapy with the 
convenience of an all-oral treatment regimen which will improve quality of life compared 
to conventional salvage therapies.  
 
Study Design: 
This is an open-label, non-randomized, investigator-sponsored, phase II study of 
venetoclax in combination with DEC-C in patients with myeloid diseases who relapse 
with AML after allogeneic HCT. 
 
Patient Populations: 
Adult patients, >18 years of age with relapse/progression to AML after allogeneic HCT, 
who have not previously progressed while receiving venetoclax or other BCL-2 inhibitor, 
are eligible. Subjects with active GVHD, acute or uncontrolled infections, or with white 
blood cell count >25,000/µl that cannot be controlled with hydroxyurea are not eligible.  
 
Patients who develop grade 2-4 graft versus host disease while on study will have 
treatment interrupted. Subjects will be eligible to resume therapy after GVHD returns to 
< grade 1 after discussion with the study co-chair(s). 
 
Inclusion Criteria: 
1. Age ≥18 years at the time of signing the Informed Consent Form (ICF); must 
voluntarily sign an ICF and meet all study requirements  
2. History of morphologically confirmed AML (per WHO diagnostic criteria) with 
evidence of disease recurrence (>5% blasts consistent with prior disease) that 
occurs after allogeneic HCT. Patients transplanted for another indication (e.g., 
MDS/CMML) who relapse with AML are eligible to enroll.  
3. WBC must be less than 25,000/µl for at least three days prior to C1D1 (hydroxyurea 
allowed). 
4. A bone marrow biopsy must be performed and tissue collected for entrance to the 
trial 
5. Eastern Cooperative Oncology Group Performance Status of 0 - 2  
6. Must have adequate hepatic and renal function as demonstrated by the following: 
ALT (SGPT) and/or AST (SGOT) less than or equal to 3x upper limit of normal 
(ULN); total bilirubin < 1.5 x upper limit of normal (ULN). Patients with Gilbert’s 
syndrome (hereditary indirect hyperbilirubinemia) must have a total bilirubin of < 3 x 

DEC-C/Ven in post-HCT AML 
 
 
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ULN; and calculated creatinine clearance >30 ml/min (per the Cockroft-Gault 
formula). 
7. Willingness to abide by all study requirements, including contraception, maintenance 
of a pill diary, and acceptance of recommended supportive care medications. 
 
Exclusion Criteria: 
1. Prior relapse or progression while receiving venetoclax or other commercially 
available or investigational BCL-2 inhibitor. 
2. Anticancer therapy, including investigational agents ≤2 weeks or ≤5 half-lives of the 
drug, whichever is shorter, prior to C1D1. (Use of hydroxyurea is permitted).  
3. Inadequate recovery from toxicity attributed to prior anti-cancer therapy to ≤Grade 1 
(NCI CTCAE v5.0), excluding alopecia or fatigue.  
4. History of allogeneic hematopoietic cell transplantation (HCT), or other cellular 
therapy product, within 3 months of signing consent.  
5. Clinically active acute or chronic GVHD. Patients must be off calcineurin inhibitors 
for at least 4 weeks to be eligible.  
6. Radiation therapy or major surgery within 3 weeks of signing consent.  
7. Active, uncontrolled infection. Patients with infection under active treatment and 
controlled with antibiotics are eligible. Prophylaxis is acceptable. 
8. Inability to tolerate oral medication, presence of poorly controlled gastrointestinal 
disease, or dysfunction that could affect study drug absorption. 
9. Active documented central nervous system leukemia 
10. Concurrent treatment with a non-permitted concomitant medication. 
11. Other malignancy IF currently being treated or likely to be treated in next 6 months 
except for basal or squamous cell carcinoma of the skin or cervical carcinoma in 
situ. 
12. Pregnancy or breastfeeding females 
13. Known chronic alcohol or drug abuse 
14. Clinically significant cardiovascular disease with major event or cardiac intervention 
within the past 6 months (e.g. percutaneous intervention, coronary artery bypass 
graft, documented cardiac heart failure) as determined by the investigator 
15. Any other condition deemed by the investigator to make the patient a poor candidate 
for clinical trial and/or treatment with investigational agents. 
 
Dosing Rationale:  
At dose level one, subjects will receive escalating doses of venetoclax during a “ramp” 
phase to a maximum dose of 400mg/day, and then continuously thereafter. This dose 
was chosen based on the clinical trial dosing in combination with a DNMTi partner. 
DEC-C will be dosed at decitabine 35mg and cedazuridine 100mg per day on days 1-5 
which is consistent with prior study data and approval. Cycles are every 28 days.  
 
Study Duration:  
It is estimated that this study will enroll patients from January 2022 through January 
2024. Data lock and study closure is expected in January 2025. 
 

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Statistical Analysis: 
Assuming a historical ORR of 15%, per the phase II efficacy trial, Simon’s optimal two-
stage design calls for a total of 34 patients. A preliminary efficacy assessment will be 
performed following enrollment of the first 20 patients. If >3/20 enrolled patients achieve 
a CR, this is sufficient to continue enrollment for the remainder of the study. If >9/34 
patients respond, we will reject (p<0.05) the null hypothesis that the true response rate 
of the regimen is less than or equal to 15%. If the true response rate is 35% or greater, 
this study design has 80% probability of rejecting the null hypothesis. If the true 
response rate is low at 15%, the probability of early termination is 60% with an expected 
sample size of 19 patients. 
 
Toxicity will be monitored in the expansion phase using a Bayesian approach.  Toxicity 
monitoring will begin when the 6th patient is evaluable for toxicity. It is expected that the 
toxicity rate is maintained at approximately 20% (maximum probability of DLT of 0.2, 
prior distribution (1,1), cohort size 1, and posterior probability > 80%). Enrollment will be 
paused if toxicity exceeds this rate.  
 
The maximum number of patients enrolled (n=51) reflects an anticipated drop out of 
15% (n=5) and enrollment of 6-12 additional patients if dose level 0 is deemed toxic. 
 
 
 
 
 
 

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Table 1: Schedule of Activities and Assessments – Screening & Cycle 1 
Protocol Activities 
1 Cycle = 4 weeks (28 days) 
Screening 
(Day-14  
to -1) 
CYCLE 1 
Day 1-3 
Day 5 
Day 8 
Day 15 
Day 22 
 
Clinical Assessments 
Consent, Baseline Characteristics & Eligibility1 
X 
 
 
 
 
 
Physical Exam 
X 
X14 
 
X 
X 
X 
ECOG Performance Status 
X 
X14 
 
 
 
 
Height 
X 
 
 
 
 
 
Weight 
X 
X14 
 
X 
X 
X 
Vital Signs (BP, HR & Temp)2 
X 
X 
X 
X 
X 
X 
Review of Con Meds & Adverse Events3 
X 
X 
X 
X 
X 
X 
DLT/RP2D Safety Evaluation4 
 
X 
X 
X 
X 
X 
 
Laboratory and Other Assessments 
CBC with Differential5 
X 
X 
X 
X 
X 
X 
Serum Chemistry5 
X 
X 
X 
X 
X 
X 
Mg, Phos, LDH, Uric Acid 
X 
X 
X 
X 
 
 
Coagulation Testing (PT/INR, PTT) 
X 
 
 
 
 
 
Electrocardiogram6 
X 
 
 
 
 
 
Pregnancy Test7 
X 
X7 
 
 
 
 
 
Biospecimen Collections 
Bone marrow aspiration and biopsy8 
X 
 
 
 
 
X15 
Pharmacodynamic Blood (PD)9 
X 
 
 
 
 
X 
Next Generation Sequencing10 
X 
 
 
 
 
X 
 
Treatment 
Anti-TLS hydration/prophylaxis11 
X 
X 
 
 
 
 
Decitabine/cedazuridine (oral)12 
 
X 
X 
 
 
 
Venetoclax oral administration (daily)13 
 
Ramp 
Continuous once daily oral dosing13 
 
 

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Table 2: C1D22 Marrow involved: 
Protocol Activities 
1 Cycle = 4 weeks (28 days) 
PRE-REMISSION THERAPY 
POST-REMISSION THERAPY16 
POST-TREATMENT 
CYCLE 2 
CYCLE 1 
CYCLE 2 
CYCLE 3+ 
EOT 
(≤10d after 
last study 
dose)17 
Follow-Up 
(28d + 7d 
after last 
study dose)19 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1, 5 
Day 
15 
Day 1 
Day 15 
Day 1 
 
Clinical Assessments 
Physical Exam 
X 
 
X 
 
d1 
 
X 
 
X 
X 
X 
ECOG Performance Status 
X 
 
 
 
d1 
 
X 
 
X 
X 
X 
Height 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
d1 
 
X 
 
X 
X 
X 
Vital Signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of Con Meds & Adverse Events3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DLT/RP2D Safety Evaluation4 
X 
 
 
 
 
 
 
 
 
 
 
Survival Follow-Up 
 
 
 
 
 
 
 
 
 
 
X20 
 
Laboratory and Other Assessments 
CBC with Differential5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Mg, Phos, LDH, Uric Acid 
 
 
 
 
 
 
 
 
 
X 
 
Coagulation Testing (PT/INR, PTT) 
 
 
 
 
 
 
 
 
 
X 
 
Electrocardiogram6 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy Test7 
 
 
 
 
 
 
 
 
 
X 
 
 
Biospecimen Collections 
Bone marrow aspiration and biopsy8 
 
 
 
X15 
 
 
 
 
C3d1 
EOT / PD18 
 
Pharmacodynamic Blood (PD)9 
 
 
 
X 
 
 
 
 
 
EOT / PD18 
 
Next Generation Sequencing10 
 
 
 
X 
 
 
 
 
C3d1 
EOT / PD18 
 
 
Treatment 
Decitabine/cedazuridine (RP2D)12 
 
 
 
 
Per Protocol 
 
Per Protocol 
 
Per Protocol 
 
 
Venetoclax oral administration (daily)13 
Per protocol 
 
 
 
 
 
 

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Table 3: C1D22 Marrow uninvolved:  
Protocol Activities 
1 Cycle = 4 weeks (28 days) 
POST-REMISSION THERAPY16 
POST-TREATMENT 
CYCLE 1 
CYCLE 2 
CYCLE 3+ 
EOT 
(≤10d after last 
study dose)17 
Follow-Up 
(28d + 7d after 
last study dose)19 
Day 1, 5 
Day 15 
Days 1, 5 
Day 15 
Day 1 
 
Clinical Assessments 
Physical Exam 
d1 
 
d1 
 
X 
X 
X 
ECOG Performance Status 
d1 
 
d1 
 
X 
X 
X 
Height 
 
 
 
 
 
 
 
Weight 
d1 
 
d1 
 
X 
X 
X 
Vital Signs2 
X 
X 
X 
X 
X 
X 
X 
Review of Con Meds & Adverse Events3 
X 
X 
X 
X 
X 
X 
X 
DLT/RP2D Safety Evaluation4 
d1 
 
 
 
 
 
 
Survival Follow-Up 
 
 
 
 
 
 
X20 
 
Laboratory and Other Assessments 
CBC with Differential5 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry5 
X 
X 
X 
X 
X 
X 
X 
Mg, Phos, LDH, Uric Acid 
 
 
 
 
 
X 
 
Coagulation Testing (PT/INR, PTT) 
 
 
 
 
 
X 
 
Electrocardiogram6 
 
 
 
 
 
X 
 
Pregnancy Test7 
 
 
 
 
 
X 
 
 
Biospecimen Collections 
Bone marrow aspiration and biopsy8 
 
 
 
 
C3d1 
EOT / PD18 
 
Pharmacodynamic Blood (PD)9 
 
 
 
 
 
EOT / PD18 
 
Next Generation Sequencing10 
 
 
 
 
C3d1 
EOT / PD18 
 
 
Treatment 
Decitabine/cedazuridine (RP2D)12 
Per Protocol 
 
Per Protocol 
 
Per Protocol 
 
 
Venetoclax oral administration (daily)13 
Per protocol 
 
 
 
 
 
 

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Notes: 
1. Informed consent must be obtained before any screening assessments are performed. Screening assessments are to 
be performed within 14 days prior to Day 1 of Cycle 1 unless otherwise noted. Assessments performed as standard of 
care within the screening window may be used for screening. Baseline characteristics include but are not limited to 
demographics, medical and surgical history, extent of disease, prior anti-cancer treatment. 
2. Vital Signs to include: Blood pressure (BP), heart rate (HR) and temperature. To be done at least once on days 
indicated and thereafter, ideally prior to any receipt of study drug. Any additional recordings per local site’s standard 
of care/ treating physician discretion. 
3. Review and capture of all concomitant medications will be performed as indicated. Concomitant medications include 
prescription medications and over-the-counter preparations used by a patient within at least 14 days prior to first dose 
of protocol-defined treatment and continuing through at least the 28-day Follow-Up study visit. After signing informed 
consent, adverse events will be collected and followed at least until 28 days after a patient’s final protocol-directed 
treatment with DEC-C/venetoclax (whichever occurs last) or until initiation of another anti-cancer therapy – whichever 
occurs first. 
4. Surveillance for toxicity related to DEC-C/venetoclax to establish RP2D. For patients enrolled in the dose exploration 
(or dose de-escalation) part of the study, dedicated surveillance including satisfactory assessment of the physical 
exam and safety labs is required to help detect evidence of past or present DLT as having occurred during the first 28 
days of protocol-indicated treatment. Expedited reporting of Dose Limiting Toxicity (DLT) required as outlined in 
Section 5.2.4. See Section 5.2.4 for definition of DLT and toxicities which, if experienced during the first 28 days after 
initiating protocol-indicated treatment, shall be considered dose limiting.  
5. Hematology includes white blood cell count with differential, hemoglobin, hematocrit, and platelet count. Blood 
Chemistry to include sodium, potassium, chloride, bicarbonate or carbon dioxide, blood urea nitrogen (BUN), 
creatinine, glucose, total bilirubin, AST, ALT, alkaline phosphatase, calcium, albumin, and total protein.  
6. One standard 12-lead electrocardiogram (ECG) using local site equipment during screening and EOT visits. 
Additional ECGs as clinically indicated. 
7. For women of childbearing potential: Serum pregnancy test required during screening and either serum or urine 
pregnancy test required ≤3 days prior to first dose of protocol-indicated treatment and at End-of-Treatment. A woman 
of childbearing potential is defined as any female who has experienced menarche who has not undergone surgical 
sterilization (e.g. bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy) at least 4 weeks prior to first 
dose of protocol-indicated treatment, or who is not postmenopausal. Menopause is defined clinically as 12 months of 
amenorrhea in a woman over 45 in the absence of other biological or physiological causes.  
8. Patients must have at least 2-3 mL of bone marrow aspirate material obtained within 14 days of beginning treatment 
on this study. Post-enrollment tissue to be collected on Cycle 1 Day 22, Cycle 2 Day 22 (only if C1 Day 22 marrow is 

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involved), post-remission Cycle 3 Day 1 (acceptable windows up to 3 days before or after); and at End-of-Treatment 
(≤14 days after treatment was discontinued) or at time of suspected progressive disease. 
9. On a day of a bone marrow biopsy, matching peripheral blood pharmacodynamic (PD) blood samples are to be drawn 
PRIOR to procedure for correlative research. At any time during the study, if additional biopsy is performed as 
standard-of-care, then a sample of the tissue, if available, may be requested for research purposes. 
Pharmacodynamic studies will be drawn to assess the impact of DEC-C/venetoclax on immune function/recovery 
during treatment and correlated with clinical/study outcomes.  
10. All patients will have next generation sequencing (NGS) performed on their relapsed marrow and all subsequent 
marrows performed while on study. If the standard of care NGS report is available prior to enrollment, this should not 
be repeated. If NGS testing is not indicated per the institutional standard of care, additional bone marrow aspirate 
may be sent to VUMC and NGS will be performed as a research test.  
11. During the first three days of therapy, tumor lysis syndrome (TLS) precautions will include scheduled outpatient visits 
with TLS laboratory studies. Therapy with a uric acid reducing agent (e.g., allopurinol initiated at least 2-3 days prior 
to the start of therapy) is required. Laboratory monitoring for TLS (per institution standard of care) will occur prior to 
the first dose on cycle 1 day 1 and continue for the first three days of cycle 1. Unless contraindicated, allopurinol must 
be continued through the end of cycle 1. Intravenous fluids should be administered daily during the ramp-up period. 
Patients with clinical evidence of TLS should be hospitalized. 
12. The study will provide decitabine/cedazuridine (DEC-C) to the sites. Treatment with DEC-C will begin on Cycle 1 Day 
1 after receiving anti-TLS hydration/prophylaxis. It is intended that patients will receive DEC-C until progression of 
disease, unacceptable toxicity, revocation of consent, or for up to 12 months of post-remission therapy. DEC-C is to 
be taken without food at the same time each day. See Section 5.2.1.2. 
13. Sites will obtain commercial (standard of care) venetoclax. Venetoclax will begin on Cycle 1 Day 1 after receiving anti-
TLS hydration/prophylaxis. Venteoclax dosing is ramped to 400mg/day. It is intended that patients will receive 
venetoclax until progression of disease, unacceptable toxicity, revocation of consent, or for up to 12 months of 
maintenance. Venetoclax is taken with food at the same time each day. See Section 5.2.1.1. 
14. On Cycle 1, Day 1 only: Physical exam; ECOG performance status; and weight will be obtained unless performed 
within the prior 7 days. Confirmation of a negative pregnancy test is required in all women of childbearing potential 
prior to beginning protocol-directed therapies.  
15. All patients will undergo bone marrow aspiration and biopsy on cycle 1 day 22 to assess treatment response and for 
correlative studies. Patients with at least a partial response (PR) to treatment who receive a second cycle of full-
intensity therapy will have repeat biopsy at cycle 2 day 22. Aspirate and matching PD blood samples will be sent for 
correlative studies. 

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16. Beginning in the post-remission phase: To accommodate scheduling, Day 1 and 15 visits/procedures may occur with 
flexibility of ± 3 days. 
17. Reasonable effort should be made to complete End-of-Treatment (EOT) procedures on the day it is decided a patient 
will no longer receive protocol-indicated treatment. These procedures must be completed subsequent to and not later 
than 10 days after investigator decision to permanently discontinue protocol-indicated treatment with DEC-C or 
venetoclax (whichever treatment occurs last) and prior to any subsequent anti-cancer therapy. 
18. At End-of-Treatment: If patient discontinues study treatment for reason other than progressive disease confirmed by 
biopsy procedure (e.g. due to adverse event), then every effort should be made to obtain fresh biopsy samples to 
evaluate response and to obtain biospecimens including matching PD blood samples for exploratory research. If 
progressive disease is suspected between scheduled study biopsies (e.g. due to peripheral blood counts), then fresh 
biopsy and PD blood samples must be collected in a subsequent procedure to evaluate for progressive disease and 
to obtain bio specimens for research purposes; if progressive disease is confirmed in that procedure and the patient 
will terminate the study as a result, then these procedures may be used as the end of treatment procedures. 
19. Follow-up clinic visit to be completed within 28 to 35 days after patient’s final protocol-indicated treatment with DEC-C 
or venetoclax (whichever occurs last). Documented attempt(s) must be made for patient return to the study clinic. It 
will not be considered a protocol deviation if the patient is physically unable to return for the follow-up visit; such 
circumstance should be recorded in the study documents, and as much of the follow-up information as possible 
should be obtained from local and outside facilities. Note: The study may continue to request results of laboratory 
data conducted outside of the study but related to peripheral blood counts or bone marrow biopsy, until progressive 
disease is ultimately confirmed. 
20. Each patient will be followed for survival every 3 months (± 14 days) after patient’s final protocol treatment with DEC-
C or venetoclax (whichever occurs last) until death, end of the study, until patient withdraws consent, or for a 
maximum of 2 years after the patient’s final protocol-indicated treatment – whichever comes first. Survival contact can 
be made via clinic visit, chart review, obituary or similar observation (e.g. Social Security death index), or by 
telephone. 
 
 
 
 

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Figure 1: Study Schema – Pre-Remission Phase. All patients will initiate therapy as outlined below. Patients who achieve 
a leukemia free state on bone marrow biopsy may interrupt therapy and will proceed to the post-remission phase of the 
study.  
 
 
 
 
 

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Figure 2: Study Schema – Initiation of post-remission therapy. Post-remission treatment will begin after patients with 
marrow aplasia recover counts (defined as absolute neutrophil count >1,000/µl and platelets >50,000/µl). In the setting of 
bone marrow aplasia and > Grade 2 neutropenia/thrombocytopenia, a BMBx will be performed every six weeks until count 
recovery or evidence of recurrent disease. If the day 22 bone marrow biopsy is cellular but negative for leukemia, and 
there is concern for persistent disease, post-remission therapy may begin without interruption. 
 
 

Contents 
1 
INTRODUCTION .......................................................................................................................................... 17 
 
BACKGROUND ................................................................................................................................................... 17 
1.1.1 
Venetoclax ........................................................................................................................................... 17 
1.1.2 
Clinical Experience ............................................................................................................................... 18 
1.1.3 
Efficacy ................................................................................................................................................. 19 
1.1.4 
Safety ................................................................................................................................................... 19 
 
ORAL DECITABINE AND CEDAZURIDINE (DEC-C) ....................................................................................................... 20 
1.2.1 
Clinical Experience ............................................................................................................................... 21 
1.2.2 
Efficacy ................................................................................................................................................. 21 
1.2.3 
Safety ................................................................................................................................................... 22 
 
STUDY RATIONALE .............................................................................................................................................. 22 
1.3.1 
Dose Schedule and Rationale ............................................................................................................... 22 
2 
STUDY OBJECTIVES ..................................................................................................................................... 23 
 
PRIMARY OBJECTIVES: ......................................................................................................................................... 23 
 
SECONDARY OBJECTIVES: ..................................................................................................................................... 23 
3 
STUDY DESIGN ............................................................................................................................................ 23 
 
OVERALL STUDY DESIGN AND PLAN ....................................................................................................................... 23 
 
STUDY DURATION AND DATES .............................................................................................................................. 24 
4 
STUDY POPULATION SELECTION ................................................................................................................. 24 
 
STUDY POPULATION............................................................................................................................................ 24 
 
INCLUSION CRITERIA: .......................................................................................................................................... 24 
 
EXCLUSION CRITERIA: .......................................................................................................................................... 25 
5 
STUDY TREATMENTS .................................................................................................................................. 25 
 
TREATMENTS ADMINISTERED ................................................................................................................................ 25 
5.1.1 
Tumor Lysis Syndrome Prophylaxis ...................................................................................................... 25 
5.1.2 
Study Treatments ................................................................................................................................. 26 
 
STUDY DRUG DOSING AND ADMINISTRATION .......................................................................................................... 26 
5.2.1 
Dosing Instructions for Patients ........................................................................................................... 26 
5.2.2 
Dose Schedules for Evaluation (Pre-remission Phase only) .................................................................. 28 
5.2.3 
Toxicity Grading ................................................................................................................................... 29 
5.2.4 
Dose-Limiting Toxicity .......................................................................................................................... 29 
5.2.5 
Safety Cohort Review ........................................................................................................................... 32 
5.2.6 
Supportive Care and Dose Reduction Guidelines ................................................................................. 32 
5.2.7 
Dose modifications............................................................................................................................... 35 
5.2.8 
Conditions Not Requiring Dose Reduction ........................................................................................... 37 
5.2.9 
Venetoclax/DEC-C Dose Reduction for Decreased Glomerular Filtration Rate .................................... 37 
5.2.10 
Supportive Care Recommendations for TEAEs/potential Adverse Drug Reactions occurring in 
conjunction with venetoclax............................................................................................................................... 37 
5.2.11 
Concomitant Medication and Treatment ........................................................................................ 37 
5.2.12 
Contraception requirements ........................................................................................................... 38 
5.2.13 
Off-Treatment Criteria .................................................................................................................... 39 
 
RESTRICTIONS AND PROHIBITED MEDICATIONS ........................................................................................................ 39 
5.3.1 
Antifungal prophylaxis ......................................................................................................................... 40 
 
MEDICATION STORAGE ........................................................................................................................................ 40 

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STUDY DRUG ACCOUNTABILITY ............................................................................................................................. 40 
TREATMENT COMPLIANCE ............................................................................................................................................. 41 
6 
STUDY PROCEDURES ................................................................................................................................... 42 
 
ENROLLMENT PROCEDURES .................................................................................................................................. 42 
 
DEFINITIONS ...................................................................................................................................................... 44 
6.2.1 
Adverse Event (AE) ............................................................................................................................... 44 
6.2.2 
Serious adverse event (SAE) ................................................................................................................. 44 
6.2.3 
Expectedness ........................................................................................................................................ 44 
6.2.4 
Attribution............................................................................................................................................ 44 
 
REPORTING PROCEDURES..................................................................................................................................... 45 
6.3.1 
General Considerations ........................................................................................................................ 45 
6.3.2 
Serious Adverse Events ........................................................................................................................ 46 
6.3.3 
Institutional Review Board ................................................................................................................... 46 
6.3.4 
Food and Drug Administration (FDA) ................................................................................................... 47 
6.3.5 
Reporting to Grantor and Funder ........................................................................................................ 47 
7 
STUDY ACTIVITIES ....................................................................................................................................... 49 
 
DESCRIPTION OF PROCEDURES .............................................................................................................................. 49 
7.1.1 
Informed Consent ................................................................................................................................. 49 
7.1.2 
Medical History .................................................................................................................................... 49 
7.1.3 
Physical Examination, Vital Signs, Height/Weight, and ECOG Score ................................................... 49 
7.1.4 
Concomitant Medications .................................................................................................................... 50 
7.1.5 
Safety Assessments .............................................................................................................................. 50 
7.1.6 
Clinical Laboratory Tests ...................................................................................................................... 50 
7.1.7 
Electrocardiography ............................................................................................................................. 51 
7.1.8 
Pregnancy Test ..................................................................................................................................... 51 
7.1.9 
Bone marrow aspiration and biopsy .................................................................................................... 51 
7.1.10 
Pharmacodynamic (PD) Blood Samples .......................................................................................... 52 
 
SCREENING (DAY -14 TO DAY -1) .......................................................................................................................... 52 
7.2.1 
Screening Procedures ........................................................................................................................... 52 
7.2.2 
Screen Failures ..................................................................................................................................... 53 
 
CYCLE 1 (PRE-REMISSION THERAPY) ...................................................................................................................... 53 
7.3.1 
Cycle 1, Day 1 ....................................................................................................................................... 53 
7.3.2 
Cycle 1, Day 2, 3, & 5 ........................................................................................................................... 53 
7.3.3 
Cycle 1, Day 8 ....................................................................................................................................... 53 
7.3.4 
Cycle 1, Day 15 ..................................................................................................................................... 54 
7.3.5 
Cycle 1, Day 22 ..................................................................................................................................... 54 
 
CYCLE 2 (PRE-REMISSION THERAPY; ONLY IF C1D22 MARROW IS INVOLVED) ................................................................. 54 
7.4.1 
Cycle 2, Day 1 ....................................................................................................................................... 54 
7.4.2 
Cycle 2, Day 8 ....................................................................................................................................... 55 
7.4.3 
Cycle 2, Day 15 ..................................................................................................................................... 55 
7.4.4 
Cycle 2, Day 22 ..................................................................................................................................... 55 
 
POST-REMISSION CYCLE 1 (IF REMISSION CONFIRMED/COUNTS RECOVERED) .................................................................. 55 
7.5.1 
Post-remission Cycle 1, Day 1 .............................................................................................................. 55 
7.5.2 
Post-remission Cycle 1, Day 5 .............................................................................................................. 56 
7.5.3 
Post-remission Cycle 1, Day 15 ............................................................................................................ 56 
 
POST-REMISSION CYCLE 2 (IF REMISSION CONFIRMED/COUNTS RECOVERED) .................................................................. 56 
7.6.1 
Post-remission Cycle 2, Day 1 .............................................................................................................. 56 
7.6.2 
Post-remission Cycle 2, Day 5 .............................................................................................................. 56 
7.6.3 
Post-remission Cycle 2, Day 15 ............................................................................................................ 56 
 
POST-REMISSION CYCLE 3 (ONLY IF REMISSION CONFIRMED/COUNTS RECOVERED) .......................................................... 57 
7.7.1 
Post-remission Cycle 3, Day 1 .............................................................................................................. 57 

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POST-REMISSION CYCLE 4+ (IF REMISSION CONFIRMED/COUNTS RECOVERED) ................................................................ 57 
7.8.1 
Post-remission Cycle 4+, Day 1 ............................................................................................................ 57 
7.8.2 
End of Treatment (≤ 10 days after last dose of study treatment) ........................................................ 57 
 
28 DAY FOLLOW-UP VISIT ASSESSMENTS ................................................................................................................ 58 
 
SURVIVAL FOLLOW-UP .................................................................................................................................... 58 
8 
CORRELATIVE STUDIES ................................................................................................................................ 59 
 
SPECIFIC AIMS ................................................................................................................................................... 59 
 
STUDY METHODS: ............................................................................................................................................... 59 
8.2.1 
Assess the phenotypic and functional changes of post-HCT DEC-C/ venetoclax therapy on B and T cell 
subsets 59 
8.2.2 
Correlate changes in B and T cell subsets with clinical data, including DEC-C/venetoclax dosing 
schedules and patient characteristics. ............................................................................................................... 60 
9 
PLANNED STATISTICAL METHODS: .............................................................................................................. 60 
 
GENERAL CONSIDERATIONS .................................................................................................................................. 60 
 
DISEASE ASSESSMENTS ........................................................................................................................................ 60 
 
DOSE DE-ESCALATION DESIGN .............................................................................................................................. 60 
9.3.1 
General Analysis Considerations .......................................................................................................... 61 
9.3.2 
Adverse Events ..................................................................................................................................... 61 
9.3.3 
Laboratory Data ................................................................................................................................... 62 
9.3.4 
Vital Signs and Physical Examinations ................................................................................................. 62 
10 
REGULATORY AND ETHICAL COMPLIANCE .................................................................................................. 63 
 
PROTOCOL REVIEW AND AMENDMENTS ............................................................................................................. 63 
 
INFORMED CONSENT ...................................................................................................................................... 63 
 
ETHICS AND GOOD CLINICAL PRACTICE .............................................................................................................. 64 
 
CONFIDENTIALITY .......................................................................................................................................... 64 
 
STUDY TERMINATION ..................................................................................................................................... 64 
 
MULTI-CENTER GUIDELINES ............................................................................................................................ 64 
10.6.1 
Protocol Review and Amendments ................................................................................................. 64 
10.6.2 
Study Documentation ...................................................................................................................... 65 
10.6.3 
Records Retention ........................................................................................................................... 65 
10.6.4 
Publication ...................................................................................................................................... 66 
10.6.5 
Administrative and Regulatory Requirements ................................................................................ 66 
10.6.6 
Auditing and Monitoring: ................................................................................................................ 66 
10.6.7 
Data Handling and Record Keeping ................................................................................................ 67 
10.6.8 
Data Verification ............................................................................................................................. 67 
10.6.9 
Study Closure ................................................................................................................................... 67 
10.6.10 
Protocol Deviations ......................................................................................................................... 67 
10.6.11 
Changes to Protocol and Informed Consent Document .................................................................. 68 
11 
REFERENCES: .............................................................................................................................................. 68 
APPENDIX 1: EXCLUDED AND CAUTIONARY MEDICATIONS AND DIETARY RESTRICTIONS.................................... 70 
 
 
 
 
 

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1 
INTRODUCTION 
 
Background 
Acute myeloid leukemia, excluding acute promyelocytic leukemia, is generally 
associated with poor clinical outcomes. Patients with poor-risk clinical and molecular 
features experience a shortened survival with a minority surviving beyond 5 years.1,2,3,4 
Similarly, patients with high-grade myeloid malignancies, including myelodysplastic 
syndrome (MDS) and chronic myelomonocytic leukemia (CMML), are at risk for 
leukemic transformation with rates approaching 40%.5 For poor-risk patients, allogeneic 
HCT is the only potentially curative therapy, however, post-HCT relapse is common and 
as many 85% of poor-risk AML patients will experience recurrence of their underlying 
disease.6 In a registry analysis, 15% of post-HCT relapsed AML patients achieved a 
subsequent complete remission (CR). Less than 5% of patients who relapsed within 6 
months, and 12% of patients who relapsed 6-24 months after HCT were alive at 3 
years.7 
 
Dysregulation of anti-apoptotic proteins, including BCL2, is responsible for tumor 
maintenance and survival. Venetoclax is a selective BCL2 inhibitor that increases cell 
death/apoptosis in hematologic malignancies. In chronic lymphoid leukemia, a disease 
heavily reliant on the loss of apoptosis, overall response rates (ORR) exceed 80% with 
venetoclax.8 In AML, anti-apoptotic pathways are more heterogeneous. Venetoclax, in 
combination with DNMTis or low dose cytarabine, results in CR/CRi rates of 60-75% in 
the treatment naïve (TN) setting.9,10 Off-label use in the relapsed/refractory (R/R) 
disease is an emerging treatment paradigm with an ORR of 12-51%. In a series of post-
HCT AML patients treated with venetoclax-based salvage therapies at Vanderbilt 
University Medical Center (16/21 with a DNMTi partner), our group reported that the 
combination is safe and effective with an ORR of 42.1%.11 Interrupting therapy in 
patients with a treatment response improved safety and reduced toxicity after HCT. 
 
Based on our published experience, and other retrospective data in the R/R AML, this 
phase 2 trial will prospectively assess the ORR of venetoclax/DNMTi salvage therapy 
after allogeneic HCT.11,12,13 Partnering venetoclax with DEC-C combines the efficacy of 
venetoclax/DNMTi therapy with the convenience of an all-oral treatment regimen which 
will reduce the burden of treatment relative to conventional salvage therapies.  
1.1.1 
Venetoclax 
Venetoclax (also referred to as ABT-199 and GDC-0199) is a selective and orally 
bioavailable small-molecule inhibitor of BCL-2, an anti-apoptotic protein. 
Overexpression of BCL-2 has been demonstrated in CLL cells where it mediates tumor 
cell survival and has been associated with resistance to chemotherapeutics. 
 
Venetoclax helps restore the process of apoptosis by binding directly to the BCL-2 
protein, displacing pro-apoptotic proteins like BIM, triggering mitochondrial outer 

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membrane permeabilization and the activation of caspases. In nonclinical studies, 
venetoclax has demonstrated cytotoxic activity in tumor cells that overexpress BCL-2.14 
 
Antiapoptotic Bcl-2 family members are associated with tumor initiation, disease 
progression, and chemotherapy resistance, as well as autoimmunity. Overexpression of 
Bcl-2 is a major contributor to the pathogenesis of some lymphoid malignancies; 
antagonism of the action of these proteins may enhance response to therapy and 
overcome resistance, and thus, these proteins are compelling targets for anti-tumor 
therapy.15 
 
Venetoclax was first approved in the United States (US) on 11 April 2016 through 
accelerated approval for a New Drug Application (NDA) by the Food and Drug 
Administration (FDA). On 08 June 2018, the US FDA approved venetoclax in 
combination with rituximab therapy and the venetoclax expanded monotherapy. This 
approval confirmed the clinical benefit of venetoclax in the relapsed or refractory (R/R) 
chronic lymphocytic leukemia (CLL) population with or without deletion of the p13 
locus on chromosome 17 (17p del); thus the initial accelerated approval has been 
converted to a full approval. On 21 November 2018, venetoclax in the US was granted 
accelerated approval for the treatment of acute myeloid leukemia AML (in combination 
with azacitidine/ decitabine or low-dose cytarabine).9,10,14 On 15 May 2019, the US FDA 
approved venetoclax in combination with obinutuzumab for treatment of previously 
untreated patients with CLL or SLL. 
 
In the US, venetoclax is indicated for the treatment of adult patients with CLL or small 
lymphocytic lymphoma (SLL). In addition, it is approved in combination with azacitidine 
or decitabine or low dose cytarabine (LDAC) for the treatment of newly diagnosed AML 
in adults who are age 75 years or older, or who have comorbidities that preclude use of 
intensive induction chemotherapy.  
1.1.2 
Clinical Experience 
As of 28 November 2020, on the basis of data available in the clinical databases for 
company-sponsored studies with unblinded data, a total of 4599 subjects have been 
exposed to at least 1 dose of venetoclax across company-sponsored studies. Of these 
subjects: 4203 oncology subjects, 299 healthy volunteers, 24 subjects with hepatic 
impairment, and 73 SLE subjects. Of the 4203 oncology subjects, 4101 were adults in 
the venetoclax oncology program (1199 in monotherapy studies and 2902 in 
combination therapy studies): 1684 with CLL/SLL, 1011 with AML, 498 with MM, 573 
with NHL/MCL, 181 with MDS, and 57 with ALL/LL, and 10 with solid tumors. The 
remaining oncology subjects included 102 pediatric subjects in the venetoclax program 
and 74 oncology subjects in studies conducted with other investigational new drug (IND) 
compounds outside the venetoclax program.  
 

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1.1.3 
Efficacy 
Efficacy data indicates that venetoclax has anti-tumor activity as both monotherapy and 
in combination with other therapeutic agents and continues to show promising efficacy 
in oncology subject populations. 
 
The ORR in subjects with CLL/SLL was 74% (IRC-assessed) and 79% (investigator-
assessed) for venetoclax monotherapy (Study M12-175 and Study M13-982, 
respectively), ranged from 29% to 42% for ibrutinib- or idelalisib-resistant CLL subjects 
in Study M14-032, and was 86% for venetoclax administered in combination with 
rituximab (Study M13-365). The ORR in subjects with NHL was 18% to 38% for 
venetoclax monotherapy (Study M12 -175) and 67% for venetoclax in combination with 
BR (Study M12-630). 
 
In subjects with AML, the ORR was 19% for venetoclax monotherapy (Study M14-212) 
and was 77% for venetoclax in combination with azacitidine/decitabine (Study M14-358) 
and 62% for patients treated with venetoclax in combination with low dose cytarabine 
(M14-387).9,10 Off-label use in R/R AML, in combinations consistent with the FDA label, 
is increasing with an ORR of 12-51%.11 
1.1.4 
Safety 
As of 28 November 2020, a total of 1011 adult AML subjects treated with venetoclax in 
the oncology clinical program had open-label or unblinded safety data available, 
including 32 subjects who received venetoclax monotherapy for R/R AML and 979 
subjects who received venetoclax in combination with other therapeutic agents that 
include the following: dinaciclib, alvocidib, gilteritinib, and AMG 176 in R/R AML; 
azacitidine and decitabine in AML ineligible for intensive chemotherapy; and 
hypomethylating agents and LDAC in previously untreated AML ineligible for intensive 
chemotherapy. Additionally, 10 previously untreated AML subjects in mainland China 
are known to have received venetoclax in combination with azacitidine in the open-label 
Chinese safety cohort of the otherwise blinded Study M15-656/VIALE-A, and 431 
previously untreated AML subjects with blinded data received either venetoclax in 
combination with azacitidine or azacitidine with placebo in Study M15-656/VIALE-A. 
 
The safety data in AML and the benefit risk profile of venetoclax, in both monotherapy 
and combination therapy have been characterized. The safety profile was similar across 
monotherapy and combination treatment in terms of type and severity of TEAEs, 
although with some numerical differences, so the safety data for the combination 
studies have been pooled for the AML indication. Most subjects experienced adverse 
events, and the most common were nausea, diarrhea, and febrile neutropenia. 
Approximately 96% of subjects experienced grade ≥ 3 adverse events (87.5% for 
monotherapy; 96.9% for combination therapy). The most common grade ≥ 3 adverse 
events for monotherapy were febrile neutropenia, malignant neoplasm progression, 
pneumonia, and hypokalemia. The most common grade ≥ 3 events for venetoclax 
combination therapy were febrile neutropenia, thrombocytopenia, and neutropenia. 
Serious adverse events were reported in 79.3% of subjects, and the most common SAE 

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for both venetoclax monotherapy and combination therapy was febrile neutropenia. 
Findings from the analysis based on the exposure adjusted incidence rates were 
consistent with the findings from the analysis based on the subject incidence rates. The 
reported adverse events were consistent with the natural progression of AML, the 
known safety profile of venetoclax and any combination therapy and/or any concomitant 
treatments or coexisting comorbid conditions. 
 
The overall incidence of TLS is 8.9% (4/45) in Study M16-183 and 10.0% (3/30) in 
Study M16-186. Across the AML venetoclax program, TLS was reported for 21 subjects 
(3.5%) across all unblinded and open-label AML studies, including 11 events of clinical 
TLS and 10 events of laboratory TLS (LTLS).  
 
The clinical CTLS events occurred for 5 subjects treated with venetoclax + alvocidib or 
dinaciclib (2 in Study M16-186, 3 in Study M16-183), 4 subjects treated with venetoclax 
+ LDAC (Study M16-043/VIALE-C), 1 subject treated with venetoclax + gilteritinib 
(Study M16-802), and after venetoclax discontinuation for 1 subject treated with 
venetoclax + LDAC (Study M14-387). Two events of CTLS were fatal (Study M16-
043/VIALE-C), and 3 additional events of CTLS led to discontinuation of venetoclax (1 
in Study M16-043/VIALE-C, 1 in Study M16-183, and 1 in Study M16-186). Of the 2 
fatal events, one was in a subject with moderate renal insufficiency; the other was in a 
subject who was already hospitalized for subconjunctival and periorbital hemorrhage at 
the time of study drug initiation and in whom additional causes of death were 
pneumonia and intra-alveolar hemorrhage. 
 
Of the 10 cases of LTLS, 1 event (Study M14-212) occurred after the subject had 
discontinued venetoclax and started another line of therapy, and 1 event (Study M16-
043/VIALE-C) did not meet the Howard criteria but were reported as TLS by the 
investigator because of kidney injury. The remaining 8 events of LTLS occurred with 
combination treatments of venetoclax + LDAC (2 in Study M14-387, 3 in Study M16-
043/VIALE-C), venetoclax + dinaciclib (1 in Study M16-183), venetoclax + azacitidine (1 
in Study M19-072), and venetoclax + alvocidib (1 in Study M16-186). One event led to 
discontinuation of venetoclax and the other 9 cases resolved without discontinuation of 
venetoclax. No events of TLS were reported in combination Study M14-358 (venetoclax 
+ hypomethylating agents). Neutropenia and febrile neutropenia are expected in this 
population. Neutropenia events were generally manageable per standard of care and 
dose modifications; and no clear relationship with increased rate of infection was found. 
Serious infections, including sepsis, have been reported in subjects receiving 
venetoclax treatment, and generally responded to dose interruption and standard 
management (e.g., antibiotics and supportive care) with few subjects requiring dose 
reduction. However, serious events with fatal outcome have been reported. 
 
Oral decitabine and cedazuridine (DEC-C) 
DNA methyltransferase inhibitors (DNMTis), such as decitabine and azacitidine, are 
effective treatment modalities for hematologic cancers and are FDA-approved for higher 
risk myelodysplastic syndromes (MDS). These agents demonstrate clinical activity in 
AML. Consecutive daily dosing for a minimum of 5 or 7 days in 28-day cycles is the 

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labelled schedule and continued monthly treatment for patients who respond is 
considered the standard of care to delay relapse.16 Typical intravenous 
(IV)/subcutaneous (SQ) dosing requires a 1-hour IV infusion or a large-volume SQ 
injection.  
 
A drug product composed of cedazuridine (E7727), a cytidine deaminase (CDA) 
inhibitor, and decitabine has improved the convenience associated with DNMTi therapy 
and is approved for the treatment of patients with MDS. Because cedazuridine inhibits 
CDA in the gut and liver, the oral decitabine cedazuridine (also referred to as DEC-C or 
ASTX727) is a fixed-dose combination (FDC) facilitates oral administration of 
decitabine, achieving exposure and hypomethylation activity similar to IV decitabine at 
the currently approved dosing schedule of 20 mg/m2 daily for 5 days. Intra-patient 
pharmacokinetic (PK) comparison and safety data from the phase 1-2 studies confirm 
exposure similar to IV decitabine.  
 
DEC-C is the oral FDC of cedazuridine + decitabine. Cedazuridine is a CDA inhibitor 
and decitabine is a nucleoside hypomethylating agent known to induce demethylation 
through DNA methyltransferase inhibition. Decitabine is a substrate of CDA. The 
combination of cedazuridine + decitabine has been shown to increase systemic 
decitabine exposure (AUC) following oral administration.  
1.2.1 
Clinical Experience  
The ASTX727 clinical program includes a total of 7 clinical trials. Results from 
ASTX727-01 (Phase 1), ASTX727-01 (Phase 2), ASTX727-02, and ASTX727-04 
include analyses of primary PK and/or PD endpoints, efficacy/preliminary efficacy 
(ASTX727-01 Phase 1, ASTX727-01 Phase 2, and ASTX727-02), and safety.  
 
As of 14 April 2021, a total of 385 subjects have received any dose of cedazuridine. Of 
these 385, Eight healthy subjects received only cedazuridine in the completed 
absorption, distribution, metabolism, and excretion (ADME) study E7727-01. Forty-
seven subjects with lower risk MDS (low-risk or Int-1 per IPSS) received 100 mg 
cedazuridine and lower doses of decitabine (≤20mg) in the low-dose ASTX727 clinical 
program.  
 
In addition to the above studies, ASTX727 is also currently being evaluated in 
combination with ASTX660 (a novel small molecule nonpeptidomimetic IAP antagonist) 
in Study ASTX660-02 in subjects with AML as well as several investigator-sponsored 
trials of ASTX727, including studies in combination with venetoclax. 
1.2.2 
Efficacy 
DEC-C was recently approved for adults with MDS (>INT-1 by IPSS) and CMML-1 
following two open-label, randomized (1:1) cross-over studies that compared 
safety/exposure between oral/IV decitabine. All patients received oral decitabine from 
cycle 3 onward. In the ASTX727-01-B study, 80 adult patients (MDS with INT-2 or 
higher disease, CMML) were enrolled. The CR rate was 21%. 60% of patients on study 

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experienced a clinical benefit and 50% of transfusion dependent patients became 
transfusion independent. The median time to progression to AML or death was 12.1 
months.17 In the ASTX727-02 study, 133 patients were enrolled and comparability 
(99%) between IV and PO decitabine. Response rates were similar; 21% of patients 
achieved a CR with a median CR duration of 7.5 months. 53% of patients achieved 
transfusion independence, however, treatment was complicated by Gr 3/4 cytopenias in 
>50% of patients while on study.18 The recommended dose of DEC-C is 1 tablet 
(decitabine 35mg and cedazuridine 100mg) daily on days 1-5 per 28 day cycle. 
1.2.3 
Safety 
Subjects in the Dose Escalation Stage of Study ASTX727-01 received oral decitabine 
alone, cedazuridine alone, and IV decitabine alone on specific days during Cycles 1 and 
2. During the remainder of the study, cedazuridine and oral decitabine were 
administered together for full 5-day cycles.18 It is difficult to evaluate safety for the single 
dose of the individual agents, however, based on the large safety margin of 
cedazuridine alone (no-observed-adverse-effect level is ~40 fold higher than the human 
therapeutic dose) compared with decitabine, it is believed that the DEC-C safety data 
primarily reflect the effects of decitabine.  
 
Serious treatment emergent adverse events occurred in up to 69% of patients treated 
on study. The most common include febrile neutropenia (18.2-26.5%), pneumonia (6.1-
13.6%), bacteremia (0-4.5%), sepsis (3.7-13.8%) and cellulitis (4.5-6.1%). Non-serious 
TEAEs include nausea (34.5%), thrombocytopenia (41.4%), constipation (24.1%), 
neutropenia (41.4%), and fatigue (31%). 
 
 Study Rationale 
Venetoclax/DNMTi combination therapy is an important therapeutic option for elderly 
and/or unfit patients with treatment naïve AML with CR/CRi rates of 60-75%.9,10 Off-
label use in combination with DNMTi/LDAC is increasing with ORRs in the 12-51% 
range. In a series from Vanderbilt University Medical Center, we reported the outcomes 
of 21 post-allogeneic HCT patients who were treated with venetoclax-based salvage 
therapy (16/21 with a DNMTi partner).11 Treatment interruptions after achieving a 
response were associated with improved safety and reduced toxicity. Partnering 
venetoclax with DEC-C is an extension of this prior work that will combine the efficacy of 
venetoclax/DNMTi therapy with the convenience of an all-oral treatment regimen that 
will improve quality of life compared to conventional salvage therapies.  
 
1.3.1 
Dose Schedule and Rationale 
 
Venetoclax dosing 
All patients who initiate therapy on this study will have venetoclax ramped to a dose of 
400mg/day.  In the dose de-escalation phase of this study, venetoclax will be dosed 
continuously in 28 day cycles in dose level 1 and dose level -1. In dose level -2, 

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venetoclax will be dosed 21/28 days. This dosing was selected based on the FDA label 
in treatment naïve AML. Dose modifications follow the venetoclax US Prescribing 
Information.  
 
For additional information regarding venetoclax dosing, see Figure 1 and 2. 
 
Oral decitabine and cedazuridine dosing 
In the dose de-escalation phase of this study, oral decitabine and cedazuridine (DEC-C) 
will be dosed as 35mg/100 (decitabine 35mg and cedazuridine 100mg) daily on days 1-
5 per 28 day cycle in dose level 1.  In dose level -1 and dose level -2, DEC-C will be 
administered on days 1-4. This dosing was selected based on the FDA label in MDS. 
Dose modifications follow the oral decitabine and cedazuridine US Prescribing 
Information. 
 
For additional information regarding venetoclax dosing, see Figure 1 and 2. 
 
 
 
2 
STUDY OBJECTIVES 
 
Primary Objectives: 
1. To assess the effect of DEC-C/venetoclax on the investigator-assessed 
composite CR rate (CR/CRh/CRi) 
 
Secondary Objectives: 
1. To assess the rate of partial response (PR) and morphologic leukemia free 
state (MLFS) following treatment with DEC-C/venetoclax 
2. To assess the relapse free survival of patients treated with DEC-C/venetoclax 
3. To assess overall survival of patients treated with DEC-C/venetoclax 
4. To assess the safety and tolerability of DEC-C/venetoclax in the post-HCT 
setting 
5. To assess the rates of measurable residual disease negativity in patients 
achieving a CR. 
 
 
3 
STUDY DESIGN 
 
Overall Study Design and Plan 
This is an open-label, non-randomized, investigator-sponsored, phase II study of 
venetoclax in combination with DEC-C in patients with myeloid diseases who relapse 
with AML after allogeneic HCT. 

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Study Duration and Dates 
It is estimated that this study will enroll patients from January 2022 through January 
2024. Data lock and study closure is expected in January 2025. 
 
 
 
4 
STUDY POPULATION SELECTION 
 
Study Population 
Adult patients, >18 years of age with relapsed/progression to AML after allogeneic HCT, 
who have not previously progressed while receiving venetoclax or other BCL-2 inhibitor, 
are eligible. Subjects with active GVHD, acute or uncontrolled infections, or with white 
blood cell count >25,000/µl that cannot be controlled with hydroxyurea are not eligible.  
 
Patients who develop grade 3/4 graft versus host disease while on study will have 
treatment interrupted. Subjects will be eligible to resume therapy after GVHD returns to 
< grade 1 after discussion with the study co-chair(s). 
 
Inclusion Criteria: 
1. Age ≥18 years at the time of signing the Informed Consent Form (ICF); must 
voluntarily sign an ICF and meet all study requirements  
2. History of morphologically confirmed AML (per WHO diagnostic criteria) with 
evidence of disease recurrence (>5% blasts consistent with prior disease) that 
occurs after allogeneic HCT. Patients transplanted for another indication (e.g., 
MDS/CMML) who relapse with AML are eligible to enroll.  
3. WBC must be less than 25,000/µl for at least three days prior to C1D1 (hydroxyurea 
allowed). 
4. A bone marrow biopsy must be performed and tissue collected for entrance to the 
trial. 
5. Eastern Cooperative Oncology Group Performance Status of 0 - 2  
6. Must have adequate hepatic and renal function as demonstrated by the following: 
ALT (SGPT) and/or AST (SGOT) less than or equal to 3x upper limit of normal 
(ULN); total bilirubin < 1.5 x upper limit of normal (ULN). Patients with Gilbert’s 
syndrome (hereditary indirect hyperbilirubinemia) must have a total bilirubin of < 3 x 
ULN; and calculated creatinine clearance >30 ml/min (per the Cockroft-Gault 
formula). 
7. Willingness to abide by all study requirements, including contraception, maintenance 
of a pill diary, and acceptance of recommended supportive care medications. 
 

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Exclusion Criteria: 
1. Prior relapse or progression while receiving venetoclax or other commercially 
available or investigational BCL-2 inhibitor. 
2. Anticancer therapy, including investigational agents ≤2 weeks or ≤5 half-lives of the 
drug, whichever is shorter, prior to C1D1. (Use of hydroxyurea is permitted).  
3. Inadequate recovery from toxicity attributed to prior anti-cancer therapy to ≤Grade 1 
(NCI CTCAE v5.0), excluding alopecia or fatigue.  
4. History of allogeneic hematopoietic cell transplantation (HCT), or other cellular 
therapy product, within 3 months of signing consent.  
5. Clinically active acute or chronic GVHD.  Patients must be off calcineurin inhibitors 
for at least 4 weeks to be eligible.  
6. Radiation therapy or major surgery within 3 weeks of signing consent.  
7. Active, uncontrolled infection. Patients with infection under active treatment and 
controlled with antibiotics are eligible. Prophylaxis is acceptable. 
8. Inability to tolerate oral medication, presence of poorly controlled gastrointestinal 
disease, or dysfunction that could affect study drug absorption. 
9. Active documented central nervous system leukemia 
10. Concurrent treatment with a non-permitted concomitant medication. 
11. Other malignancy IF currently being treated or likely to be treated in next 6 months 
except for basal or squamous cell carcinoma of the skin or cervical carcinoma in 
situ. 
12. Pregnancy or breastfeeding females 
13. Known chronic alcohol or drug abuse 
14. Clinically significant cardiovascular disease with major event or cardiac intervention 
within the past 6 months (e.g. percutaneous intervention, coronary artery bypass 
graft, documented cardiac heart failure) as determined by the investigator 
15. Any other condition deemed by the investigator to make the patient a poor candidate 
for clinical trial and/or treatment with investigational agents. 
 
 
5 
STUDY TREATMENTS 
 
Treatments Administered 
5.1.1 
Tumor Lysis Syndrome Prophylaxis 
All patients are required to receive standard tumor lysis prophylaxis. During the ramp-up 
phase (See Section 5.2.1.1), TLS precautions may include intravenous fluids, uric acid 
lowering agents, and daily visits with TLS laboratory studies drawn before each dose. 
Initiation of allopurinol should occur 2-3 days prior to the start of therapy and is 
continued through the end of Cycle 1 if no clinically significant TLS is observed. If there 
is clinical or biochemical evidence of TLS as an outpatient, hospitalization should be 
considered.  
 

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At any time, more stringent monitoring and/or prophylaxis may be utilized at the 
discretion of treating physician based on risk factors such as renal function, tumor 
burden or other comorbidities. 
5.1.2 
Study Treatments 
 
Venetoclax (venclexta) 
Venetoclax (venclexta) is a tan, oval tablet with a “V” debossed on one side and “50” or 
“100” on the other. The venetoclax 10mg formulation is a tan, round tablet with a “V” 
debossed on one side and a “10” on the other. 
 
Venetoclax will be obtained as a standard of care therapy by the treating clinician/ 
treatment team. Venetoclax is not provided by the study.  
 
Decitabine cedazuridine (DEC-C or INQOVI) 
The DEC-C (INQOVI) tablet is a fixed-dose combination of decitabine 35mg and 
cedazuridine 100mg for oral administration. The drug product is a red, oval shaped, 
film-coated, immediate-release tablet. The drug products are either plain faced on both 
sides or have a debossed marking of “H35” on one side and plain faced on the other.  
 
DEC-C is provided by the study. 
 
Study Drug Dosing and Administration 
5.2.1 
Dosing Instructions for Patients 
Study medications will be dosed according to the schedules provided below and in 
Figure 1 and 2. For doses of oral medications to be taken on non-clinic days, patients 
will be provided with medication to take home.  
 
Venetoclax 
Venetoclax should be taken with food and water at the same time each day, generally 
within 30 minutes of a meal. The tablets should be swallowed whole and not crushed or 
broken. Patients should drink 6-8 glasses of water daily for two days before initiating 
therapy with venetoclax and during the escalation period. On days that venetoclax is 
taken with DEC-C, venetoclax should be taken with breakfast at least 2 hours after 
DEC-C is taken.  
 

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Each patient is scheduled to receive oral 
venetoclax per the dosing schedule in 
Figure 3, beginning with an initial dose 
ramp period during Cycle 1. On the first 2 
days of initial treatment (e.g. Week 1 of 
Cycle 1), each patient’s daily dose of 
venetoclax is scheduled to be 100mg and 
then 200mg. Beginning on day 3, each 
patient is scheduled to continue oral 
venetoclax on a continuous schedule of 
400mg daily. 
 
In the absence of unacceptable adverse 
event requiring dose reduction, it is 
intended that all patients will receive 
venetoclax by the same dose and 
schedule. Patients will take venetoclax 
tablets with a meal and water at 
approximately the same time each day. 
Venetoclax tablets should be swallowed whole and not chewed, crushed, or broken 
prior to swallowing.  
 
Missed Doses 
If a dose is missed within 8 hours of the time it is usually taken, the subject should take 
the missed dose as soon as possible. If a dose is missed by more than 8 hours, the 
subject should not take the missed dose. In either scenario, the subject should resume 
the usual dosing schedule the next day.  
 
Vomited Doses: 
If the subject vomits after dosing, the vomiting episode and the time it occurred should 
be recorded in the dosing diary. No additional dose should be taken that day. The next 
prescribed dose should be taken at the usual time. Investigators should consider pre-
medicating the subject with antiemetics if vomiting is anticipated to be a recurring issue. 
 
Oral Decitabine and cedazudridine  
Oral decitabine-cedazuridine (DEC-C) should be taken at the same time each day, 
typically in the morning. Patients should have an empty stomach with no food for 2 
hours before and at least two hours after administration. Anti-acid medications should 
be taken at night. The tablets should be swallowed whole and not crushed or broken.  
 
Missed Doses 
If a dose is missed within 12 hours of the time it is usually taken, the subject should take 
the missed dose as soon as possible. If a dose is missed by more than 12 hours, the 
subject should not take the missed dose. In either scenario, the subject should resume 
the usual dosing schedule the next day and proceed with completing the entire number 
of planned treatment days per cycle.  
Figure 3. Dose ramp and steady state dosing 
during cycle 1 of pre-remission phase.  

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Vomited Doses: 
If the subject vomits after dosing, the vomiting episode and the time it occurred should 
be recorded in the dosing diary. No additional dose should be taken that day. The next 
dose should be taken at the usual time. Investigators should consider pre-medicating 
the subject with antiemetics if vomiting is anticipated to be a recurring issue. 
 
Venetoclax/DEC-C combination therapy: 
On days involving dosing of both venetoclax and DEC-C, the DEC-C should be taken 
orally (PO) daily on an empty stomach (morning before breakfast) with no food for 2 
hours before and at least 2 hours after administration. Venetoclax should be taken daily 
with breakfast at least 2 hours after DEC-C.  
 
In the post-remission phase of the study, patients may take venetoclax with a meal and 
the DEC-C at bedtime (with an empty stomach).  Both agents should be taken at 
approximately the same time each day. 
 
A dosing diary will be used to enhance compliance. 
5.2.2 
Dose Schedules for Evaluation (Pre-remission Phase only) 
The study will follow a dose de-escalation design. Cycles are 28 days. 
 
Pre-remission phase: 
Dose Level 1:  
DEC-C 100mg/35mg on days 1-5 
 
 
 
Venetoclax 400mg/day x 28 days 
 
Dose Level -1:  
DEC-C 100mg/35mg on days 1-4 
 
 
 
Venetoclax 400mg/day x 28 days 
 
Dose Level -2:  
DEC-C 100mg/35mg on days 1-4 
 
 
 
Venetoclax 400mg/day x 21/28 days 
 
Three initial patients will be enrolled at dose level 1 during the pre-remission phase of 
treatment. If there are 0 dose limiting toxicities (DLTs), then enrollment will proceed at 
this dose level. If there is 1 DLT, then 3 additional subjects will be enrolled. If >2 DLTs in 
six patients, dose level -1 will be evaluated using a similar approach, followed by dose 
level -2. See Table 4. 
 
 
Table 4: Dose De-escalation Rules 

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Number of Patients with Drug-Related 
DLT at a Given Dose Level 
Dose De-escalation Step 
0 of 3 
Proceed as RP2D 
1 of 3 
Treat 3 more patients at the same dose level 
≥ 2 of 3 
Enrollment at this dose level stops. Proceed to 
next lower dose level 
≤ 1 of 6 
Proceed as RP2D 
≥ 2 of 6 
Proceed to next lower dose level 
 
All patients will be considered evaluable for DLT unless they cannot complete the first 
cycle of therapy due to withdrawal of consent or disease progression. A patient who is 
not DLT-evaluable will be replaced. Cohort review discussions will be held between the 
study chair and other investigator(s) to confirm dose escalation, reductions, and cohort 
expansions. 
5.2.3 
Toxicity Grading 
The NCI CTCAE version 5.0 will be used for grading the severity of AEs and 
modifications to the dosing of venetoclax and DEC-C will be made according to this 
severity grading. If more than 1 type of toxicity occurs concurrently, the most severe 
grade will determine the modification. For purpose of any necessary definition, “baseline 
value” is defined as the most immediately known value in place prior to patient’s first 
receipt of protocol-indicated treatment on Cycle 1, Day 1. 
 
Severity criteria (NCI/CTCAE): 
The term “severe” is used to describe the intensity of an AE; the event itself could be of 
relatively minor clinical significance (e.g., ‘severe’ headache). This is not the same as 
“serious.” Seriousness of AEs is based on the outcome of an AE and usually associated 
with events that pose a threat to a patient’s life or functioning. 
 
The severity of the AE will be graded according to the NCI/CTCAE Grading Scale (see 
the CTCAE web page at http://ctep.cancer.gov for details). For AEs not covered by 
CTCAE, the severity will be characterized as “mild,” “moderate,” or “severe” according 
to the following definitions: 
• Mild events are usually transient and do not interfere with the patient’s daily 
activities. 
• Moderate events introduce a low level of inconvenience or concern to the patient 
and may interfere with daily activities. 
• Severe events interrupt the patient’s usual daily activities. 
5.2.4 
Dose-Limiting Toxicity  
A dose-limiting toxicity (DLT) is defined as any toxicity that occurs up to day 28 during 
the dose de-escalation (pre-remission) phase and is at least possibly related to study 
drug administration. This does not include toxicity with a clear alternative explanation 
(e.g., disease progression) or transient (≤72 hours) abnormal laboratory values without 

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associated clinically significant signs or symptoms based on investigator determination. 
All DLTs will be assessed by the investigator using CTCAE v5.0 criteria.  
 
To be considered evaluable, subjects must fulfill the following minimum criteria: 
• All doses of DEC-C. 
• 75% of doses of venetoclax during the first cycle (e.g., 21/28 or 16/21 days) 
 
All patients who initiate venetoclax/DEC-C, receive at least one dose of each, and 
experience a DLT are evaluable regardless of whether the minimum criteria above are 
met.  
 
Subjects experiencing toxicity that results in dose-holds will remain evaluable provided 
the minimum criteria outlined above are met. Patients that require dose reductions 
during the DLT evaluation period (e.g., first 28 days after initiation of the first dose of 
study treatment/C1D1) will not be considered a DLT so long as they receive the 
minimum doses at the prescribed dose level outlined above. 
 
Patients who achieve a morphologic remission on C1D22 BMBx, have not experienced 
a DLT, and have treatment interrupted due to favorable treatment response will be 
considered evaluable if they complete 75% of protocol-directed doses (i.e., a patient 
who achieves a remission and is instructed to stop venetoclax on C1D24 is considered 
evaluable provided they received at least 18/24 venetoclax doses, or 75%) and will not 
be replaced.  
 
Patients missing >25% of venetoclax doses, or any DEC-C doses due to adverse 
event(s), will be considered a DLT provided the AEs are considered related. If 
unrelated, the patient may be replaced as described above. 
 
Definition of Dose-Limiting Toxicity – Non-hematologic 
• Grade 3 nausea, vomiting, dehydration, diarrhea, or fatigue lasting > 3 days 
despite optimal supportive medications. Patients who require tube feeds or total 
parenteral nutrition will be considered a DLT. 
• Any other Grade 3 non-hematological toxicity with the following exceptions: 
o Grade 3 or 4 electrolyte abnormalities that: 
 Improve with supportive care to ≤ Grade 2 within 72 hours 
 Are deemed not medically significant (i.e. hospitalization not 
indicated or non-life-threatening) by the investigator. 
o Hair loss 
o Grade 3 AST, ALT, or alkaline phosphatase elevations that last <72 hours 
• Any other Grade 4 non-hematologic toxicity. 
• Patients meeting criteria for Hy’s Law as follows: 
o Aminotransferase elevations, often much greater than 3x ULN, with 
elevation in serum total bilirubin to >2xULN without initial findings of 
cholestasis (elevated serum alkaline phosphatase). 
o No other reason is identified to explain the combination of increased 
aminotransferase and total bilirubin, such as viral hepatitis, pre-existing 

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acute liver disease, or another drug capable of causing the observed 
injury. 
• Any grade 5 non-hematologic toxicity will be considered a DLT. 
 
Definition of Dose-Limiting Toxicity – Hematologic: 
• Neutropenia: Progression/development of grade 4 neutropenia and bone marrow 
aplasia without evidence of disease that extends >2 weeks beyond the end of a 
treatment cycle. 
 
• Thrombocytopenia: Progression/development of grade 4 thrombocytopenia and 
bone marrow aplasia without evidence of disease that extends >2 weeks beyond 
the end of a treatment cycle. 
 
Exceptions 
Adverse events that meet the above definitions but that are clearly unrelated to study 
drug will not be DLTs. 
 
In rare instances, an event may fall within the definition of a DLT, as defined above, but 
the event may be considered not to be a DLT (e.g., not be clinically meaningful). If this 
occurs, the study chair and other investigator(s) will review the event and supporting 
data. The reasons for not considering the event to be a DLT will be clearly documented 
with supporting rationale. 
 
Patients who have experienced a DLT do not automatically require discontinuation of 
protocol-indicated treatment, unless the nature or severity of the DLT is also an adverse 
event that would require permanent discontinuation of study treatment as elsewhere 
defined by the protocol (e.g. Section 5.2.4). Rather, a patient who has experienced a 
DLT should be evaluated for consideration of an appropriate dose hold or dose 
modification which, if consistent with the protocol, would allow continued dosing under 
revised circumstance. 
 
A dose limiting toxicity (DLT) must be reported by the site using expedited 
notification procedures. Within 1 business day of investigator awareness of an 
adverse event meeting DLT criteria, the event must be reported to the sponsor-
investigator by both of the following two mechanisms: 
 
1) recorded in the electronic case report form (eCRF) and 
 
2) separate email alert to coordinating.center@vumc.org  
 
If a DLT meets seriousness criteria, such event must also be reported as an SAE (see 
protocol Section 6.2 and Section 6.3). 
 
For the purpose of ensuring an appropriate opportunity to determine the recommended 
phase 2 dose (RP2D) of venetoclax/DEC-C, a subject who is withdrawn from the study 
prior to completing the DLT assessment window (e.g. first 28 days after initiating 

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protocol-indicated treatment on Cycle 1, Day 1) for reasons other than a DLT will be 
considered not evaluable for DLT and will be replaced.  
 
Additionally, over the first 28 days after initiating study therapy, if a patient discontinues 
study treatment for reasons clearly not related to protocol-indicated treatment (in the 
judgement of the study chair and other investigator(s)) and fails to complete the 
minimum number of doses of venetoclax/DEC-C, then that patient may be considered 
not evaluable for response and be replaced with a new patient. 
5.2.5 
Safety Cohort Review 
The study chair, in consultation with the investigator(s), will determine whether the dose 
will be de-escalated and/or the RP2D dose for the pre-remission therapy phase. 
5.2.6 
Supportive Care and Dose Reduction Guidelines 
 
Infection 
Appropriate broad-spectrum IV antibiotics and/or antifungal agents should be started 
immediately in patients who develop fever or other signs of systemic infection. In 
patients with minor infections, venetoclax/DEC-C may be continued in parallel with 
treatment. Venetoclax dosing should be adjusted to reflect drug interactions.  
 
Treatment with venetoclax and DEC-C should be interrupted in any patient with Grade 4 
infection, clinical sepsis (in the absence of documented infection), or neutropenic fever. 
 
After the infection is resolved, venetoclax/DEC-C should be restarted at the previous 
dose level and per the following guidance: 
• In patients prior to achieving remission, venetoclax/DEC-C may be restarted after 
the patient is clinically recovered (e.g., fever is resolved with no evidence of active 
infection).  
• In patients who have achieved a clinical remission, venetoclax/DEC-C may be 
restarted after the ANC returns to Grade ≤ 2 or baseline, fever has resolved, and 
patient’s condition is stable.  
If the neutropenic fever is persistent, or for ≥2 occurrences, consultation with the study 
chair is recommended.  
 
Colony Stimulating Factors: 
Colony stimulating factors may be used in patients who achieved a CR and have a 
duration of neutropenia ≥35 days, develop neutropenic fever, or significant infectious 
complication at any time, as deemed warranted to maintain safety of the patient per the 
investigator. 
 

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Dose Reduction Guidelines 
Venetoclax is generally well-tolerated; the most common toxicities observed are fatigue, 
headache, nausea, diarrhea, hematologic toxicity, and electrolyte abnormalities. Non-
hematologic grade 3/4 toxicity is rare. DEC-C is also well-tolerated.  
 
The NCI CTCAE version 5.0 will be used for grading the severity of AEs; the study 
treatment modifications described below are applied according to this severity grading. 
Toxicity will be documented as described in Section 5.2.3. If more than one type of 
toxicity occurs concurrently, the most severe grade will determine the modification. For 
purpose of any necessary definition, “baseline value” is defined as the most immediately 
known value in place prior to patient’s first receipt of protocol-indicated treatment on 
Cycle 1, Day 1. 
 
Pre-remission Phase 
Treatment interruptions during the pre-remission phase, as well as the reason, must be 
documented.  
 
Dose reductions are to be avoided for patients during cycle 1 in the dose finding portion 
of the study. Figure 1 and Table 5 summarizes the starting doses (Dose Level 1) and 
dose levels. General supportive care guidelines are provided in Section 5.2.6. Outside 
of the dose finding portion of the study, dose reductions of venetoclax and/or DEC-C for 
adverse events may take place at any time as otherwise consistent with the protocol.  
 
Table 5: Venetoclax/DEC-C Dose Level Summary (Pre-remission Phase) 
DOSE LEVEL 
VENETOCLAX 
DEC-C 
1 
400mg once daily  
Continuous Day 1-28∆ 
100mg/35mg once daily  
Days 1-5 
-1 
400mg once daily  
Continuous Day 1-28∆ 
100mg/35mg once daily  
Days 1-4 
-2 
400mg once daily  
Continuous Day 1-21∆ 
100mg/35mg once daily  
Days 1-4 
* Cycles are every 28 days. 
∆ Venetoclax dosing will be ramped on C1D1 and C1D2 per Figure 3. 
During the pre-remission phase, it is intended that venetoclax will be dosed 
continuously per the dose level summary (Table 5) and will not be interrupted unless the 
day C1D22 BMBx is negative for leukemia. Missed days of venetoclax due to treatment 
interruption in a patient with aplastic marrow that is negative for AML, who are otherwise 
tolerating therapy well and without evidence of a DLT, will not influence evaluability (i.e., 
required minimum number of venetoclax doses).  
 
Initiating Post-remission Phase (Cycle 1) 

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Patients will begin the post-remission phase of the study after achieving blast clearance 
from their marrow. Patients with marrow aplasia must recover peripheral blood counts 
with ANC of >1000/mm3 / 1 x 109/L. Patients with cellular marrows may proceed to the 
post-remission phase of the study without count recovery if the treating physician 
believes the cellularity is disease related. Discussion with the study chair is 
recommended. 
 
Patients with marrow aplasia on C1D22 or C2D22 BMBx will have venetoclax 
interrupted until the absolute neutrophil count (ANC) recovers to >1000/mm3 / 1 x 109/L. 
If persistent grade 4 cytopenias, repeat BMBx will be performed at D42. If persistent 
marrow aplasia without disease, patients will be managed expectantly until >1000/mm3 / 
1 x 109/L. A BMBx will be repeated every 6 weeks until ANC recovery. At that time, 
patients will enter the post-remission phase (See Figure 2). 
 
To proceed with each cycle of post-remission therapy, platelets/ANC must be improved 
to grade 2 or higher: 
 
Platelets 
>50,000/mm3 / 50.0 x 109/L 
 
Neutrophils  >1000/mm3 / 1 x 109/L 
 
 
Venetoclax and DEC-C are generally intended to be dosed in combination but may be 
separably dosed for up to 28 consecutive days. The dose levels of venetoclax and 
DEC-C are indicated in Table 5.  
 
In the event of an adverse event deemed by the study physician as unrelated to 
protocol-indicated treatment, the study physician may choose to precautionarily interrupt 
venetoclax and/or DEC-C for up to 28 days, but no dose reduction of either agent 
should occur.  
 
Venetoclax and/or DEC-C may be delayed for any adverse event, laboratory 
abnormality, or intercurrent illness which, in the judgment of the investigator, warrants 
delaying the dose of DEC-C and/or venetoclax. If either or both drugs are interrupted for 
>4 weeks for reason other than treatment-related cytopenias, discussion with the study 
chair is recommended.  
 
Subsequent Post-remission Therapy (Cycle 2+) 
Patients without clinical or laboratory evidence of relapse will continue to receive 
therapy with DEC-C/venetoclax for maintenance of response (See Figure 1 and 2). 
Subsequent post-remission cycles will be initiated after evidence of count recovery, 
defined as:  
 
Platelets 
>50,000/mm3 / 50.0 x 109/L 
 
Neutrophils  >1000/mm3 / 1 x 109/L 
 
In patients who recover counts within 6 weeks of CxD1, and are otherwise tolerating 
therapy, subsequent post-remission cycles will occur at the same dose level.  
 

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If count recovery is delayed >6 weeks beyond CxD1, patients will be reduced by one 
dose level (e.g., a patient with count recovery lasting 7 weeks after post-remission C1 
will dose C2 at dose level -1).  
 
For patients with delayed count recovery (>6 weeks) at dose level -3, discussion with 
the study chair is recommended. 
 
Table 6: Venetoclax/DEC-C Dose Level Summary (Post-remission Phase) 
DOSE LEVEL 
VENETOCLAX 
DEC-C 
1 
400mg/day dosed 
continuously  
100mg/35mg 
Days 1-5 
-1 
400mg/day 
21/28 days 
100mg/35mg 
Days 1-4 
-2 
400mg/day 
14/28 days 
100mg/35mg 
Days 1-3 
-3 
400mg/day 
7/28 days 
100mg/35mg 
Days 1, 3, and 5 
* Cycles are every 28 days. 
Patients who are experiencing low-grade tolerability symptoms and are deriving clinical 
benefit from the treatment may have their dose reduced, or subsequent cycle delayed, 
at the discretion of the PI. Dose reductions should be done in accordance with Table 6. 
Patients whose dose or schedule is reduced may subsequently be re-escalated to the 
previous dose upon improvement of the tolerability, at the discretion of the PI. PI may 
consult with the study chair as necessary. 
5.2.7 
Dose modifications 
Table 7: Toxicity Dose Adjustment Guidelines 
Event 
Occurrence 
Action 
Grade 4 neutropenia 
with or without fever 
or infection 
 
OR 
 
Grade 4 
thrombocytopenia 
 
Occurrence prior to 
achieving remission* 
• Transfuse blood products, 
administer prophylactic 
and treatment anti-
infectives as clinically 
indicated. 
• In most instances 
venetoclax and DEC-C 
cycles should not be 
interrupted due to 
cytopenias prior to 
achieving remission 
First occurrence after 
achieving remission and 
lasting ≤ 7 days 
• Delay subsequent 
treatment cycle of 

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venetoclax and DEC-C 
and monitor blood counts. 
• Administer G-CSF if 
clinically indicated (see 
Section 5.2.6.2) 
• Once toxicity has resolved 
to ≤ Grade 2, resume 
venetoclax/ DEC-C at the 
same dose. 
Subsequent occurrences in 
cycles after achieving 
remission and lasting ≥ 7 
days. 
• Delay subsequent 
treatment cycle of 
venetoclax and DEC-C 
and monitor blood counts. 
• Administer G-CSF if 
clinically indicated (see 
Section 5.2.6.2) 
• Once toxicity has resolved 
to ≤ Grade 2, resume 
venetoclax and DEC-C at 
one dose level lower (see 
Table 6) 
*Consider interim bone marrow biopsy for patients who may have achieved early 
remission 
Table obtained from current venetoclax USPI.  Modifications relevant to this study are 
indicated in underline and bold.  
 
Hematologic Toxicity – Additional Considerations 
If after applying the above recommendations for first and subsequent occurrences of 
hematologic toxicities as outlined and further dose modifications are desired for DEC-C, 
consider consultation with the study chair. General principles for dose modifications: 
1. There will be no dose reduction of either agent based on hematologic toxicity 
during the pre-remission phase of this study. 
2. Within the post-remission phase, dose reductions of venetoclax and DEC-C 
should follow Table 6. 
Non-hematologic Toxicity – Additional Considerations 
Delay the next cycle for the following non-hematologic adverse reactions and resume at 
the same or reduced dose of DEC-C and venetoclax upon resolution to patient baseline 
or ≤ Grade 1. 
1. Serum creatinine > 2mg/dl  
2. Serum bilirubin > 2x ULN 
3. AST or ALT >2x ULN 
4. Active or uncontrolled infection 

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5.2.8 
Conditions Not Requiring Dose Reduction 
The following conditions are exceptions to the dose-modification guidelines: 
• Alopecia of any grade. 
• Electrolyte or serum analyte (e.g., urate) abnormalities that are reversible to the 
patient’s baseline with standard interventions. 
• Isolated values of ≥ Grade 3 alkaline phosphatase, defined as asymptomatic 
elevations in alkaline phosphatase without elevation of other liver function studies 
(e.g. AST/ALT or bilirubin). Determination of liver versus bone etiology should be 
made, and evaluation of gamma-glutamyl transferase, 5’ nucleotidase, or other liver 
enzymes should be performed. 
5.2.9 
Venetoclax/DEC-C Dose Reduction for Decreased Glomerular Filtration 
Rate  
• If CrCl declines during treatment and is believed to be unrelated to venetoclax/DEC-
C, the dosing of these medications may be maintained provided that the patient’s 
condition is closely monitored. 
• If CrCl declines to < 30 mL/min, the venetoclax should be held.  
5.2.10 
Supportive Care Recommendations for TEAEs/potential Adverse Drug 
Reactions occurring in conjunction with venetoclax  
Supportive measures for optimal medical care include prophylaxis against tumor lysis 
syndrome (TLS) (see Section 5.1.1) 
 
Prophylactic anti-emetic therapy is recommended and will be prescribed at the 
discretion of the treating clinician. 
5.2.11 
Concomitant Medication and Treatment 
Concomitant medications include any prescription or over-the-counter preparation, 
including vitamins, dietary supplements, and oral herbal preparations taken during the 
study.  
Patients may continue their baseline medication(s) unless otherwise prohibited by the 
inclusion/exclusion criteria of study protocol and Appendix 1. Any diagnostic, 
therapeutic, or surgical procedure performed from signing the informed consent form 
(CF) through 28 day follow-up should be recorded, including the dates, description of 
the procedure(s), and any clinical findings, if applicable. 
 Permitted Concomitant Medication  
Patients will receive concomitant medications to treat symptoms, AEs, and intercurrent 
illnesses that are medically necessary as part of standard care. Medications to treat 
concomitant diseases like diabetes, hypertension, etc., are permitted.  
 

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Appropriate anti-coagulation is allowed during the study (e.g., low molecular weight 
heparin, direct factor Xa inhibitors, etc.). Warfarin is allowed during the study provided 
patients are monitored for INR twice a week during the first two cycles of therapy, then 
weekly to biweekly thereafter at the discretion of the treating physician. 
 Use of Blood Products 
During treatment, patients may receive red blood cell (RBC) or platelet transfusions, if 
clinically indicated, per institutional guidelines. It is recommended that patients who 
require repeated transfusion support, in the absence of marrow disease and despite 
dose reductions, be discussed with the study sponsor. 
5.2.12 
Contraception requirements 
Patients should not become pregnant or father a child while on this study because the 
study treatments in this study can affect an unborn baby. Women should not breastfeed 
a baby while on this study. It is important that patients understand the need to use birth 
control while on this study. Female patients of childbearing potential (See Table 1, 
footnote 7) with male partners able to father children, defined as men without a 
medical/surgical cause of azoospermia, must agree to use two methods of 
contraception (one highly effective and one effective) and have a negative serum 
pregnancy test at Screening, and male patients must use an effective barrier method of 
contraception if sexually active with a female of childbearing potential. 
 
Highly effective methods include:  
• Hormonal contraceptives (e.g., combined oral contraceptives, patch, vaginal ring, 
injectables, and implants)  
• Intrauterine device or intrauterine system 
• Vasectomy or tubal ligation. 
 
Effective methods include:  
• Barrier methods of contraception (e.g., male condom, female condom, cervical cap, 
diaphragm, contraceptive sponge). 
 
Notes: 
No barrier method by itself achieves a highly effective standard of contraception. The 
proper use of diaphragm or cervical cap includes use of spermicide and is considered 
one barrier method. 
 
The cervical cap and contraceptive sponge are less effective in parous women. The use 
of spermicide alone is not considered a suitable barrier method for contraception. 
 
When used consistently and correctly, “double barrier” methods of contraception (e.g., 
male condom with diaphragm, male condom with cervical cap) can be used as an 
effective alternative to the highly effective contraception methods described above. 
Male and female condoms should not be used together as they can tear or become 
damaged. 

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Alternatively, the following fulfill the contraception requirements: 
• A sexual partner who is surgically sterilized or post-menopausal as defined in See 
Table 1, footnote 7. 
• Total (true) abstinence (when this is in line with the preferred and usual lifestyle of 
the patient), is an acceptable method of contraception. NOTE: Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception. 
• The method of acceptable contraception must be explained to both male and female 
potential patients. In order to be eligible for the study, patients must agree to use to 
use the methods of birth control described above throughout the study and for 3 
months following the last dose of study treatment at the time of consent for the 
study. Please see Table 1, footnote 7 for additional safety information related to 
pregnancy. 
 
5.2.13 
Off-Treatment Criteria 
Participants will be removed from study when any of the following criteria apply: 
• Disease progression 
• Unacceptable toxicity   
• 
Lost to follow-up 
• 
Withdrawal of consent  
 
 
Restrictions and Prohibited Medications 
Concurrent Therapies: 
Concurrent therapy with any other approved or investigative anticancer therapeutic is 
not allowed. Other investigational agents should not be used during the study.  
 
 
Diet: 
There are no dietary restrictions on this study. Patients should maintain adequate 
caloric and fluid intake. Grapefruit, starfruit, and Seville oranges should be avoided 
during the study period given interactions with CYP3A4. 
 
Medications: 
Venetoclax should not be used with strong CYP3A inhibitors (e.g., ketoconazole, 
ritonavir, clarithromycin, itraconazole, voriconazole) at initiation, during ramp-up, and 
pre-remission phase of treatment. Concomitant use of venetoclax with moderate 
CYP3A inhibitors (e.g. erythromycin, ciprofloxacin, diltiazem, fluconazole, 
isavuconazole, verapamil), or strong CYP3A inducers (e.g. carbamazepine, phenytoin, 
rifampin, St. John's wort), or moderate CYP3A inducers (e.g. bosentan, efavirenz, 
etavirine) may be used, if clinically appropriate, during the post-remission phase with 
appropriate dose adjustments. See Table 8 and Appendix 1 for a list of representative 
products. 

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5.3.1 
Antifungal prophylaxis 
Prophylactic antifungal therapy with CYP3A4 inhibitor activity (eg, fluconazole, 
posaconazole, and voriconazole) are prohibited 7 days or 5 half-lives, whichever is 
greater, prior to C1D1and through the pre-remission phase of therapy. Alternative 
antifungal therapy should be considered per institutional guidelines. During subsequent 
cycles, investigators may use prophylactic antifungal therapy as guided per local 
institutional practices. If the therapy of choice is a drug with CYP3A4 inhibitor activity, 
dose adjustments of venetoclax are required as detailed in Table 8.  
 
Table 8: Drug interaction and dose reduction of venetoclax 
Drug Interaction 
Dose Reduction of Venetoclax 
No CYP3A or P-gp inhibitor activity 
No dose reduction (400mg daily) 
Posaconazole 
Dose reduction to 70mg daily 
Other strong CYP3A inhibitor activity 
(e.g., voriconazole) 
Dose reduction to 100mg daily 
Moderate CYP3A inhibitor activity (e.g., 
fluconazole; or drug with P-gp inhibitor 
activity) 
Dose reduction at least by 50% or to 
200mg daily.  
 
 
Medication Storage 
Venetoclax tablets will be obtained by the clinical team as “standard of care.” 
Venetoclax should be stored in accordance with written instructions provided by the 
patient’s pharmacy. 
 
DEC-C will be provided by the study sponsor in high-density polyethylene (HDPE) bottle 
with a child resistant closure. Each bottle contains either 1 or 2 desiccant canisters for 
moisture absorption. The desiccant canisters should remain in the bottle at all times and 
must not be ingested. DEC-C is store at controlled room temperature (20 – 25°C) in the 
original package provided. 
 
Study Drug Accountability  
Venetoclax will be obtained standard of care by the patient’s treatment team.  
 
DEC-C will be provided by the study sponsor. Sites must request study drug by 
submitting an order form directly to the drug supplier for the study drug to be shipped to 

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the site pharmacy. The investigator or designee will verify and acknowledge receipt of 
all study drug shipments by signing and returning all required forms.  
 
Overall study drug accountability and destruction records (DEC-C only) will be 
maintained by the Sponsor-Investigator. The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of the inventory and 
disposition of unused material. 
 
DEC-C should not be used for any purpose outside the scope of this protocol, nor may it 
be transferred or licensed to any party not participating in the clinical study. Data for 
DEC-C is confidential/proprietary and shall be maintained as such by the investigators. 
 
All drug supplies provided by the drug supplier must be kept in an appropriate, limited 
access, secure place until used or returned to the drug supplier for destruction. Drug 
supplies will be counted and reconciled at the site before being returned.  
 
Selection and Timing of Dose for Each Subject 
The investigator is responsible for ensuring accountability for DEC-C, including 
maintenance of adequate drug accountability records. 
 
The investigator or designee will supervise study drug treatment given in the clinic and 
instruct the patient on study medication self-administration. 
 
Drug accountability records should include an appropriate inventory of DEC-C including: 
 
• Confirmation that DEC-C supplied by the study was delivered to the trial site. 
• Record of each dose of DEC-C dispensed. 
• Return of unused DEC-C provided by the study to the Sponsor-Investigator or 
designee, or documentation of destruction at site (if drug destruction by the site is 
authorized by sponsor-investigator or designee). 
 
Records should specify relevant dates, quantities, batch numbers, use-by dates and 
patient numbers, as applicable. 
 
The investigator, or designee, should maintain records that adequately document: 
 
• That patients were provided the doses specified by the clinical trial protocol, and 
 
• That all DEC-C provided by the study was fully reconciled, and documentation will 
be provided to the respective drug supplier upon request. 
Treatment Compliance 
The Sponsor-Investigator or other study staff will supervise study treatment given in the 
clinic and instruct the patient on study treatment self-administration. Patients will be 
given a dosing diary on which to document their dosing compliance. 
 
Patients will be asked to bring their study treatment containers and dosing diary with 

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them at each visit and compliance with protocol-defined study treatment intake will be 
checked by pill count and review of the dosing diary. 
 
Compliance to study medication will be recorded by study personnel after discussion 
with the patient and drug accountability. Compliance to study treatment will be done by 
the investigator and recorded in source documents. The date will be recorded as per 
study treatment schedule. The principal investigator or the designee will account for the 
number of tablets dispensed against those returned by the patient. Any deviations and 
missed doses will be recorded in the site’s internal database and drug accountability 
logs with the reasons for subsequent verification. 
 
The investigator will try to ensure complete compliance with the dosing schedule by 
providing timely instructions to the patients. In case of non-compliance, the patients will 
be instructed again. 
 
6 
STUDY PROCEDURES 
 
Enrollment Procedures 
The Vanderbilt-Ingram Cancer Center (VICC) Coordinating Center will coordinate 
enrollment in the study. 
 
Prior to registration, a copy of the IRB approval at the site will be requested and kept on 
file at the Vanderbilt-Ingram Cancer Center (VICC) Coordinating Center. Eligible 
participants will be entered on study centrally at the VICC Coordinating Center. All 
sites should email the Coordinating Center at coordinating.center@vumc.org to verify 
slot availability prior to enrollment.  
 
All patients MUST be registered with the VICC prior to the start of protocol treatment. 
Registration can only be conducted during the business hours of 8AM – 5PM 
Central Time, Monday through Friday.  
 
1) All sites must email the VICC CTSR Coordinating Center at 
coordinating.center@vumc.org to notify of upcoming registration and ensure 
slot availability. The following information should be included in this email: 
o Study number 
o Patient initials 
o Disease type  
o Anticipated consent date 
o Anticipated start date  
 
2) If a subject ID number is required prior to patient enrollment (e.g. at screening due to 
sample collection requirement), the site must submit the following documents with 
their email notification to the Coordinating Center: 
• Copy of the patient’s signed and dated Informed Consent including 
documentation of the consent process. 

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• HIPAA authorization form (if separate from the main consent form) 
• VICC Patient Enrollment Form 
The Coordinating Center will then provide a subject ID number via email. 
 
3) Email the following documents to the Coordinating Center for eligibility review and 
patient enrollment (coordinating.center@vumc.org): 
• Copy of the patient’s signed and dated Informed Consent, including 
documentation of the consent process. 
• HIPAA authorization form (if separate from the main consent form) 
• VICC Patient Enrollment Form 
• Eligibility supporting documents such as pathology reports, laboratory 
tests, etc. or EMR access. Note: all source documents should be de-
identified and screening/subject ID number added prior to sending. 
• Signed and completed Eligibility Checklist. To be eligible for registration to 
the study, the participant must meet each inclusion and exclusion criterion 
listed in the eligibility checklist.  
 
Note: VICC Coordinating Center requires 3 business days to review all documents and 
confirm eligibility. Registrations will only be accepted with prior notice and discussion 
with the Lead Institution. Please email the clinical trials office (CTO) if enrollment is 
needed sooner at coordinating.center@vumc.org.  
 
 
Upon satisfactory review of eligibility documents submitted, the Coordinating Center will 
approve enrollment and issue a subject ID number if one was not issued at screening. 
Once registration/enrollment confirmation from Coordinating Center is received, 
proceed with protocol procedures. 
 
Please contact the assigned Study Contact with any questions regarding this process. 
You can also reach out to your assigned CRA once the study is activated.  
 
The VICC Coordinating Center will assign Subject ID numbers to all patients whose 
eligibility has been confirmed. Only patients deemed eligible will be registered to 
investigational treatment. Sequence/study ID numbers will not be re-used if a patient 
screen fails. Following registration, eligible participants should begin study treatment 
consistent with the protocol no later than 14 days after registration/enrollment by the 
VICC Coordinating Center. If a participant does not receive protocol therapy following 
registration within the allowed time period, the participant’s registration on the study will 
be canceled. The Study Contact should be notified of cancellations as soon as possible. 
Patients being re-screened will need to consent to repeated procedures. As such, the 
Coordinating Center will require a new, signed Informed Consent document.  
Issues that would cause treatment delays should be discussed with the Protocol Chair.  
 
As is generally accepted, standard of care procedures performed prior to consent, but 
within the protocol defined screening window for each assessment, can be used for 
study purposes. All research-only procedures must be performed after patient consent. 

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Definitions 
6.2.1 
Adverse Event (AE) 
An adverse event is any undesirable sign, symptom or medical condition or experience 
that develops or worsens in severity after starting the first dose of study treatment or 
any procedure specified in the protocol, even if the event is not considered to be related 
to the study.  
Abnormal laboratory values or diagnostic test results constitute adverse events only if 
they induce clinical signs or symptoms or require treatment or further diagnostic tests.  
6.2.2 
Serious adverse event (SAE) 
A serious adverse event is an undesirable sign, symptom or medical condition which: 
 
• 
Is fatal or life-threatening; 
• 
Requires or prolongs inpatient hospitalization; 
• 
Results in persistent or significant disability/incapacity; 
• 
Constitutes a congenital anomaly or birth defect; or 
• 
Jeopardizes the participant and requires medical or surgical intervention to prevent 
one of the outcomes listed above.  
 
Events not considered to be serious adverse events are hospitalizations for: 
• 
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
• 
Elective or pre-planned treatment for a pre-existing condition that did not worsen 
• 
Emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission 
• 
Respite care 
6.2.3 
Expectedness  
• 
Expected: Expected adverse events are those that have been previously identified 
as resulting from administration of the agent. For the purposes of this study, an 
adverse event is considered expected when it appears in the current adverse event 
list, the Investigator’s Brochure, the package insert or is included in the informed 
consent document as a potential risk. 
• 
Unexpected: An adverse event is considered unexpected when it varies in nature, 
intensity or frequency from information provided in the current adverse event list, the 
Investigator’s Brochure, the package insert or when it is not included in the informed 
consent document as a potential risk 
6.2.4 
Attribution  
Attribution is the relationship between an adverse event or serious adverse event and 
the study treatment. Attribution will be assigned as follows: 
 

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• 
Definite – The AE is clearly related to the study treatment 
• 
Probable – The AE is likely related to the study treatment 
• 
Possible – The AE may be related to the study treatment 
• 
Unlikely - The AE is doubtfully related to the study treatment 
• 
Unrelated - The AE is clearly NOT related to the study treatment 
 
 
Reporting Procedures 
6.3.1 
General Considerations 
All adverse events will be captured on a centralized electronic case report form called 
ON-line Clinical Oncology Research Environment = Oncore 
 
Oncore is a highly secure, web based, cancer specific, and customizable system that 
provides fully integrative clinical data management and study administration capabilities 
developed in an ongoing collaborative effort with NCI designated Comprehensive 
Cancer Centers. It fully integrates study administration functionality including protocol 
tracking, patient registration, NCI reporting, review committee tracking, and SAE 
tracking, with clinical data management functionality including electronic case report 
forms (eCRF) design, clinical data capture, protocol and regulatory compliance 
monitoring. Specified members at each participating site will submit all regulatory 
documents to the Coordinating Center. 
 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs, and avoid colloquialisms and abbreviations. If known at the time of reporting, a 
diagnosis should be reported rather than individual signs and symptoms (e.g. record 
only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, it is 
acceptable to report the information that is currently available. If a diagnosis is 
subsequently established, it should be reported as follow-up information. 
 
All deaths that occur during the protocol-specified AE reporting period, regardless of 
attribution, will be reported to the appropriate parties. When recording a death, the 
event or condition that caused or contributed to the fatal outcome should be reported as 
the single medical concept. If the cause of death is unknown and cannot be ascertained 
at the time of reporting, report “Unexplained Death.” Deaths that occur during the 
protocol specified adverse event reporting period that are attributed by the investigator 
solely to progression of disease should be recorded only in the study eCRF and not 
reported as an SAE (See Section 6.2). 
 
A pre-existing medical condition is one that is present prior to initiation of protocol 
specified treatment. Such conditions should be reported as medical and surgical history. 
A pre-existing medical condition should be re-assessed throughout the trial and 
reported as an AE or SAE only if the frequency, severity, or character of the condition 
worsens during the study. When reporting such events, it is important to convey the 

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concept that the pre-existing condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE. If a patient is hospitalized to undergo a medical 
or surgical procedure because of an AE, the event responsible for the procedure, not 
the procedure itself, should be reported as the SAE. For example, if a patient is 
hospitalized to undergo coronary bypass surgery, record the heart condition that 
necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for pre-existing conditions; or 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement 
for the study; or 
• Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study. 
6.3.2 
Serious Adverse Events 
All serious adverse events, regardless of causality to study drug, will be reported to the 
Principal Investigator and/or the Study Coordinator at each institution, and also to the 
Coordinating Center. 
 
All serious adverse events must be reported to the Coordinating Center within 24 hours 
of the investigator becoming aware of the event. Events should be reported using the 
Vanderbilt SAE form, located in the packet of supplemental forms. This form must be 
fully completed and emailed (preferred), faxed, or scanned to: 
 
ATTN: VICC CTSR Personnel 
EMAIL: coordinating.center@vumc.org 
 
Follow-up information must also be reported within 24 hours of receipt of the information 
by the investigator. 
 
The Coordinating Center will disseminate information regarding serious adverse events 
to the participating sites as described in FDA guidance only in the case that the event(s) 
is/are unexpected, and is/are believed to be related (e.g., possibly, probably or 
definitely) to the study device/medication. The Coordinating Center will be responsible 
for reporting of events to the FDA and supporters, as appropriate (outlined below). 
6.3.3 
Institutional Review Board 
All adverse events and serious adverse events will be reported to the IRB per current 
institutional standards. If an adverse event requires modification of the informed 
consent, these modifications will be provided to the IRB with the report of the adverse 

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event. If an adverse event requires modification of the study protocol, these 
modifications will be provided to the IRB as soon as is possible. 
6.3.4 
Food and Drug Administration (FDA) 
In this trial, unexpected serious adverse events believed to be definitely, probably, or 
possibly related to study treatment (as determined by the sponsor-investigator) will be 
reported to the FDA via MedWatch 3500A (currently available at 
https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.p
df. Submissions by the sponsor can be submitted via fax or email and must be 
addressed to Regulatory Project Manager in the FDA review division that has 
responsibility for review of the IND. The Coordinating Center will be responsible for 
correspondence regarding adverse events with the FDA for all participating sites. 
6.3.5 
Reporting to Grantor and Funder 
The Sponsor/Investigator shall report to National Comprehensive Cancer Network 
(NCCN) and Taiho Oncology, Inc/OTSUKA all Serious Adverse Events (SAEs), and 
Pregnancy in English via a MedWatch form, in accordance with the Protocol and 
applicable law. All applicable source document(s) will also be sent to OTSUKA in 
English. The Sponsor/Investigator shall comply with OTSUKA’s reasonable follow-up 
requests.  
 
The Sponsor/Investigator will provide National Comprehensive Cancer Network (NCCN) 
and Taiho Oncology, Inc/OTSUKA with details of whom National Comprehensive 
Cancer Network (NCCN) and Taiho Oncology, Inc/OTSUKA shall address requests for 
follow up information on SAE and pregnancy cases reported from this Clinical Trial, and 
further agree to update such contact details as necessary.  
 
Transmission of these reports (initial and follow-up) will be sent electronically via email 
to ORPreports@nccn.org or fax to 215-358-7699 and Taiho Oncology, Inc via email to 
Global_Intake@otsuka-us.com within the timelines specified below: 
 
The investigator shall monitor the Clinical Trial Subject for adverse events and fulfill all 
the reporting requirements to RAs/ECs in accordance with applicable laws. The 
Investigator shall also inform National Comprehensive Cancer Network (NCCN) and 
Taiho Oncology, Inc/OTSUKA of serious adverse events: 
• Unexpected Fatal or Life Threatening Suspected Adverse Reactions- Complete 
and send MedWatch to National Comprehensive Cancer Network (NCCN) and 
Taiho Oncology, Inc/OTSUKA within 24 hours of awareness and report to 
applicable RAs/ECs within 7 calendar days of awareness. 
• Serious & Unexpected Suspected Adverse Reactions- Complete and send 
MedWatch to National Comprehensive Cancer Network (NCCN) and Taiho 
Oncology, Inc/OTSUKA within 24 hours of awareness and report to applicable 
RAs/ECs within 15 calendar days of awareness. 
• All other Serious cases (Expected and Related; Expected and Not related; 
Unexpected and Not related)- Complete and send MedWatch to National 

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Comprehensive Cancer Network (NCCN) and Taiho Oncology, Inc/OTSUKA 
within 24 hours of awareness.  
All serious adverse events need to be sent to National Comprehensive Cancer Network 
(NCCN) and Taiho Oncology, Inc/OTSUKA via a MedWatch Form. For reports from a 
non-English speaking country, English translations be sent to National Comprehensive 
Cancer Network (NCCN) and Taiho Oncology, Inc/OTSUKA Pharmacovigilance.  
 
MedWatch reports must clearly specify SAE term(s) and corresponding Investigator 
causality assessment. 
 
Serious AE reports, related or not related to the Product or where the causality is 
assessed as unknown or not provided shall be transmitted to National Comprehensive 
Cancer Network (NCCN) and Taiho Oncology, Inc/OTSUKA Pharmacovigilance group 
within 24 hours of awareness date. 
 
Special Situation Reports: 
• Drug Exposure During Pregnancy and Lactation, or Paternal Drug Exposure 
Reports: 
• The Sponsor/Investigator will report Exposure During Pregnancy and 
Lactation, or Paternal Drug Exposure on any Clinical Trial Subject while 
participating in the Clinical Trial, and following exposure to a TAIHO IMP, to 
National Comprehensive Cancer Network (NCCN) and Taiho Oncology, 
Inc/OTSUKA (as specified below) on a MedWatch Form and within 24 hours 
from first becoming aware of the pregnancy or exposure. If the partner of a 
Clinical Trial Subject becomes pregnant, the Sponsor/Investigator may collect 
information about the pregnancy and birth if the partner agrees. 
• The Subject will also be followed by the Sponsor/Investigator to determine the 
outcome of the pregnancy (including any premature termination of the 
pregnancy). Information on the status of the mother and child will be 
forwarded to National Comprehensive Cancer Network (NCCN) and Taiho 
Oncology, Inc/OTSUKA. The Sponsor/Investigator must provide final outcome 
of pregnancy to National Comprehensive Cancer Network (NCCN) and Taiho 
Oncology, Inc/OTSUKA. If any SAE(s) is observed in the Subject or 
fetus/child, then SAE(s) must also be reported to National Comprehensive 
Cancer Network (NCCN) and Taiho Oncology, Inc/OTSUKA.  
• Other Special Situation Reports, shall be transmitted to National Comprehensive 
Cancer Network (NCCN) and Taiho Oncology, Inc/OTSUKA within 24 hours of 
the awareness date. 
 
The Sponsor/Investigator shall comply with all applicable laws, including those related 
to data privacy, when undertaking these safety reporting-related obligations. Any 
SAE/special situations shall only contain anonymous or key coded information so that 
any individuals’ names or other fully identifiable information shall be redacted before 
being submitted to National Comprehensive Cancer Network (NCCN) and Taiho 

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Oncology, Inc/OTSUKA. Please note that reporter information is necessary and should 
not be redacted.  
 
Day 0 for all single case reports (including SUSARs) will be the day National 
Comprehensive Cancer Network (NCCN) and Taiho Oncology, Inc/OTSUKA is notified 
by the Sponsor/Investigator and the report meets criteria for reporting.  
 
Each party shall notify the other party within two (2) working days of becoming aware of 
any of the following urgent safety information: Major safety concerns identified in a 
clinical trial. Possible teratogenic effects of the Product or other significant hazard to 
public health. Safety issues published in the scientific and medical literature.  
 
 
7 
STUDY ACTIVITIES 
 
 
 
 
 
 
 
 
 
Description of Procedures 
7.1.1 
Informed Consent 
Eligible patients may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC/REB-approved informed consent. 
 
Informed consent must be obtained before conducting any study-specific procedures 
(e.g., all procedures described in the protocol). The process of obtaining informed 
consent should be documented in the patient source documents. 
7.1.2 
Medical History  
During screening, a complete medical history will be obtained from each patient. 
Medical history will include demographics, baseline symptoms as well as a detailed 
history of prior therapies and/or procedures for their underlying hematologic malignancy 
(e.g., chemotherapy, hormonal therapy, immunotherapy, biotherapy, radiotherapy, and 
surgery), including start and stop dates, best response, disease progression during or 
after therapy, as well as discontinuations due to intolerability or toxicity. 
7.1.3 
Physical Examination, Vital Signs, Height/Weight, and ECOG Score  
Full physical examinations (PE) will be performed prior to receiving first dose of study 
drug and at the EoT Visit and should include general appearance, skin, neck, eyes, 
ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, and 
neurological examinations. All other PEs during the study should be limited, symptom-
directed PEs, including body systems as appropriate. 
 
Information about the PE must be present in the source documentation at the study site.  
An ECOG Score Assessment will be performed during screening and Day 1 of each 
cycle. 

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7.1.4 
Concomitant Medications 
Review and capture of all concomitant medications will be performed at each visit as 
indicated in Table 1, 2, and 3. Concomitant medications include prescription 
medications and over-the-counter preparations (including vitamins, dietary 
supplements, over-the-counter medications, and herbal preparations) used by a patient 
within at least 14 days prior to first dose of protocol-defined treatment and continuing 
through at least the 28-day Follow-Up study visit. 
7.1.5 
Safety Assessments 
All clinical and laboratory adverse events, serious (SAEs) and non-serious (AEs) will be 
collected as follows: all events, serious and non-serious are collected from the day the 
patient signed the ICF up to 28-days post EOT. Safety assessments include: vital signs 
(PE), labs and investigations results – hematology, serum biochemistry, urinalysis. 
 
Adverse events will be collected at each visit along with recording of concomitant 
medications. 
 
7.1.6 
Clinical Laboratory Tests 
Table 9: Clinical Laboratory Tests 
Hematology (Blood sample: whole blood; ethylenediaminetetraacetic acid 
[EDTA]) tests including) 
Hemoglobin 
Hematocrit 
Mean 
corpuscular 
volume 
Mean 
corpuscular 
hemoglobin 
Mean 
corpuscular 
hemoglobin 
concentration 
WBC count 
WBC 
differentiala 
RBC count 
Lymphocytes 
Monocytes 
Neutrophils 
Band 
neutrophils 
Eosinophils 
Basophils 
Platelets 
Serum Chemistry (Blood sample: Serum) 
Sodium* 
Potassium* 
Chloride* 
Bicarbonate* 
BUN* 
Creatinine* 
Glucose* 
Calcium 
Phosphate 
Magnesium 
ALT* 
AST* 
Alkaline 
Phosphatase* 
Total bilirubin* 
 

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Total protein 
Albumin 
Lactate 
dehydrogenase 
Uric acid 
 
Coagulation 
Prothrombin 
time (PT) 
International 
normalization 
ratio (INR) 
Partial 
thromboplastin 
time (PTT) 
 
 
*=Limited serum chemistry 
a. WBC differential may be automated or manual as per institutional standards. 
Reticulocytes may be done only when clinically indicated. 
7.1.7 
Electrocardiography 
A standard 12-lead ECG will be performed during screening. Patients must rest for at 
least 5 minutes prior to the ECG recording. The investigator will interpret the ECG using 
one of the following categories: normal, abnormal but not clinically significant, or 
abnormal and clinically significant. The date and time the ECG was performed and the 
following parameters will be recorded: Heart rate, PR interval, QT interval, QRS interval, 
and QT corrected using Fridericia's formula (preferred) or alternatively by Bazett’s 
formula (if Bazett’s is the established site method). 
7.1.8 
Pregnancy Test 
Serum pregnancy test for women of childbearing potential required during Screening. 
Subsequent pregnancy test – either serum or urine – to be done ≤ 3 days prior to first 
dose of protocol-indicated treatment (e.g. if prior screening test was done > 3 days 
before initiating C1D1 treatment, it will need to be repeated), at EOT, and additionally if 
clinically indicated per study physician. 
 
A woman of childbearing potential (WOCBP) is defined as any female who has 
experienced menarche who has not undergone surgical sterilization (e.g. bilateral tubal 
ligation, total hysterectomy, or bilateral oophorectomy) at least 4 weeks prior to first 
dose of protocol-indicated treatment, or who is not postmenopausal. Menopause is 
defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of 
other biological or physiological causes. 
7.1.9 
Bone marrow aspiration and biopsy  
Patients must have at least 2-3 mL of bone marrow aspirate material obtained within 14 
days of beginning treatment on this study.  
 
On a day of a fresh biopsy procedure, matching peripheral Pharmacodynamic (PD) 
blood samples are to be drawn PRIOR to the fresh biopsy procedure (with the PD blood 
to be drawn ideally coincident with any Hematology and Blood Chemistry specimens – if 
such safety labs are also scheduled for collection on the day in question). 

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7.1.10 
Pharmacodynamic (PD) Blood Samples 
Pharmacodynamic blood samples for research are to be obtained during Screening 
(any time prior to first dose of study treatment if archival tissue is used to satisfy the 
requirement of baseline tumor tissue; or if a fresh baseline biopsy is done, then PD 
blood should be collected on the same-day as the biopsy – PRIOR to the biopsy 
procedure). 
 
Blood sampling for PD correlative studies will be done as summarized in the Lab 
Manual.  
 
 Screening (Day -14 to Day -1) 
7.2.1 
Screening Procedures 
Screening will include the screening procedures described below and will be performed 
within 14 days prior to the start of therapy (e.g., day -14 to day -1). Screening activities 
are summarized in Table 1. 
The Investigator should not repeat procedures that are performed as part of standard of 
care (SOC), if they are within the screening window and are done prior to signing the 
ICF. Data from SOC procedures will be part of the patient's medical history and may be 
used for study purposes. 
Prior to performing any study-based procedures, patient informed consent must be 
obtained. Screening may be divided into two (or more) clinic visits at the discretion of 
the Investigator. The procedures to be performed during screening are listed below: 
• Informed consent and baseline characteristics 
• Physical Exam  
• ECOG performance status 
• Height and weight  
• Vital signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and adverse event review. 
• CBC with differential 
• Blood chemistry including magnesium, phosphorus, LDH, and uric acid 
• Coagulation testing (PT/INR, PTT) 
• Electrocardiogram (ECG) 
• Serum or urine pregnancy test in women of childbearing potential 
• Bone marrow aspiration/biopsy with additional aspirate sent for correlative science 
• Next generation sequencing (locally done/myeloid focused) 
• PD studies (blood) 
• Anti-TLS hydration / prophylaxis Allopurinol must be initiated at least 2-3 days prior to 
the start of therapy. 

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7.2.2 
Screen Failures 
A patient found not eligible for the trial after giving informed consent is considered a 
screen-failure. The enrollment form must be completed and sent to the sponsor-
investigator or designee to confirm the outcome of the screening process. 
 
Re-screening and re-enrollment of a subject who has discontinued the study as a pre-
treatment failure (e.g. subject has not received protocol-indicated treatment) is 
permitted.  
 
A consented patient previously reported to the coordinating center as pre-treatment 
failure must be re-consented prior to undergoing re-screening.  
 
Cycle 1 (Pre-remission Therapy) 
7.3.1 
Cycle 1, Day 1 
On Cycle 1, Day 1, the following procedures must be completed, unless previously  
completed ≤ 3 days prior to a patient’s first dose of protocol-indicated treatment: 
• Physical Exam 
• ECOG performance status 
• CBC with differential 
• Blood chemistry including magnesium, phosphorus, LDH, and uric acid 
• Serum or urine pregnancy test in women of childbearing potential 
• Weight. 
• Vital Signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and Adverse Event review. 
• Surveillance for and expedited reporting of Dose Limiting Toxicity (DLT) – see Section 
5.2.4 for DLT definition. 
• Anti-TLS hydration / prophylaxis  
• Dose venetoclax/DEC-C as outlined in Table 5 and Table 6.  
7.3.2 
Cycle 1, Day 2, 3, & 5 
• CBC with differential 
• Blood chemistry including magnesium, phosphorus, LDH, and uric acid 
• Vital Signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and Adverse Event review. 
• Surveillance for and expedited reporting of Dose Limiting Toxicity (DLT) – see Section 
5.2.4 for DLT definition. 
• Anti-TLS hydration / prophylaxis  
• Dose venetoclax/DEC-C as outlined in Table 5 and Table 6.  
7.3.3 
Cycle 1, Day 8  
• CBC with differential 

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• Blood chemistry including magnesium, phosphorus, LDH, and uric acid 
• Vital Signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and Adverse Event review. 
• Surveillance for and expedited reporting of Dose Limiting Toxicity (DLT) – see Section 
5.2.4 for DLT definition. 
• Anti-TLS hydration / prophylaxis  
• Dose venetoclax as outlined in Table 5 and Table 6.  
7.3.4 
Cycle 1, Day 15  
• CBC with differential 
• Blood chemistry 
• Vital Signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and Adverse Event review. 
• Surveillance for and expedited reporting of Dose Limiting Toxicity (DLT) – see Section 
5.2.4 for DLT definition. 
• Anti-TLS hydration / prophylaxis  
• Dose venetoclax as outlined in Table 5 and Table 6.  
7.3.5 
Cycle 1, Day 22 
• CBC with differential 
• Blood chemistry  
• Vital Signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and Adverse Event review. 
• Surveillance for and expedited reporting of Dose Limiting Toxicity (DLT) – see Section 
5.2.4 for DLT definition. 
• Anti-TLS hydration / prophylaxis  
• Dose venetoclax as outlined in Table 5 and Table 6. 
• Bone marrow aspiration/biopsy with additional aspirate sent for correlative science 
• Next generation sequencing (Central/VUMC) 
• PD studies (blood) 
 
Cycle 2 (Pre-remission Therapy; only if C1D22 marrow is involved) 
7.4.1 
Cycle 2, Day 1  
• Physical Exam 
• ECOG performance status  
• Weight. 
• Vital Signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and Adverse Event review. 
• CBC with differential 
• Blood chemistry  

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• Surveillance for and expedited reporting of Dose Limiting Toxicity (DLT) – see Section 
5.2.4 for DLT definition. 
• Dose venetoclax/DEC-C as outlined in Table 5 and Table 6. 
7.4.2 
Cycle 2, Day 8 
• Vital Signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and Adverse Event review. 
• CBC with differential 
• Blood chemistry  
• Dose venetoclax as outlined in Table 5 and Table 6. 
7.4.3 
Cycle 2, Day 15 
• Physical Exam 
• Vital Signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and Adverse Event review. 
• CBC with differential 
• Blood chemistry  
• Dose venetoclax as outlined in Table 5 and Table 6. 
7.4.4 
Cycle 2, Day 22 
• Physical Exam 
• Vital Signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and Adverse Event review. 
• CBC with differential 
• Blood chemistry  
• Dose venetoclax as outlined in Table 5 and Table 6. 
• Bone marrow aspiration/biopsy with additional aspirate sent for correlative science 
• Next generation sequencing (Central/VUMC) 
• PD studies (blood) 
 
Post-remission Cycle 1 (if remission confirmed/counts recovered) 
7.5.1 
Post-remission Cycle 1, Day 1 
• Physical Exam 
• ECOG performance status  
• Weight. 
• Vital Signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and Adverse Event review. 
• CBC with differential 
• Blood chemistry  
• Surveillance for and expedited reporting of Dose Limiting Toxicity (DLT) – see Section 
5.2.4 for DLT definition (only in patients who received one pre-remission cycle) 

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• Dose venetoclax/DEC-C as outlined in Table 5 and Table 6. 
7.5.2 
Post-remission Cycle 1, Day 5 
• Vital Signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and Adverse Event review. 
• CBC with differential 
• Blood chemistry  
• Dose venetoclax/DEC-C as outlined in Table 5 and Table 6. 
7.5.3 
Post-remission Cycle 1, Day 15 
• Vital Signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and Adverse Event review. 
• CBC with differential 
• Blood chemistry  
• Dose venetoclax as outlined in Table 5 and Table 6. 
 
Post-remission Cycle 2 (if remission confirmed/counts recovered) 
7.6.1 
Post-remission Cycle 2, Day 1 
• Physical Exam 
• ECOG performance status  
• Weight. 
• Vital Signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and Adverse Event review. 
• CBC with differential 
• Blood chemistry  
• Surveillance for and expedited reporting of Dose Limiting Toxicity (DLT) – see Section 
5.2.4 or DLT definition (only in patients who received one pre-remission cycle) 
• Dose venetoclax/DEC-C as outlined in Table 5 and Table 6. 
7.6.2 
Post-remission Cycle 2, Day 5 
• Vital Signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and Adverse Event review. 
• CBC with differential 
• Blood chemistry  
• Dose venetoclax/DEC-C as outlined in Table 5 and Table 6.  
7.6.3 
Post-remission Cycle 2, Day 15 
• Vital Signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and Adverse Event review. 
• CBC with differential 

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• Blood chemistry  
• Dose venetoclax as outlined in Table 5 and Table 6.  
 
Post-remission Cycle 3 (only if remission confirmed/counts 
recovered) 
7.7.1 
Post-remission Cycle 3, Day 1 
• Physical Exam 
• ECOG performance status  
• Weight. 
• Vital Signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and Adverse Event review. 
• CBC with differential 
• Blood chemistry  
• Dose venetoclax/DEC-C as outlined in Table 5 and Table 6.  
• Bone marrow aspiration/biopsy with additional aspirate sent for correlative science 
• Next generation sequencing (Central/VUMC) 
 
Post-remission Cycle 4+ (if remission confirmed/counts recovered) 
7.8.1 
Post-remission Cycle 4+, Day 1 
• Physical Exam 
• ECOG performance status  
• Weight. 
• Vital Signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and Adverse Event review. 
• CBC with differential 
• Blood chemistry  
• Dose venetoclax/DEC-C as outlined in Table 5 and Table 6.  
7.8.2 
End of Treatment (≤ 10 days after last dose of study treatment) 
Reasonable effort should be made to complete End-of-Treatment (EOT) / Withdrawal 
procedures on the day it is decided that a patient will no longer receive protocol-
indicated treatment. 
 
The following EOT procedures must be completed subsequent to and not later than 10 
days after the patient’s last dose of protocol-indicated treatment with venetoclax/DEC-C 
(whichever treatment occurs last) and prior to any subsequent anti-cancer therapy: 
• Physical Exam  
• ECOG performance status 
• Weight  
• Vital signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and adverse event review. 

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• CBC with differential 
• Blood chemistry including magnesium, phosphorus, LDH, and uric acid 
• Coagulation testing (PT/INR, PTT) 
• Electrocardiogram (ECG) 
• Serum or urine pregnancy test in women of childbearing potential 
• Bone marrow aspiration/biopsy with additional aspirate sent for correlative science 
• Next generation sequencing (Central/VUMC) 
• PD studies (blood) 
 
 28 Day Follow-up Visit Assessments 
Documented attempt(s) must be made for patient return to the study clinic. It will not be 
considered a protocol deviation if the patient is physically unable to return for the follow-
up visit; such circumstance should be recorded in the study documents, and as much of 
the follow-up information as possible should be obtained via feasible patient contact and 
from local and outside facilities.  
 
A Follow-up clinic visit is to be completed 28 days (+7 days) after patient’s final protocol-
indicated treatment venetoclax or DEC-C (whichever occurs last), in order to undergo 
the following assessments: 
 
• Physical Exam  
• ECOG performance status 
• Weight  
• Vital signs: Blood pressure (BP), heart rate (HR) and temperature. 
• Concomitant medication and adverse event review. 
• CBC with differential 
• Blood chemistry 
 
For patients who discontinue study treatment for reason other than progressive disease 
confirmed by bone marrow aspiration and biopsy (e.g. suspicious peripheral blood 
counts), please note the study may continue to request results of laboratory data 
conducted outside of the study but related to peripheral blood counts or bone marrow 
examination, until progressive disease following venetoclax/DEC-C is ultimately 
confirmed by marrow procedure. 
 Survival Follow-up 
Each patient will be followed for survival every 3 months (± 14 days) after patient’s final 
protocol treatment with DEC-C or venetoclax (whichever occurs last) until death, end of 
the study, until patient withdraws consent, or for a maximum of 2 years after the 
patient’s final protocol-indicated treatment – whichever comes first. Survival contact can 
be made via clinic visit, chart review, obituary or similar observation (e.g. Social Security 
death index), or by telephone.  
 
 

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8 
CORRELATIVE STUDIES 
 
Specific Aims 
• Assess the phenotypic and functional changes of post-HCT DEC-C/venetoclax 
therapy on B and T cell subsets. 
• Correlate changes in B and T cell subsets with clinical data, including DEC-C/ 
venetoclax dosing schedules and patient characteristics. 
 
Study methods: 
We will assess the effect of DEC-C/venetoclax on immune subsets in post-HCT AML. 
Using B- and T-cell mass cytometry (CyTOF) panels in stimulated/unstimulated 
peripheral blood mononuclear cell (PBMC) samples, we will perform 
immunophenotyping prior to treatment, following pre-remission therapy, during post-
remission therapy, and at the end of treatment (EOT). Specimens that will be collected 
are described in Table 1. Correlative data interpreted in the context of clinical data and 
study outcomes. 
8.2.1 
Assess the phenotypic and functional changes of post-HCT DEC-C/ 
venetoclax therapy on B and T cell subsets 
Immunophenotyping will be performed to identify quatitative and functional changes in 
B-cell and T-cell subsets with the intent of furthering our understanding of the 
mechanism(s) of immune-related adverse events. These assays will include flow 
cytometry/CyTOF and cytokine analysis.  
 
We will interrogate T and B cell 
signaling, and immune function/ 
composition, by flow cytometry 
or single cell mass cytometry 
(CyTOF) using cryopreserved 
PBMCs isolated from patients 
pre-treatment and at serial 
timepoints post-treatment. The 
Cytec Aurora, will allow up to 20 
spectra at one time without 
compensation issues. Using a 
15-20 antibody immune 
oncology panels and standard operating procedures for the staining of clinical and 
preclinical samples to define the immune phenotype. Specific lymphocyte subsets can 
also be characterized with intracellular cytokines as well as cell surface markers of 
activation or polarization. For more highly multiplexed analyses a Helios mass 
cytometer (CyToF) will be employed to measure up to 35-40 protein parameters 
 on a per cell basis. We will utilize validated anti-human T-cell and B-cell antibodies for 
a comprehensive immune cell analysis. 
 
Sample 
Timepoint 
Pre-Tx 
On Treatment 
EOT 
Intense 
C1D22 
Intense 
C2D22 
Blood- PBMC 
isolation 
X 
X 
X 
X 
Blood- 
serum/plasma 
isolation 
X 
X 
X 
X 
Figure 4. Time points for clinical correlates 

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Modulation of cytokines will also be monitored by Luminex leveraging serum or plasma 
isolated from whole blood from patients pre-DEC-C/venetoclax treatment and at serial 
timepoints post-treatment. The Luminex system (Millipore/Thermo-Fisher) will be used 
with Millipore plates and beads on biospecimens collected from patients. Standard 
manufacturer-recommended protocols will be used, and MAGPIX/xPONENT will be 
used for readout of cytokine levels. Standard curves generated from positive controls 
will be used to quantitate the concentration of the cytokines. 
 
Immunological data generated from these assays will be integrated and correlated with 
patient outcomes (infection vs. no infection and response vs. no response).  
8.2.2 
Correlate changes in B and T cell subsets with clinical data, including 
DEC-C/venetoclax dosing schedules and patient characteristics. 
As DEC-C/venetoclax combination therapy is evaluated in the corresponding phase II 
trial, the study data will be analyzed in combination with the immune subset data from 
SA1. Combining these datasets will provide important clinical context in an 
immunocompromised population. Clinical features, including time from HCT to relapse, 
dosing of DEC-C/venetoclax, immunosuppression, infectious complications, and non-
relapse mortality events will be correlated with immune subset data. Body surface area 
(BSA) and body mass index (BMI) after HCT will be correlated with the depth and 
duration of cytopenias, including absolute lymphocyte count. This approach will extend 
SA1, identify clinical populations at-risk for toxicity, and inform study design and dosing 
in future DEC-C/venetoclax studies. 
 
 
9 
PLANNED STATISTICAL METHODS: 
 
General Considerations 
Statistical support for this study will be provided by the Department of Biostatistics at 
Vanderbilt University Medical Center with analyses being performed by or under the 
direction of a faculty member in biostatistics.  
 
Disease Assessments 
For the purposes of this analysis, responses will be assessed in accordance with the 
International Working Group (IWG) response criteria in acute myeloid leukemia.19 
 
Dose De-escalation Design 
Assuming a historical ORR of 15%, per the phase II efficacy trial, Simon’s optimal two-
stage design calls for a total of 34 patients. A preliminary efficacy assessment will be 
performed following enrollment of the first 20 patients. If >3/20 enrolled patients achieve 
a CR, this is sufficient to continue enrollment for the remainder of the study.  
 

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If >9/34 patients respond, we will reject (p<0.05) the null hypothesis that the true 
response rate of the regimen is less than or equal to 15%. If the true response rate is 
35% or greater, this study design has 80% probability of rejecting the null hypothesis. If 
the true response rate is low at 15%, the probability of early termination is 60% with an 
expected sample size of 19 patients. 
 
The maximum number of patients enrolled (n=51) reflects an anticipated drop out of 
15% (n=5) and enrollment of 6-12 additional patients if dose level 0 is deemed toxic. 
9.3.1 
General Analysis Considerations 
Continuous variables (e.g., age) will be summarized using the minimum, 25th, 50th 
(median), 75th, and maximum values along with the mean and standard deviation, as 
appropriate. Generally, rank based nonparametric tests will be used to compare 
continuous variables among patient subgroups. Categorical variables (e.g., objective 
response) will be summarized in frequency tables and compared among patient 
subgroups using the chi-square test. Linear regression and logistic (or ordinal logistic) 
regression will be used to construct multivariable models for continuous, binary, and 
ordinal variables, as appropriate. In addition to ORR, the distributions of progression-
free and overall survival will be estimated using the Kaplan-Meier method. We will 
consider statistical comparisons statistically, but not necessarily clinically, significant for 
p<0.05. 
 
Dose limiting toxicity (see Section 5.2.4) will be 
monitored in this phase II clinical trial using a Bayesian 
approach.  A maximum of 34 patients will be enrolled 
and toxicity monitoring will begin when the 6th patient is 
evaluable for toxicity. It is expected that the toxicity rate 
is maintained at approximately 20% (maximum 
probability of DLT of 0.2, prior distribution (1,1), cohort 
size 1, and posterior probability > 80%). Pursuant to this 
rule, patients will be monitored according to the 
stopping boundaries outlined in Table 10. For example, 
the protocol will pause for review due to excessive 
toxicity if 2 or more DLTs are experienced by the first 6 
patients treated.  9 DLTs will be allowed among 34 
patients treated. 
 
9.3.2 
Adverse Events 
Adverse Events (AEs) will be coded using the 
MedDRA dictionary and displayed in tables and 
listings using System/Organ/Class (SOC) and 
Preferred Term. 
 
Number 
of DLTs 
Of total 
number 
of 
patients 
treated  
2 
6 
3 
10 
4 
14 
5 
19 
6 
23 
7 
27 
8 
31 
9 
34 
Table 10. Toxicity stopping rules. 
The expansion phase will be 
paused for review if  DLT rate 
exceeds above. 

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Analyses of AEs will be performed for those events that are considered to be treatment 
emergent AEs (TEAEs), defined as any AE with onset or worsening of a pre-existing 
condition on or after the first administration of study medication through 28 days 
following last dose or any event considered drug-related by the investigator through the 
end of the study. AEs with partial dates will be assessed using the available date 
information to determine if treatment-emergent; AEs with completely missing dates will 
be assumed to be treatment-emergent. 
 
AEs will be summarized by patient incidence rates. In all tabulations, a patient may 
contribute only once to the count for a given AE preferred term. 
The number and percentage of patients with TEAEs will be summarized, as well as the 
number and percentage of patients with TEAEs assessed by the Investigator as at least 
possibly related to treatment. The number and percentage of patients with any Grade ≥ 
3 TEAE will be tabulated in the same manner. In the event a patient experiences 
repeated episodes of the same TEAE, the event with the highest severity and/or 
strongest causal relationship to study treatment will be used for purposes of tabulations. 
Serious AEs (SAEs) will also be tabulated. 
 
No formal hypothesis-testing analysis of AE incidence rates will be performed. 
All AEs (treatment emergent and post-treatment) will be listed in patient data listings. 
Separate by-patient listings will be provided for the following: patient deaths, SAEs, and 
AEs leading to withdrawal. 
9.3.3 
Laboratory Data  
The actual value and change from baseline for each on study evaluation will be 
summarized for each clinical laboratory parameter, including hematology and clinical 
chemistry, by arm, and for all study patients combined. In the event of repeat values, 
the last non-missing value per study day/time will be used. 
 
Severity of select clinical lab measures will be determined using CTCAE criteria (e.g., 
those measures that have a corresponding CTCAE grade classification). Labs with 
CTCAE Grades ≥ 3 will be presented in a data listing. Shift tables that present changes 
from baseline to worst on-study values relative to CTCAE classification ranges will be 
produced. 
9.3.4 
Vital Signs and Physical Examinations  
The actual value and change from baseline to each on-study evaluation will be 
summarized for vital signs for all study patients combined. By-patient listings of vital 
sign measurements will be presented in data listings. 
Physical examination results at screening will be summarized; all other abnormal 
physical examination data will be recorded. All examination findings will be presented in 
a data listing. 
 
 

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10 REGULATORY AND ETHICAL COMPLIANCE 
 Protocol Review and Amendments  
Information regarding study conduct and progress will be reported to IRB per current 
institutional standards.  
 
The trial will not be initiated until there is approval by the local IRB of the protocol, 
informed consent document and any other material used to inform the patient about the 
nature of the trial. The IRB should be duly constituted according to local regulatory 
requirements. The investigator will inform the IRB of the progress of the trial at least 
yearly.  
 
Any changes to the protocol will be made in the form of a written amendment and must 
be approved by the study chair and the local IRB prior to local implementation. All 
amendments will also be submitted as necessary to the FDA by the study chair (or 
designee). 
 
Protocol changes to eliminate an immediate hazard to a trial patient may be 
implemented by the investigator immediately. The investigator must then immediately 
inform the local IRB; and the study chair (or designee), who will communicate as 
appropriate with the FDA.  
 
The study chair (or designee) is responsible for the coordination and development of all 
protocol amendments, and will disseminate this information to the participating centers.  
 Informed Consent  
The investigator (or his/her designee) will explain to each subject the nature of the 
study, its purpose, the procedures involved, the expected duration, the potential risks 
and benefits involved and any discomfort it may entail. Each subject will be informed 
that participation in the study is voluntary, that s/he may withdraw from the study at any 
time, and that withdrawal of consent will not affect subsequent medical treatment or 
relationship with the treating physician(s) or institution. The informed consent will be 
given by means of a standard written statement, written in non-technical language, 
which will be IRB approved. The subject should read and consider the statement before 
signing and dating it, and will be given a copy of the document. No subject will enter the 
study or have study-specific procedures done before his/her informed consent has been 
obtained.  
 
In accordance with the Health Information Portability and Accountability Act (HIPAA), 
the written informed consent form (or a separate document to be given in conjunction 
with the consent document) will include a subject authorization to release medical 
information to the study sponsor and supporting agencies and/or allow these bodies, a 
regulatory authority, or Institutional Review Board access to subjects’ medical 
information that includes all hospital records relevant to the study, including subjects’ 
medical history.  

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 Ethics and Good Clinical Practice  
This study will be carried out in compliance with the protocol and Good Clinical Practice 
(GCP), as described within:  
1. 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 199639 
2. 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 
50 and 56 concerning informed consent and IRB regulations). 
3. 
Declaration of Helsinki, concerning medical research in humans 
(Recommendations Guiding Physicians in Biomedical Research Involving Human 
Subjects, Helsinki 1964, amended Tokyo 1975, Venice 1983, Hong Kong 1989, 
Somerset West 1996).  
 
The investigator agrees to adhere to the instructions and procedures described within 
the above and thereby to adhere to the principles of Good Clinical Practice with which 
the above conform. 
 Confidentiality  
It is the responsibility of the investigator to ensure that the confidentiality of all patients 
participating in the trial and all of their medical information is maintained. Case report 
forms and other documents submitted to regulatory authorities must not contain the 
name of a trial patient. All patients in the trial will be identified by a unique identifier, 
which will be used on all CRFs and any other material submitted to regulatory 
authorities. All case report forms and any identifying information must be kept in a 
secure location with access limited to the study staff directly assisting with the trial.  
 Study Termination  
The study chair reserves the right to terminate the study at any site and at any time. 
Reasons for study termination may include, but are not limited to, the following:  
• 
Investigator non-compliance with the protocol, GCP or regulatory requirements  
• 
Insufficient enrollment  
• 
Safety concerns  
• 
Decision by suppliers to modify or discontinue the availability, development or 
manufacture of DEC-C.  
• 
A request to discontinue the study by the IRB or FDA.  
 
The study chair will promptly notify investigators, the IRB and FDA if the study is 
terminated for any reason. 
 Multi-Center Guidelines  
10.6.1 
Protocol Review and Amendments  
Information regarding study conduct and progress will be reported to the IRB per the 
current institutional standards of each participating center.  
 

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Any changes to the protocol will be made in the form of an amendment and must be 
approved by the IRB of each institution prior to local implementation.  
 
The study chair (or designee) is responsible for the coordination and development of all 
protocol amendments. Once approved by the study chair, Vanderbilt will disseminate 
this information to the participating centers. 
10.6.2 
Study Documentation  
Each participating site is responsible for submitting copies of all relevant regulatory 
documentation to the coordinating center. The required documents include, but are not 
limited to the following: local IRB approvals (e.g., protocol, consent form, amendments, 
patient brochures and recruitment material, etc.), IRB membership rosters, summary of 
unanticipated problems or protocol deviations, and documentation of expertise of the 
investigators. The coordinating center will provide each participating site with a 
comprehensive list of the necessary documents. It is the responsibility of the 
participating sites to maintain copies of all documentation submitted to the coordinating 
center.  
 
The requirements for data management, submissions, and monitoring are outlined 
below. The participating sites will submit all the research related information inclusive of: 
 
• Source documents (patient registration list, CRF info, toxicity assessments, 
tumor measurements / responses, etc.) are required to be provided within 30 
days of visit or 10 days in advance of a monitoring visit or audit. 
 
• Essential Documents (IRB approval documents, financial disclosure forms, 1572, 
delegation of authority log, protocol training, etc.) are required to be provided 
within one week of receiving the updated documents. 
 
Personnel from the VICC Clinical Trial Shared Resource (CTSR) will monitor the trial 
and may periodically visit the investigative site to assure proper conduct of the trial and 
proper collection of the data. The investigators at other sites will allow the monitor to 
review all source documents used in the preparation of the case reports.  
10.6.3 
Records Retention  
United States (US) FDA regulations (21 CFR §312.62[c]) require that records and 
documents pertaining to the conduct of this study and the distribution of investigational 
drug, including CRFs, consent forms, laboratory test results, and medication inventory 
records, must be retained by each Principal Investigator for 2 years after marketing 
application approval. If no application is filed, these records must be kept 2 years after 
the study is discontinued and the US FDA and the applicable national and local health 
authorities are notified.  
 
Following closure of the study, each participating center will maintain a copy of all site 
study records in a safe and secure location. The coordinating center will inform the 
investigator at each site at such time that the records may be destroyed. 

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10.6.4 
Publication  
It is understood that any manuscript or releases resulting from the collaborative 
research must be approved by the Study Chair and will be circulated to applicable 
participating sites/investigators prior to submission for publication or presentation. 
10.6.5 
Administrative and Regulatory Requirements  
This is an investigator-initiated study. The Study Chair and sponsor-investigator, Sanjay 
Mohan, is conducting the study and acting as the sponsor. Therefore, the legal/ethical 
obligations of the Study Chair include both those of a sponsor and those of a principal 
investigator. 
10.6.6 
Auditing and Monitoring: 
The Vanderbilt-Ingram Cancer Center (VICC) oversees patient safety and data 
monitoring for its investigator-initiated and NIH-NCI funded clinical trials through its Data 
and Safety Monitoring Committee (DSMC). The purpose of the DSMC is to ensure the 
efficient implementation and management of the VICC Data and Safety Monitoring Plan 
(DSMP). The Committee maintains authority to intervene in the conduct of studies as 
necessary to ensure clinical research performed at VICC achieves the highest quality 
standards. 
 
The VICC DSMC meets on a quarterly basis and ad hoc to discuss data and safety 
monitoring of clinical trials and to oversee the VICC DSMP. Internal audits for 
compliance with adverse event reporting, regulatory and study requirements, and data 
accuracy and completion are conducted according to the VICC DSMP according to 
study phase and risk. The committee reviews all serious adverse events (SAE) on 
Vanderbilt sponsored investigator-initiated studies on a quarterly basis and provides 
DSMC SAE review reports to the Vanderbilt IRB. 
 
The trial additionally will be monitored by the VICC Multi-Institutional Coordinating 
Center. The actual frequency of monitoring will depend on the enrollment rate and 
performance of the site. Monitoring will be conducted through onsite and/or remote 
monitoring, teleconferences with the Investigator and site staff, and appropriate 
communications by mail, fax, email, or telephone. The purpose of monitoring is to 
ensure that the study is conducted in compliance with the protocol, standard operating 
procedures (SOPs), and other written instructions, and to ensure the quality and 
integrity of the data.  
 
During scheduled monitoring visits, investigators and the investigational site staff must 
be available to discuss the progress of the trial, make necessary corrections to case 
report form entries, respond to data clarification requests, provide required regulatory 
documents, and respond to any other trial-related inquiries of the monitor.  
 
In addition to the above, the FDA may review the conduct or results of the study at the 
investigational site. 

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10.6.7 
Data Handling and Record Keeping  
An electronic case report form (eCRF) is required and must be completed for each 
included participant. The completed dataset should not be made available in any form to 
third parties, except for authorized representatives of appropriate Health/Regulatory 
Authorities, without written permission from Vanderbilt.  
 
To enable evaluations and/or audits from health authorities and Vanderbilt, each site 
investigator agrees to keep records including: The identity of all participants (sufficient 
information to link records; e.g., hospital records), all original signed informed consent 
forms, copies of all source documents, and detailed records of drug disposition. To 
comply with international regulations, the records should be retained by the investigator 
in compliance with regulations.  
 
Queries resulting from review of the eCRFs will be generated for the site and 
corrections will be made by the study site personnel. This will be done on an ongoing 
basis.  
10.6.8 
Data Verification 
Data will be collected via eCRFs and entered into the database per Coordinating Center 
guidelines. The Coordinating Center will check data accuracy by performing source data 
verification. Source data verification is a direct comparison of the entries made on the 
CRFs against the appropriate source documentation. This will be conducted remotely, 
with the possibility of on-site verification periodically. Discrepancies in the data will be 
brought to the attention of the investigator and/or the investigator’s staff. Any necessary 
corrections will be made directly to the eCRFs or via queries by the investigator and/or 
the investigator’s staff. 
10.6.9 
Study Closure  
The Coordinating Center reserves the right to discontinue a site at any time during the 
study for medical or administrative reasons such as: 
• Unsatisfactory enrollment; 
• GCP noncompliance; 
• Inaccurate or incomplete data collection; 
• Falsification of records; 
• Failure to adhere to the study protocol. 
10.6.10 Protocol Deviations 
The Coordinating Center is responsible for implementing and maintaining quality 
assurance and quality control to ensure that studies are conducted according to the 
protocol, GCP, and all applicable regulatory requirements. A protocol deviation is any 
noncompliance with the protocol. Noncompliance can be on the part of the study 
participant, the investigator, or the study site staff. Deviations to the protocol are not 
permitted except when necessary to eliminate an immediate hazard to study subjects. 

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10.6.11 Changes to Protocol and Informed Consent Document 
Any change to the protocol or informed consent document must be reviewed and 
approved by the Coordinating Center before being submitted to the Institutional Review 
Board/Independent Ethics Committee at participating institutions. Amendments should 
not be implemented until all necessary approvals have been obtained, except when 
necessary to eliminate an immediate hazard to study subjects. 
 
 
11 REFERENCES: 
1. 
Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in 
acute myeloid leukemia: determination of prognostic significance of rare recurring 
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Breems DA, Van Putten WL, De Greef GE, et al. Monosomal karyotype in acute myeloid 
leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol. 
Oct 2008;26(29):4791-4797. 
3. 
Haferlach C, Alpermann T, Schnittger S, et al. Prognostic value of monosomal karyotype 
in comparison to complex aberrant karyotype in acute myeloid leukemia: a study on 824 
cases with aberrant karyotype. Blood. Mar 2012;119(9):2122-2125. 
4. 
Pasquini MC, Zhang MJ, Medeiros BC, et al. Hematopoietic Cell Transplantation 
Outcomes in Monosomal Karyotype Myeloid Malignancies. Biol Blood Marrow 
Transplant. Feb 2016;22(2):248-257. 
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Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine 
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group B. J Clin Oncol. May 2002;20(10):2429-2440. 
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Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 
2017 ELN recommendations from an international expert panel. Blood. 01 
2017;129(4):424-447. 
7. 
Bejanyan N, Weisdorf DJ, Logan BR, et al. Survival of patients with acute myeloid 
leukemia relapsing after allogeneic hematopoietic cell transplantation: a center for 
international blood and marrow transplant research study. Biol Blood Marrow 
Transplant. Mar 2015;21(3):454-459. 
8. 
Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with Venetoclax in Relapsed 
Chronic Lymphocytic Leukemia. N Engl J Med. Jan 2016;374(4):311-322. 
9. 
DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or 
azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. Jan 
2019;133(1):7-17. 
10. 
Wei AH, Strickland SA, Hou JZ, et al. Venetoclax Combined With Low-Dose Cytarabine 
for Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase 
Ib/II Study. J Clin Oncol. May 2019;37(15):1277-1284. 

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11. 
Byrne M, Danielson N, Sengsayadeth S, et al. The use of venetoclax-based salvage 
therapy for post-hematopoietic cell transplantation relapse of acute myeloid leukemia. 
Am J Hematol. 09 2020;95(9):1006-1014. 
12. 
DiNardo CD, Rausch CR, Benton C, 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. 03 2018;93(3):401-407. 
13. 
Aldoss I, Yang D, Aribi A, et al. Efficacy of the combination of venetoclax and 
hypomethylating agents in relapsed/refractory acute myeloid leukemia. Haematologica. 
09 2018;103(9):e404-e407. 
14. 
VENCLEXTA (venetoclax) [Prescribing Information]. AbbVie Inc. and Genentech USA, Inc. 
April 2016. 
15. 
Tai YT, Landesman Y, Acharya C, et al. CRM1 inhibition induces tumor cell cytotoxicity 
and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and 
therapeutic implications. Leukemia. 01//print 2014;28(1):155-165. 
16. 
Cabrero M, Jabbour E, Ravandi F, et al. Discontinuation of hypomethylating agent 
therapy in patients with myelodysplastic syndromes or acute myelogenous leukemia in 
complete remission or partial response: retrospective analysis of survival after long-
term follow-up. Leuk Res. May 2015;39(5):520-524. 
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Garcia-Manero G, Griffiths EA, Steensma DP, et al. Oral cedazuridine/decitabine for MDS 
and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. 
Blood. 08 2020;136(6):674-683. 
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Savona MR, McCloskey JK, Griffiths EA, Lee KWL, Al-Kali A, Zeidan AM. Clinical Efficacy 
and Safety of Oral Decitabine/Cedazuridine in 133 Patients with Myelodysplastic 
Syndromes (MDS) and Chronic Myelomonocytic Leukemia. Paper presented at: 62nd 
ASH Annual Meeting and Exposition2020; Virtual. 
19. 
Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, 
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Oncology. Dec 15 2003;21(24):4642-4649. 
 
 
 
 

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APPENDIX 1: EXCLUDED AND CAUTIONARY MEDICATIONS AND 
DIETARY RESTRICTIONS 
Excluded throughout the study: 
• Grapefruit and grapefruit products. 
• Seville Oranges (including marmalade containing Seville oranges) 
• Starfruit. 
• Concurrent therapy with any other approved or investigative anticancer 
therapeutics. 
• Other investigational agents. 
Excluded during venetoclax ramp-up phase; and  
Cautionary when receiving venetoclax at the steady state dose: 
• Strong CYP3A inhibitors. 
• Strong CYP3A inducers. 
• Moderate CYP3A inhibitors 
 Exclude during the first cycle and consider alternative 
medications. 
 If a subject requires use of these medications at the venetoclax 
plateau dose, use with caution and reduce the venetoclax dose 
by 50% for moderate inhibitors. After discontinuation of a 
moderate CYP3A inhibitor, wait for 3 days before the venetoclax 
dose is increased back to the initial target dose. 
• Moderate CYP3A inducers 
 Exclude during the ramp-up phase and consider alternative 
medications. 
Cautionary throughout the study: 
• Warfarin (closely monitor the international normalized ratio, INR). 
• P-gp substrates 
• BCRP substrates 
• OATP1B1/1B3 substrates 
• P-gp inhibitors 
• BCRP inhibitors