A Phase II Study of Azacitidine, Venetoclax and Trametinib for Patients With Acute Myeloid Leukemia or Higher-Risk Myelodysplastic Syndrome
Phase: PHASE2
Conditions: Recurrent Acute Myeloid Leukemia, Recurrent Chronic Myelomonocytic Leukemia, Recurrent Myelodysplastic Syndrome, Refractory Acute Myeloid Leukemia, Refractory Chronic Myelomonocytic Leukemia, Refractory Myelodysplastic Syndrome
Sponsor: M.D. Anderson Cancer Center

 
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A phase II study of azacitidine, venetoclax and 
trametinib for patients with acute myeloid leukemia or 
higher-risk myelodysplastic syndrome 
 
Principal Investigator: 
 
Nicholas Short, MD 
Department of Leukemia,  
University of Texas MD Anderson Cancer Center 
1515 Holcombe Boulevard Unit 428 
Houston, Texas 77030 
Tel – 713-563-4485 
E-mail – nshort@mdanderson.org 
 
Co-Principal Investigator: 
 
Farhad Ravandi, MD 
 Department of Leukemia,  
University of Texas MD Anderson Cancer Center 
1515 Holcombe Boulevard Unit 428 
Houston, Texas 77030 
Tel – 713-745-0394 
E-mail – fravandi@mdanderson.org 
 
 
 

 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ....................................................................... 2 
2.  
STUDY OBJECTIVES AND ENDPOINTS ................................ 4 
3. 
SELECTION OF PATIENTS ...................................................... 4 
3.1 Inclusion Criteria ..................................................................... 4 
3.2 Exclusion Criteria .................................................................... 5 
4. 
TREATMENT OF SUBJECTS ................................................... 6 
5. 
CONCOMITANT MEDICATIONS ............................................ 11 
6. 
STUDY PROCEDURES .......................................................... 12 
7. 
EFFICACY AND SAFETY ASSESSMENTS ........................... 13 
8. 
REPORTING REQUIREMENTS .............................................. 14 
9. 
OUTSIDE PHYSICIAN PARTICIPATION ............................... 16 
10. 
STATISTICAL METHODS ....................................................... 17 
11.     REFERENCES ........................................................................ 17 
 
 
 
 
 
 
 

 
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1. 
INTRODUCTION 
For older patients who cannot tolerate intensive chemotherapy, single agent hypomethylating agents such 
as azacitidine or decitabine are commonly used based on studies showing that they improve survival 
compared to low-dose cytarabine or supportive care alone.1,2 More recently, the combination of the Bcl-2 
inhibitor venetoclax with a hypomethylating agent is emerging as a new standard of care for older patients 
with newly diagnosed AML who are unfit for standard intensive chemotherapy.3,4  An ongoing study is 
evaluating the safety and efficacy of venetoclax in combination with either decitabine or azacitidine for 
patients ≥65 years of age with previously untreated AML and who are ineligible for chemotherapy.4 At the 
most recent update, 145 patients were treated with a median age of 74 years (range, 65-86 years). 
Cytogenetics were poor risk in 49% of patients. The 30-day and 60-day mortality rates were 3% and 8%, 
respectively.  The complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate for the 
entire cohort was 66% with a median duration of CR/CRi of 11.0 months. The median overall survival (OS) 
for the entire cohort was 17.5 months, and the 1 year-OS rate was 59%. These results represent the best 
survival data for older, unfit patients with newly diagnosed AML yet reported.  A subsequent phase III study 
of venetoclax plus azacitidine versus azacitidine alone showed a significant improvement in OS in the 
azacitidine and venetoclax arm, although data have not yet been presented. 
 
Several retrospective studies have been published evaluating the safety and efficacy of venetoclax plus a 
hypomethylating agent in patients with relapsed/refractory AML. A study from MD Anderson evaluated the 
outcomes of 43 patients with relapsed/refractory myeloid malignancies (n=39, 91% with AML) who received 
venetoclax in combination with other agents.5 Thirty-one of the evaluated patients (72%) received 
venetoclax with a hypomethylating agent. Most patients (84%) were treated in salvage 2 or later (range 2-
8) with a median of 3 prior treatment regimens. Objective response rate (ORR) was achieved in 9 (21%) 
patients, including 2 (5%) with CR, 3 (7%) with CRi, and 4 (9%) with morphologic leukemia-free state 
(MLFS). Of the 9 responding patients, all responded within 1 cycle of venetoclax combination therapy. 
These nine responding patients included eight (26%) of the patients treated with an HMA combination. With 
a median follow-up of 3 months, the estimated 6-month OS rate was 24%. In another study of venetoclax 
in combination with hypomethylating agents in relapsed/refractory AML from City of Hope, 33 patients were 
treated.6 The median number of prior therapies was 2 (range, 1-8). Twenty patients (61%) had failed HMA 
therapy previously and 13 patients (39%) had prior allogenic stem cell transplantation. The ORR was 64% 
(N=21), with 10 patients (30%) achieving CR, 7 (21%) achieving CRi and 4 (12%) achieving MLFS. With a 
median follow-up of 6.5 months, the 1-year OS rate was 53%. The group at Memorial Sloan Kettering 
Cancer Center has also reported their experience with venetoclax in combination with either low-dose 
cytarabine or a hypomethylating agent in patients with R/R myeloid malignancies.7 A total of 24 patients 
were treated (n=8 with hypomethylating agent; N=16 with low-dose cytarabine). Twenty-three patients 
(96%) had a diagnosis of AML. The median number of prior treatments was 3 (range, 1-8); 6 patients (29%) 
had prior stem cell transplantation. Of 21 patients evaluable for efficacy, the ORR was 29%, including a CR 
rate of 24% (n=5) and PR rate of 5% (n=1). With a median follow-up of 4.1 months, the 3-month OS rate 
was 72%. 
 
Despite the promising results with azacitidine plus venetoclax, the development of resistance is common. 
The addition of novel agents to chemotherapy or hypomethylating agent backbone regimens may improve 
outcomes for patients with AML.8  One major driver of resistance in patients treated with venetoclax-based 
combinations is alteration of the MAPK signaling pathway. For example, mutations in KRAS or NRAS are 
present in 10-25% of patients at the time of diagnosis and are associated with a lower likelihood of response 
to hypomethylating agent plus venetoclax combinations.9,10 New treatment-emergent Ras pathway-activing 
mutations (e.g. mutations in FLT3, NRAS/KRAS, PTPN11, etc.) are also commonly observed at the time of 
relapse in these patients.11 The development of effective therapies capable of producing long-term 
remissions in this population of patients with AML harboring Ras pathway-activating mutations is an unmet 
need. Given the high frequency of Ras-activating mutations at relapse and their role in both primary and 

 
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secondary venetoclax resistance, combination strategies that incorporate agents that target this signaling 
pathways before the development of resistance may help to delay or prevent relapse. Preclinical studies 
suggest that dual targeting of BCL2 and the MAPK pathway may be synergistic in the treatment of AML.12  
 
Trametinib is an oral MEK inhibitor that is FDA approved (in combination with the BRAF inhibitor dabrafenib) 
for malignant melanoma, non-small cell lung cancer, and anaplastic thyroid cancer that harbors a BRAF 
mutation. Trametinib has also shown clinical activity in patients with relapsed/refractory AML harboring a 
RAS mutation. In a phase I/II study from MD Anderson, the toxicity profile of trametinib was consistent with 
that reported in the solid tumor literature.13 The recommended phase 2 dose of trametinib was 2mg daily. 
In patients with relapsed/refractory AML or MDS with an NRAS or KRAS mutation, trametinib monotherapy 
resulted in an overall response rate of 20%, and the overall response rate was 27% in patients with CMML 
with an NRAS or KRAS mutation. Given the single-agent activity of trametinib in RAS-mutated AML, 
combination strategies that incorporate trametinib for patients with RAS mutations are warranted. 
 
We therefore propose of a phase II study of the combination of azacitidine, venetoclax and trametinib for 
patients with relapsed/refractory AML or high-risk MDS harboring Ras pathway-activating mutations. Given 
the established role of Ras pathway-activating mutations in primary or secondary resistance to venetoclax 
monotherapy or hypomethylating agent plus venetoclax combinations,11,14 there is also a rationale for early 
integration of MEK inhibition prior to the development of acquired Ras pathway mutations. The goal of this 
approach is to prevent (or delay) the emergence of venetoclax-resistant RAS-mutated subclones that 
contribute to relapse. In the present study we therefore propose to also evaluate the combination of 
azacitidine, venetoclax, and trametinib in patients with newly diagnosed AML irrespective of RAS mutation 
status, with the goal of prolonging remission durations and survival through prevention of treatment-
emergent Ras pathway mutations. This frontline cohort would be opened only after safety is established in 
a safety lead-in of patients with relapsed/refractory AML or high-risk MDS. 
 
2.  
STUDY OBJECTIVES AND ENDPOINTS 
2.1. Primary Objectives 
 
Cohort A: To determine overall survival rate at 1 year of the regimen in patients with 
newly diagnosed AML  
 
Cohort B: To determine the complete remission(CR)/Complete remission without 
recovery of counts (CRi)/morphologic leukemia-free state (MLFS) rate of the regimen 
in patients with relapsed/refractory AML or high-risk MDS 
 
2.2 
Secondary Objectives 
 
To assess other efficacy endpoints (CR rate, minimal residual disease negativity by 
flow cytometry, relapse-free survival, event-free survival, and overall survival) 
 
To assess proportion of patients proceeding to HSCT 
 
To determine the safety of the combination regimen 
 
2.3 
Exploratory Objectives 
 
To evaluate the impact of baseline genomic alterations on response and survival of 
the combination regimen  
 
To evaluate clonal evolution from diagnosis to relapse 
 

 
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3. 
SELECTION OF PATIENTS 
Patients will be selected from those referred to the Leukemia department at M D Anderson 
Cancer Center through the normal of process of referral. Eligible patients will be registered after 
the process of consenting on the MD Anderson protocol and data monitoring system. 
 
3.1 
Inclusion Criteria 
1. Diagnosis: 
a) Cohort A (frontline): Adults ≥18 years with newly diagnosed AML.  
b) Cohort B (relapsed/refractory): Adults ≥18 years with relapsed/refractory AML or 
relapsed/refractory MDS or CMML that is intermediate-2 or high-risk by the 
International Prognostic Scoring System with ≥10% blasts harboring a Ras 
pathway-activating mutation. Eligible mutations include: activating mutations of KIT, 
HRAS/NRAS/KRAS, BRAF, CBL or PTPN11 or loss of function mutation of NF1. 
Other mutations not listed here that are anticipated to activate Ras signaling may 
be considered for enrollment after discussion with the PI. 
 
2. Performance status 2 (ECOG Scale).  
 
3. Adequate liver and renal function as defined by the following criteria: 
a) Total serum bilirubin < 2.5 x upper limit of normal (ULN), unless due to Gilbert’s 
syndrome, hemolysis or the underlying leukemia approved by the PI  
b) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 3 x ULN, 
unless due to the underlying leukemia approved by the PI 
d)  Creatinine clearance ≥30 mL/min  
 
4. Ability to swallow 
 
5. Signed informed consent  
 
3.2 
Exclusion Criteria 
 
1. Patients suitable for and willing to receive intensive induction chemotherapy (cohort A 
only) 
 
2. Active serious infection not controlled by oral or intravenous antibiotics (e.g. persistent 
fever or lack of improvement despite antimicrobial treatment).   
 
3. Patients with a prior or concurrent malignancy whose natural history or treatment is not 
anticipated to interfere with the safety or efficacy assessment of the investigational 
regimen may be included only after discussion with the PI 
 
4. Consumed strong inducer of CYP3A or p-glycoprotein within 3 days of study 
enrollment.  Agents include but are not limited to: carbamazepine, phenytoin, rifampin, 
and St. John’s wart. 
 
5. Treatment with any investigational antileukemic agents or chemotherapy agents in the 
last 7 days before study entry, unless full recovery from side effects has occurred or 
patient has rapidly progressive disease judged to be life-threatening by the investigator. 

 
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Prior recent treatment with corticosteroids, hydroxyurea and/or cytarabine (given for 
cytoreduction) permitted. 
 
6. Pregnant women will not be eligible; women of childbearing potential should have a 
negative pregnancy test prior to entering on the study and be willing to practice 
methods of contraception throughout the study period and for at least 6 months after 
the last dose of study drugs. Women do not have childbearing potential if they have 
had a hysterectomy or are postmenopausal without menses for 12 months. In addition, 
men enrolled on this study should understand the risks to any sexual partner of 
childbearing potential and should practice an effective method of birth control 
throughout the study period and for at least 4 months after the last dose of study drugs. 
Lactating women (or those planning to breastfeed) should not breastfeed during 
treatment of trametinib and for at least 2 months after the last dose of trametinib. 
 
4. 
TREATMENT OF SUBJECTS 
4.1. Variations in doses of the study agents or supportive care medications or dose schedules 
other than those suggested below are allowed if deemed to be in the best interest of 
patients. Such changes should be discussed with the PI before they are instituted.  
 
4.2. Treatment Overview – This will be a phase II, single-arm, open-label study conducted 
solely at MD Anderson Cancer Center. There will be an initial safety lead-in of 6 patients 
with relapsed/refractory AML. Patients with newly diagnosed AML will not be enrolled until 
safety of the combination is confirmed during this safety lead-in. 
 
Cohort A will enroll patients with newly diagnosed AML and Cohort B will enroll patients 
with relapsed/refractory AML or higher-risk MDS or CMML. 
 
The regimen consists of up to 24 cycles of the combination of azacitidine, venetoclax, and 
trametinib.  Each cycle is anticipated to be 28 days in length, although cycle delays may be 
made due to delayed count recovery, intercurrent illness, etc. 
 
4.3 
Cycle 1 (Induction) – Patients will receive the following agents: 
 
Azacitidine 75 mg/m2 IV or SC (according to patient preference) on days 1-7 of each 
cycle 
 
Venetoclax 100mg on day 1, 200mg on day 2, 400mg on days 3-28 
 
Trametinib 2mg orally daily 
 
Bone marrow will be performed on cycle 1 day 21 (±7 days). For patients in marrow 
remission (i.e. bone marrow blasts <5% or insufficient sample due to hypoplastic or 
aplastic marrow), venetoclax may be held at the discretion of the treating physician after 
discussion with the PI in order to allow for peripheral blood count recovery.   
 
4.4 
Cycles 2-24 (Consolidation) – Patients will receive the following agents: 
 
Azacitidine 75 mg/m2 IV or SC (according to patient preference) on days 1-7 of each 
cycle 
 
Venetoclax 400 mg orally daily on days 1-21 
 
Trametinib 2mg orally daily 
 
4.5 
Number of patients 

 
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A total of 40 patients will be enrolled (20 in each cohort). All patients on this study will be 
enrolled at a single site (MD Anderson Cancer Center). Patients will be considered enrolled 
on the day the patient is fully registered in CORE. 
 
 
4.6 
General Considerations 
 
It is strongly recommended that patients in Cohort A remain hospitalized until day 28 
of cycle 1 or the time of ANC > 500, whichever occurs first.  Subsequent cycles may 
be given as an outpatient. 
 
Venetoclax should be administered with food 
 
Trametinib should be administered on an empty stomach (1 hour before or 2 hours 
after a meal) 
 
Prevention of infection 
o 
Prophylactic antibiotics may be given with each course until neutrophil 
recovery to 500/L or greater  
o 
Suggestions include:  Levaquin 500 mg orally daily (or other appropriate 
antibacterial agent); caspofungin or other appropriate antifungal agent; 
valacyclovir 500 mg orally daily or acyclovir 400 mg orally twice daily or other 
appropriate antiviral agent.  
 
Azacitidine administration 
o 
Azacitidine may be given on days 5-2-2 which is 5 consecutive weekdays 
(Days 1-5) with rest on the 2 weekend days (Days 6 and 7) and then dosing 
the first two weekdays of the next week (Days 8 and 9) of each 28-day cycle 
as determined by treating physician. Azacitidine may be administered by 
MDACC or local physician, inclusive of regional care centers.  Commercial 
supplies and institutional standards for administration of azacitidine will be 
used and records will be obtained from the local physician.  
o 
Both subcutaneous and IV forms of azacitidine administration are FDA-
approved and are considered interchangeable, and route will be based on 
patient and physician preference. 
o 
Azacitidine administration and premedications will be per institutional 
standards.  
 
As venetoclax and trametinib are obtained commercially, some patients may have 
delays in beginning either agent due to financial or other logistical considerations. 
Even if one or both of these agents is not yet available, patients may begin 
azacitidine on day 1.  Venetoclax and trametinib should be started when it is obtained 
and continued as above. To make up for missed initial doses of venetoclax, the 
venetoclax course may be extended up through day 28 of the cycle, although the 
patient may not take more than the total number of intended days of venetoclax. 
Failure to begin venetoclax or trametinib on day 1 will not be considered a protocol 
deviation. 
 
If azacitidine, trametinib and/or venetoclax are held or discontinued due to toxicity or 
any other reason (see section 7), the patient may continue on study with the 
remaining agent(s). 
 
Azacitidine, trametinib, and venetoclax will be charged to the patient/insurance. If 
trametinib is not approved by insurance, we will obtain through patient assistance 
programs. Our leukemia physicians, PAs, and pharmacists have extensive 
experience with obtaining off-label trametinib for patients with leukemia. 

 
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 
Any expired or unused drug study medications will be destroyed according to 
institutional policy.  This will include also any leftover medication returned by the 
patient. 
 
Delays in cycles are acceptable depending on recovery for cytopenias or other side 
effects, logistical concerns, or patient/physician preference in the best interest of the 
patient. 
 
4.7 
Suggested Standard Dose Reductions/Modifications: 
Toxicity will be evaluated according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 5.0. Recommendations for dose 
modifications are below. Variations in dose reductions or the administration of azacitidine, 
venetoclax or trametinib other than those suggested below are allowed in the best interest of 
patients. Such patients should be discussed with the principal investigator. 
 
 
Venetoclax 
o Non-hematological toxicity - If grade 3 or 4 non-hematologic toxicity is 
attributable to venetoclax, dose interruption of venetoclax is required. Patients 
who experience drug-related grade 3 non-hematological toxicity may be given a 
subsequent course one dose level below the previous course, but the patient 
must have recovered to grade ≤1 before start of the next course. If a patient 
requires more than 2 dose reductions for grade 3 non-hematologic toxicity, 
venetoclax will be discontinued. If a patient has drug-related grade 4 non-
hematological toxicity, venetoclax will be discontinued. The dose of venetoclax 
can be decreased during a cycle, at the discretion of treating physician and PI, 
for chronic grade 2 non-hematological toxicity. Other dose modifications may be 
considered as clinically indicated with documentation and approval of the PI. The 
dose reduction guidelines for venetoclax are in the table below: 
 
Current Venetoclax 
Dose 
Reduced Dose 
400mg 
200mg 
200mg 
100mg 
100mg 
50mg 
50mg 
20mg 
20mg 
Hold venetoclax 
 
Alternatively, at the discretion of the treating physician, the duration of venetoclax administration 
can be decreased (e.g. decrease from 21-day to 14-day administration) rather the dose being 
reduced. This may be performed due previous toxicity or concern for future myelosuppression or 
toxicity. Such modifications should be discussed with the PI and documented in the medical 
record. 
 
In addition to above suggested dosing levels, venetoclax dosing may be interrupted during the 
course of treatment for tolerance/toxicity concerns in the judgement of the treating physician. 
Missed doses do not need to be made up.   
 

 
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o Hematologic toxicity 
 Dose interruptions or modifications will be made for grade 4 
hematological toxicities only if PI strongly feel that the cytopenias are 
related to venetoclax and not related to underlying disease or the use of 
other agents. Patients with baseline neutropenia or those who have 
significant bone marrow involvement may be particularly at high risk.  
 If a subject achieves CRi or has a morphologically leukemia free bone 
marrow after completion a cycle, venetoclax may be interrupted for up to 
14 days after the last day of the cycle or until recovery of ANC >500/μL.  
 If a subject presents with new onset grade 4 neutropenia for more than 1 
week during subsequent cycles, unless it is thought to be due to the 
underlying disease, venetoclax dosing may be interrupted until ANC 
recovery to >500/µL in consultation with the study PI. Venetoclax may be 
re-initiated at a lower dose per discussion between the treating physician 
and the study PI. The dose reduction guidelines for venetoclax are in the 
table above (same as for non-hematologic toxicity). 
 
Azacitidine 
o 
Cytopenias are common in the patient population studied in this trial.  Dose 
modification for azacitidine for grade 3-4 hematologic toxicities will be 
considered only if the PI strongly feel that the cytopenias were related to 
azacitidine and after appropriate dose reductions of venetoclax have been 
made, as above. 
 
Current Azacitidine Dose 
Reduced Dose 
75mg/m2 
50mg/m2 
50mg/m2 
37.5mg/m2 
37.5mg/m2 
Hold azacitidine 
 
o 
Further reductions beyond what is shown in the table above or alternative 
reductions (e.g. 75mg/m2 x 5 days) may be allowed if recommended by the 
treating physician and after discussion with the PI. 
o 
If the reduced dose is well tolerated and the toxicity leading to dose reduction 
was ≤Grade 3, has resolved, and does not reoccur, the dose may resume at 
the original dose level in the next cycle 
o 
If unexplained reductions in serum bicarbonate < 20 mEq/L or elevations of 
BUN or serum creatinine occur, consider reducing or holding the dose of 
azacitidine 
o 
If indicated, bone marrow evaluation will be performed to establish whether 
continued myelosuppression is related to persistent or progressing leukemic 
infiltration.   
 
Trametinib 
o 
Cytopenias are common in the patient population studied in this trial.  Dose 
modification for trametinib for grade 3-4 hematologic toxicities will be 
considered only if the PI strongly feel that the cytopenias were related to 
trametinib and after appropriate dose reductions of azacitidine and/or 
venetoclax have been made, as above. 
o 
The following table provides dose reduction guidelines for trametinib 

 
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Current Trametinib Dose 
Reduced Dose 
2mg 
1.5mg 
1.5mg 
1mg 
1mg 
Hold trametinib 
 
o 
Cutaneous 
 
Grade 2: Reduce dose level 
 Grade 2 that does not improve within 3 weeks after dose reduction or 
Grade 3-4: Hold trametinib for up to 3 weeks. If improved, then reduce 
dose 
 Intolerable Grade 2 or Grade 3-4 that does not improve within 3 weeks 
after dose reduction: Discontinue trametinib 
o 
Cardiac 
 Asymptomatic, absolute decrease in LVEF of 10% or greater from 
baseline and is below institutional lower limits of normal (LLN) from 
pretreatment value: Hold trametinib for up to 4 weeks 
 Asymptomatic, absolute decrease in LVEF of 10% or greater from 
baseline and is below LLN that improves to normal LVEF value within 4 
weeks following interruption: If improved within 4 weeks, then reduce 
dose 
 Symptomatic congestive heart failure or absolute decrease in LVEF of 
greater than 20% from baseline that is below LLN or absolute decrease 
in LVEF of 10% or greater from baseline and is below LLN that does not 
improve to normal LVEF value within 4 weeks following interruption: 
Discontinue trametinib 
o 
Ocular 
 Retinal pigment epithelial detachments (RPED): Hold trametinib for up to 
3 weeks.  
 
If improves within 3 weeks, then resume with same or reduced 
dose 
 
If does not resolve within 3 weeks, then reduce dose or 
permanently discontinue  
 Retinal vein occlusion: Discontinue trametinib 
o 
Interstitial lung disease/pneumonitis: Discontinue trametinib 
o 
Other non-hematological toxicity possibly or probably related to trametinib (e.g. 
diarrhea) 
 Grade 3: Hold trametinib for up to 3 weeks 
 If Grade 3 adverse reaction improves to Grade 0-1 following interruption 
within 3 weeks: Reduce dose  
 Grade 4 adverse reaction or Grade 3 adverse reaction that does not 
improve to Grade 0-1 within 3 weeks: Discontinue trametinib 
 
4.8 Prophylaxis and Management of TLS 
 
There is a potential for TLS, especially in those with elevated pretreatment LDH levels, 
elevated leukocyte count, renal dysfunction, and dehydration. To mitigate the risk for 

 
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TLS, subjects will receive tumor lysis prophylaxis, including hydration (e.g., oral, 
intravenous) and treatment with an agent to reduce the uric acid level (e.g., allopurinol, 
rasburicase) prior to and during at least the first 1 week of cycle 1. For subjects who had 
dose delay or interruptions, TLS prophylactic measures may need to be implemented 
based on the disease status prior to resuming treatment. TLS prophylaxis must be 
initiated in all such subjects prior to the first venetoclax dose or first new escalated dose. 
 
 
In cycle 1 during venetoclax dose-escalation, TLS chemistry tests (calcium, inorganic 
phosphorus, potassium, uric acid, and creatinine) should be checked on the first day of 
venetoclax and each day of a new dose prior to venetoclax dosing.  TLS chemistry tests 
should also be checked approximately between 4-12 hours after each new dose of 
venetoclax (i.e. during the venetoclax ramp-up). 
 
4.9 
Definition of DLT  
 
A DLT will be defined as any of the following adverse events that cannot be considered 
primarily related to the underlying malignancy, a comorbid condition, or a concomitant 
medication, occurring between day 1 and day 28 of cycle 1 (with the exception of 
hematologic toxicity which may be assessed up to day 42  of cycle 1) 
 
Any ≥ grade 3 non-hematologic toxicity with the following exceptions: 
 
Grade 3 alopecia 
 
Grade 3 nausea, vomiting, diarrhea with electrolyte abnormalities lasting less than 48 
hours that are not clinically significant and that does not require total parenteral 
nutrition (TPN), tube-feeding, or hospitalization 
 
Grade 3 or 4 liver abnormalities (AST, ALT, or alkaline phosphatase) that resolve to 
< grade 2 within 5 days 
 
Grade 3 hyperbilrubinemia that resolves to < grade 2 within 5 days 
 
Grade 3 indirect hyperbilirubinemia 
 
Infection, unless the infection resulted from unexpectedly complicated by the degree 
or duration of myelosuppression in the absence of persistent leukemia. 
 
Patients who receive at least a full course of therapy will be considered to be evaluable for 
toxicity/DLT and will not be replaced unless the PI determines that further additional patients 
at that dose level are required for safety purposes. 
 
For patients who do not receive venetoclax and/or trametinib on day 1 of cycle 1 due to 
logistical and/or financial reasons, the DLT period will be extended to 28 days from the first 
dose of venetoclax and/or trametinib (whichever starts later).  For evaluation of neutropenia-
related DLT, the DLT period will be 42 days from the first dose of venetoclax and/or 
trametinib (which ever starts later). 
 
Hematologic toxicity will be defined as failure to recover ANC > 500/µL or platelet count 
> 25,000/µL by day 42. This will be considered DLT. However, for patients with > 5% blasts, 
myelodysplastic changes, or evidence of disease by flow cytometry/cytogenetics, failure to 
recover neutrophil or platelet count will not be considered a DLT as this could be the result of 
persistent disease. 
 

 
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5. 
CONCOMITANT MEDICATIONS 
 
Concomitant medications will be documented in the subject’s electronic medical 
record. 
 
G-CSF is allowed if needed to hasten count recovery at the discretion of the treating 
physician 
 
Use of hydroxyurea during the study may be permitted as clinically indicated, on a 
case-by-case basis and after discussion with the PI 
 
Intrathecal chemotherapy for prophylaxis or treatment of known or suspected CNS 
disease may be permitted as clinically indicated, on a case-by-case basis and after 
discussion with the PI 
 
Patients may be concurrently enrolling in supportive care clinical trials with exclusion 
medications that listed below. Other investigational agents that are used for 
treatment of other cancers will not be allowed. 
 
Strong CYP3A or p-glycoprotein inducers are not permitted while on study.  These 
agents include but at not limited to: carbamazepine, phenytoin, rifampin and St. 
John’s wart. 
 
Moderate CYP3A inducers and moderate or strong CYP3A inhibitors are discouraged 
while on study. If a patient requires use of moderate CYP3A inducers, use with 
caution. In many instances, such as antifungal prophylaxis with “azole” therapy in 
neutropenic patients, CYP3A inhibitors are required in AML patients. Venetoclax 
should be administered at 50% dose reduction in the setting of moderate CYP3A 
inhibitors (i.e. isavuconazole, ciprofloxacin, diltiazem) and 75% dose reduction with 
strong CYP3A inhibitors (e.g. voriconazole), with the exception of posaconazole in 
which an ~83% dose reduction should be used (i.e. 70mg with posaconazole). The 
venetoclax dose reduction should continue for the duration of co-administration. In 
the event the co-administered CYP3A inhibitor is discontinued, the assigned 
venetoclax dose should be resumed 2-3 days after discontinuation.  During the 
venetoclax ramp-up, these agents must be held; however, they may be started or 
resumed 24-72 hours after the highest planned dose of venetoclax is given, along 
with the appropriate dose reduction of venetoclax as above. No dose reductions will 
be performed for azacitidine or trametinib based on concomitant medications. 
 
Drugs involving these enzymes and transporters can be found in the following 
webpage: http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
 
6. 
STUDY PROCEDURES  
6.1. Pre-Treatment Evaluation 
1. History and physical examination, including vital signs, height, weight, and performance 
status 
2. CBC with differential, electrolytes (potassium, calcium, magnesium, bicarbonate, 
phosphorus), LDH, uric acid, creatinine, liver function tests (AST and/or ALT and total 
bilirubin). Differential does not need to be performed if white blood cell count is <0.4 K/µL. 
3. Bone marrow aspirate, cytogenetics, 81-gene mutation panel (or similar mutation screen) 
must have be sent within 4 weeks of enrollment.  
4. Peripheral blood and bone marrow samples for correlative studies 

 
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13 
5. Pregnancy test in female patients of appropriate age and menopausal state within 1 week 
of first dose 
6. Echocardiogram or MUGA scan to assess cardiac function within 4 weeks of first dose 
 
All pretreatment evaluation must be performed within 2 weeks of first dose of the study drug, 
unless otherwise specified as above. 
 
6.2 Evaluation During Study 
1. History and physical examination, including vital signs and weight prior to each cycle 
2. Evaluation for toxicity assessment prior to each cycle 
3. Assessment of concomitant medications prior to each cycle 
4. In addition to TLS monitoring during the venetoclax ramp-up period (section 4.8), CBC 
with differential, electrolytes (potassium, calcium, magnesium, bicarbonate, phosphorus), 
LDH, uric acid, creatinine, liver function tests (AST and/or ALT and total bilirubin) at least 
1-2 times per week during cycle 1, then prior to each subsequent cycle. Differential does 
not need to be performed if white blood cell count is <0.4 K/µL. 
5. Echocardiogram or MUGA scan to assess cardiac function every 2-3 months (for patients 
still on trametinib) 
6. Bone marrow aspiration (including flow cytometry for MRD, and cytogenetics [for patients 
in whom last bone marrow had abnormal cytogenetics]) to be performed at a minimum 
on: 
a. Cycle 1 day 21 (±7 days) – For patients in marrow remission on the Cycle 1 day 
21 bone marrow (i.e. bone marrow blasts <5% or insufficient sample due to 
hypoplastic or aplastic marrow), venetoclax may be held at the discretion of the 
treating physician after discussion with the PI in order to allow for peripheral 
blood count recovery.   
b. Cycle 1 day 28 (±7 days) – will be performed at least 7 days after C1D21 (± 7 
days) if marrow remission is not achieved. 
c. Cycle 2 day 28 (±7 days) – only required for patients who did not achieve 
CR/CRi at end of cycle 1 
d. Cycle 4 day 28 (±7 days) 
During bone marrows at end of cycles 1, 2, and 4 and at the time of relapse, additional 
aspirate will be collected for correlative studies, including single-cell sequencing. After the 
end of cycle 4 bone marrow, additional bone marrow assessments should be performed 
every 2-4 cycles or as clinically indicated.  
 
 
Pre 
Cycle 1 
 
Cycle 2 
 
Cycle 3 
 
Cycles 4+ 
End of 
Treatment 
Follow-
Up 
Informed consent 
X 
 
 
 
 
 
 
History + physical 
X 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
Every cycle 
 
 
Performance Status 
X 
 
 
 
 
 
 
Concomitant medication and 
AE assessment 
X 
X 
X 
X 
Every cycle 
 
 
Toxicity assessment 
 
X 
X 
X 
Every cycle 
X 
X 
CBC with diff 
X 
X 
X 
X 
Every cycle 
 
 
Electrolytes (potassium, 
calcium, magnesium, 
bicarbonate phosphorus), 
LDH, uric acid, creatinine, 
liver function tests (AST or  
ALT, total bilirubin) 
X 
X 
X 
X 
Every cycle  
 
 
Bone marrow aspirate 
X 
X 
X1 
 
X2 
 
 

 
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Pregnancy test (If indicated) 
X 
 
 
 
 
 
 
Echocardiogram or MUGA3 
X 
 
 
 
 
 
 
Peripheral blood for 
correlative studies 
X 
 
 
 
 
 
 
1 Only required for patients who did not achieve CR/CRi at end of cycle 1 
2 Every 2-4 cycles or as clinically indicated 
3 Repeat every 2-3 months while on therapy (for patients still on trametinib) 
 
Failure to obtain samples for correlative work (e.g. single-cell sequencing) during either the pre-treatment 
evaluation or during study will not result in a protocol deviation. 
 
6.3  End of treatment visit 
 
At the time of withdrawal, the following study procedures visit should be completed: 
1. 
Evaluation for toxicity assessment 
 
 
6.4  Follow-up 
 
Thirty days after last dose of the study drugs toxicity assessment will be recorded.  This may 
be done over the phone with a member of the study staff. 
 
6.5  Long-Term Follow-up 
After discontinuing study treatment (unless discontinuing due to withdrawal of consent) 
patients will be followed for disease progression, relapse, and survival. Patients will be 
followed for survival every 6 months (±3 months) until death via brief phone call, even after 
being taken off treatment. For patients registered on our long-term follow-up umbrella 
protocol DR09-0223, survival follow-up may be conducted under that protocol. 
 
 
7.  EFFICACY AND SAFETY ASSESSMENTS 
7.1. CRITERIA FOR RESPONSE 
Response assessment will be conducted by the PI using standard criteria 15 and recorded in the patient’s 
electronic medical record. 
1. Response Criteria for AML: 
a. Complete Remission (CR): Normalization of the peripheral blood and bone 
marrow with 5% or less blasts in normocellular or hypercellular marrow with a 
granulocyte count of 1 x 109/L or above, and platelet count of 100 x 109/L. 
Complete resolution of all sites of extramedullary disease is required for CR. 
b. CR without minimal residual disease (CRMRD-) = CR with negativity by multi-
color flow cytometry. 
c. Complete remission without recovery of counts (CRi): Peripheral blood and 
marrow results as for CR, but with incomplete recover of counts (platelets < 100 
x 109/L or neutrophils < 1 x 109/L). 
d. Morphologic leukemia-free state (MLFS) = Bone marrow blasts <5%; absence 
of blasts with Auer rods; absence of extramedullary disease; no hematologic 
recovery required. At least 200 cells should be enumerated or cellularity of the 
bone marrow should be at least 10%. 

 
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15 
e. Partial remission (PR) = All hematologic criteria of CR; decrease of bone 
marrow blast percentage to 5% - 25%, and decrease of pretreatment bone 
marrow blast percentage by ≥50%. 
f. 
Stable disease (SD) = Absence of CRMRD-, CR, CRi, PR, MLFS; and criteria 
for PD not met. 
g. Progressive disease (PD) = Evidence for an increase in bone marrow blast 
percentage and/or increase of absolute blast count in the blood: 
i. >50% increase in marrow blasts (must be confirmed by repeat marrow 
examination ≥4 weeks later) over baseline (a minimum 15% point 
increase is required in cases with <30% blasts at baseline; or persistent 
marrow blast percentage of >70% over ≥3 months; without at least a 
100% improvement in ANC to an absolute level of >0.5 x 109/L [500/µL], 
and/or platelet count to >50 x 109/L [50,000/µL] non-transfused); or 
ii. >50% increase in peripheral blasts to >25 x 109/L (25,000/µL) in the 
absence of differentiation syndrome; or 
iii. New extramedullary disease. 
h. Hematologic relapse (after CRMRD-, CR or CRi) = Bone marrow blasts ≥5% or 
appearance of blasts in the blood, or development of extramedullary disease. 
i. 
Molecular relapse (after CRMRD-) = Recurrence of MRD by flow cytometry. 
j. 
The following types of response or treatment failure will be recorded in medical 
record CR (CR, CR-MRD, or CRi) or what type of treatment failure (SD, PD, 
hematologic relapse or molecular relapse) they had. 
i. Complete Remission (CR, CR-MRD, or CRi) 
ii. Treatment Failure (stable disease, progression or relapse) 
iii. Inevaluable 
iv. Not Applicable (N/A) 
2. For patients with MDS or CMML, the response criteria from the International Working 
Group as summarized in Cheson BD et al. Blood 2006;108(2):419-25 will be used. 
 
7.2. EVALUATION OF TOXICITY 
1. Toxicities will be graded according to the NCI Common Toxicity Criteria for Adverse 
Event Reporting Version 5.0.  The toxicity of the regimen will be monitored continuously 
during the course of the study. 
 
7.3. CRITERIA TO STOP TREATMENT 
1. Failure to achieve CR/CRi/MLFS after 6 cycles of treatment, unless the patient is deemed 
to be deriving clinical benefit (e.g. blast reduction not meeting criteria for CR/CRi/MLFS) 
as assessed by the treating physician and PI 
2. Unacceptable toxicity judged to be related to therapy by the investigator, as defined by 
the NCI Common Toxicity Criteria (irreversible or prolonged (> 42 days) grade 4 
hematological toxicity or grade 4 non-hematological toxicity thought to be related to 
azacitidine, trametinib or venetoclax), unless it has been judged by the treating physician 
and PI that the patient is achieving clinical benefit. 
3. Pattern of non-compliance by the patient with protocol requirements or patient's request 
to be removed from the study. 
4. Relapse, defined as >5% bone marrow blasts not attributed to hematopoietic recovery, 
occurring after initial response to therapy 
5. At the discretion of the treating physician and/or PI 
 

 
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Patients coming off treatment due to the above issues will continue to be followed for 
survival outcomes. 
 
7.4 DEFINITION OF STUDY ENDPOINTS 
1. Relapse-free survival is the time from documented CR/CRi until relapse or death. 
 
2. Event-free survival is the time from the first day of treatment until any treatment failure 
(lack of response within 6 cycles of treatment, relapse, or death). 
 
3. Overall response rate is defined as the percentage of patients achieving CR or CRi. 
 
4. Overall survival is defined as the time from the first day of treatment to time of death 
from any cause. 
 
In the primary analysis, survival will not be censored for stem cell transplant. 
 
8. REPORTING REQUIREMENTS 
 
Adverse event reporting will be as per the NCI criteria and the MDACC Leukemia Specific 
Adverse Event Recording and Reporting Guidelines (refer to appendix E). 
 
It is the responsibility of the PI and the research teams to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, and Institutional Review Board (IRB) policy. 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related 
to study drug. Medical conditions/diseases present before starting study drug are only considered 
adverse events if they worsen after starting study drug. Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy. 
 
              The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for all adverse events for 
subjects enrolled. 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. ( 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50).   
 
 
9. OUTSIDE PHYSICIAN PARTICIPATION DURING TREATMENT 
 
9.1 MDACC Physician communication with the outside physician is required prior to the patient 
returning to the local physician. This will be documented in the patient record. 
 
9.2 A letter to the local physician outlining the patient's participation in a clinical trial will request 
local physician agreement to supervise the patient's care 

 
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17 
 
9.3 Protocol required evaluations outside MDACC will be documented by telephone, fax or e-
mail.  Fax and/or e-mail will be reviewed by the MDACC physician and any additional medical 
intervention is required it will be documented within the patient’s medical record 
 
9.4 Changes in drug dose and/or schedule must be discussed with and approved by the MDACC 
physician investigator, or their representative prior to initiation, and will be documented in the 
patient’s medical record. 
 
9.5 A copy of the informed consent, treatment schema and evaluation during treatment will be 
provided to the local physician.   
 
9.6 Documentation to be provided by the local physician will include drug administration records, 
progress notes, reports of protocol required laboratory and diagnostic studies and 
documentation of any hospitalizations. 
 
9.7 The home physician will be requested to report to the MDACC physician investigator all life 
threatening events within 24 hours of documented occurrence. 
 
9.8 For non MD Anderson laboratory results, the principal investigator (or physician designee) 
will review laboratory results, determine clinical significance, and sign and date the results. 
 
10.   STATISTICAL METHODOLOGY 
This is an open label, phase II study with a lead-in phase to assess the MTD and the efficacy of the 
combination regimen of azacitidine, venetoclax, and trametinib in patients with AML or MDS/CMML. A 
total of 40 patients will be enrolled for the study: 20 patients with newly diagnosed AML (Cohort A) and 20 
patients with relapsed/refractory AML or higher-risk MDS or CMML (Cohort B). 
 
In order to confirm the safety of azacitidine, venetoclax, and trametinib, there will be a lead-in phase for 
the regimen safety. The regimen will initially be explored in 6 eligible patients meeting criteria for 
enrollment in Cohort B (i.e. relapsed/refractory). If none or only one of the 6 patients experiences DLT in 
first cycle attributable to the treatment components, the phase II portion of the study will proceed as 
detailed below.  The patients treated in this confirmatory phase will be counted towards the phase II 
component of the study.  If DLT attributable to the components is observed in 2 or more of these initial 6 
patients, accrual to the phase II portion of the study will be deferred, and a lower dose of the combined 
agents would be assessed based on the investigators’ decision, which will be implemented with 
amendment to the study.  
 
 
Cohort A: 
The historical 1-year overall survival rate (OSR) for newly diagnosed patients is 59% and for this cohort 
the target OSR is 65% for the experimental treatment.  A >30% clinically significant drug-related grade 3 
or higher toxicity rate occurred in the 1st cycle is considered unacceptable.  A sample size of 20 patients 
ensures that, if the cohort is not terminated early, a posterior 95% credible interval for OSR will be (0.38, 
0.78) under the assumption of a 59% of OSR and prior Beta (1.18, 0.82). Thus, interim monitoring rules, 
assuming the prior distributions below, were constructed that meet the following two conditions, 
1) Stop if Prob[p(OSR, H) + δOSR  > P(OSR, E) | data]  > 0.95, where δOSR = 0.06 or 
2) Stop if Prob[p(TOX,H) + δTOX < p(TOX,E)| data] > 0.90, where δTOX = 0, 

 
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18 
where p(OSR, H) and p(OSR, E) are the true OSR for the historical and experimental treatments, 
respectively. The p(TOX, H), and p(TOX, E) are the toxicity rates for the historical and experimental 
treatments, respectively. The first rule provides for stopping the study if the data suggest that it is unlikely 
(i.e., probability < 5%) that OSR rate of the regimen is greater than 65%. The second condition will stop 
the study early if excessive therapy-related grade 3 or higher toxicity (>30%) is highly probable (i.e., 
probability >90%) for the combination treatment.  Monitoring for toxicity and futility will not begin until 4 
patients have been evaluated, and cohort size for future evaluations is 4. 
The monitoring rule for the toxicity and OSR rates, based on these assumptions and monitoring 
conditions above is found in Table 1. For example, accrual will cease if 3 or more patients experience 
toxicities among the first 4 patients. Accrual will cease if none of first 4 patients treated are alive. 
 
Table 1. Stopping boundary for efficacy and toxicity 
# patients 
evaluated 
Stop the cohort if there are this number of patients 
# alive 
with toxicities 
4 
0 
3-4 
8 
0-2 
5-8 
12 
0-4 
6-12 
16 
0-7 
8-16 
20 
Stop due to maximum sample size 
Stop due to maximum sample size 
 
Table 2 shows the operating characteristics for simultaneous monitoring response and toxicity rates. The 
probability of stopping the study early if the true OSR rate of the combination treatment was 65% and the 
true toxicity rate was 30% was 25%.  Probabilities of stopping early for high true toxicity rates (i.e., 50%) 
were 74% when the true OSR was 65%. 
Table 2. Operating characteristics for simultaneous monitoring response and toxicity rates  
True Toxicity Rate 
True OSR 
Prob(stop the cohort early) 
0.20 
0.55 
0.3163 
 
0.60 
0.2037 
 
0.65 
0.1255 
 
0.70 
0.0793 
 
0.75 
0.0566 
0.30 
0.55 
0.4135 
 
0.60 
0.3169 
 
0.65 
0.2498 
 
0.70 
0.2102 
 
0.75 
0.1907 
0.40 
0.55 
0.5940 
 
0.60 
0.5271 
 
0.65 
0.4806 
 
0.70 
0.4532 
 
0.75 
0.4397 
0.50 
0.55 
0.7956 

 
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19 
Table 2. Operating characteristics for simultaneous monitoring response and toxicity rates  
True Toxicity Rate 
True OSR 
Prob(stop the cohort early) 
 
0.60 
0.7619 
 
0.65 
0.7386 
 
0.70 
0.7247 
 
0.75 
0.7179 
 
Multc Lean Desktop (version 2.1.0) was used to generate the toxicity and futility stopping boundaries and 
the operating characteristics table. In order to utilize the software for the design, a 59% constant rate, a 
6% delta and beta (1.18, 0.82) priors were assumed for the standard treatment response rate and 
experimental treatment response prior distribution, respectively. In addition, a 30% constant rate and beta 
(0.6, 1.4) priors were assumed for the standard treatment toxicity rate and experimental treatment toxicity 
prior distribution, respectively. 
 
 
 
 
 
Cohort B: 
 
The target CR/CRi/MLFS rate is 35% evaluated within 6 cycles of treatment. A >30% clinically significant 
drug-related grade 3 or higher toxicity rate occurred in the 1st cycle is considered unacceptable.  A 
sample size of 20 patients ensures that, if the cohort is not terminated early, a posterior 95% credible 
interval for CR/CRi/MLFS will be (0.17, 0.56) under the assumption of a 35% of CR/CRi/MLFS and prior 
Beta (0.7, 1.3). Thus, interim monitoring rules, assuming the prior distributions below, were constructed 
that meet the following two conditions, 
1) Stop if Prob[p(CR/CRi, E) < 0.35  | data]  > 0.95, or 
2) Stop if Prob[p(TOX, E) > 0.30 | data] >0.93,  
where p(CR/CRi/MLFS, E) and p(TOX, E) are the true CR/CRi/MLFS and toxicity rates for the regimen. 
The first rule provides for stopping the study if the data suggest that it is unlikely (i.e., probability < 5%) 
that CR/CRi/MLFS rate of the regimen is greater than 35%. The second condition will stop the study early 
if excessive therapy-related grade 3 or higher toxicity (>30%) is highly probable (i.e., probability >93%) for 
the combination treatment.  Monitoring for toxicity and futility will not begin until 4 patients have been 
evaluated, and cohort size for future evaluations is 4. 
The monitoring rule for the toxicity and CR/CRi/MLFS rates, based on these assumptions and monitoring 
conditions above is found in Table 3. For example, accrual will cease if 3 or more patients experience 
toxicities among the first 4 patients. Accrual will cease if no patient experience an overall response in the 
first 8 patients treated. 
 
Table 3. stopping boundary for efficacy and toxicity 
# patients evaluated 
Stop the cohort if there are this number of patients 
# patients with CR/CRi/MLFS 
# patients with toxicities 
4 
Never stop 
3-4 
8 
0 
5-8 

 
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20 
12 
0-1 
7-12 
16 
0-2 
8-16 
20 
Stop due to maximum sample size 
Stop due to maximum sample size 
 
Table 4 shows the operating characteristics for simultaneous monitoring response and toxicity rates. The 
probability of stopping the study early if the true CR/CRi/MLFS of the combination treatment was 35% 
and the true toxicity rate was 30% was 21%.  Probabilities of stopping early for high true toxicity rates 
(i.e., 50%) were 75% when the true CR/CRi/MLFS was 35%. 
 
 
Table 4. Operating characteristics for simultaneous monitoring response and toxicity rates  
True Toxicity Rate 
True CR/CRi/MLFS 
Prob(stop the cohort early) 
0.20 
0.25 
0.2785 
 
0.30 
0.1728 
 
0.35 
0.1076 
 
0.40 
0.0709 
 
0.45 
0.0519 
0.30 
0.25 
0.3628 
 
0.30 
0.2694 
 
0.35 
0.2118 
 
0.40 
0.1794 
 
0.45 
0.1626 
0.40 
0.25 
0.5372 
 
0.30 
0.4695 
 
0.35 
0.4276 
 
0.40 
0.4041 
 
0.45 
0.3919 
0.50 
0.25 
0.7544 
 
0.30 
0.7184 
 
0.35 
0.6962 
 
0.40 
0.6837 
 
0.45 
0.6772 
 
Multc Lean Desktop (version 2.1.0) was used to generate the toxicity and futility stopping boundaries and 
the operating characteristics table. In order to utilize the software for the design, a 35% constant rate and 
beta (0.7, 1.3) priors were assumed for the standard treatment response rate and experimental treatment 
response prior distribution, respectively. In addition, a 30% constant rate and beta (0.6, 1.4) priors were 
assumed for the standard treatment toxicity rate and experimental treatment toxicity prior distribution, 
respectively. 
 
Analysis Plan: Demographic/clinical characteristics and safety data of the patients will be summarized 
using descriptive statistics such as mean, standard deviation, median and range.  

 
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For the primary efficacy analysis, we will estimate the CR/CRi/MLFS for the combination treatment (defined 
as the proportion of patients achieving CR or CRi or MLFS within 6 cycles of treatment), along with the 95% 
credible interval. This regimen will be considered worthy of further investigation if a CR/CRi/MLFS rate of 
at least 35% is achieved for frontline patients (Cohort B). Other efficacy endpoints (e.g. CR rate, CR/CRi 
rate, minimal residual disease negativity, or proportion of patients proceeding to HSCT) will also be 
estimated along with 95% credible intervals. The association between response and patient’s clinical 
characteristics (e.g., baseline apoptotic protein levels, baseline FLT3 allelic ratio, or baseline genomic 
alterations) will be examined by Wilcoxon’s rank sum test or Fisher’s exact test, as appropriate.  
 
For each subject, relapse-free survival (RFS), event-free survival (EFS) and overall survival (OS) will be 
calculated. The distribution of time-to-event endpoints (OS, EFS and OS) will be estimated using the 
method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups (e.g., 
baseline genomic alterations will be made using the log-rank tests. 
 
 
 
11.  DATA CONFIDENTIALITY 
Epic is the source for all patient data.  Patient data will be extracted from Epic to Department Database 
(MOCLIA).  This secure database resides in the MDACC IT environment and is an institutionally 
approved database for use as described in this protocol.  
 
 
12.  PROTOCOL MONITORING 
This protocol will be monitored by the MD Anderson Data Safety Monitoring Committee (DSMC). 
 
13. REFERENCES 
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Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care 
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Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase III trial of 
decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the 
treatment of older patients with newly diagnosed acute myeloid leukemia. Journal of clinical oncology : official 
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DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or 
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4. 
DiNardo CD, Pollyea DA, Jonas BA, et al. Updated Safety and Efficacy of Venetoclax with Decitabine or 
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DiNardo CD, Rausch CR, Benton C, et al. Clinical experience with the BCL2-inhibitor venetoclax in 
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Aldoss I, Yang D, Aribi A, et al. Efficacy of the combination of venetoclax and hypomethylating agents in 
relapsed/refractory acute myeloid leukemia. Haematologica 2018. 
7. 
Goldberg AD, Horvat TZ, Hsu M, et al. Venetoclax Combined with Either a Hypomethylating Agent or 
Low-Dose Cytarabine Shows Activity in Relapsed and Refractory Myeloid Malignancies. Blood 2017;130:1353-. 
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Short NJ, Ravandi F. Acute Myeloid Leukemia: Past, Present, and Prospects for the Future. Clinical 
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DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-
naive, elderly patients with acute myeloid leukemia. Blood 2019;133:7-17. 
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Chyla B, Daver N, Doyle K, et al. Genetic Biomarkers Of Sensitivity and Resistance to Venetoclax 
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DiNardo CD, Tiong IS, Quaglieri A, et al. Molecular patterns of response and treatment failure after 
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Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN 
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