Clinical trial NCT04487106
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
Start date: 2020-07-21; Completion date: 2024-01-25
Enrollment: 21 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial investigates how well azacitidine, venetoclax, and trametinib work in treating patients with acute myeloid leukemia or higher-risk myelodysplastic syndrome that has come back (relapsed) or has not responded to treatment (refractory). Chemotherapy drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax and trametinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. The goal of this study is learn if the combination of azacitidine, venetoclax, and trametinib can help to control acute myeloid leukemia or myelodysplastic syndrome.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine overall survival rate at 1 year of the regimen in patients with newly diagnosed acute myeloid leukemia (AML). (Cohort A) II. To determine the complete remission (CR)/complete remission without recovery of counts (CRi) rate of the regimen in patients with relapsed/refractory AML or high-risk myelodysplastic syndrome (MDS). (Cohort B)

SECONDARY OBJECTIVES:

I. To assess other efficacy endpoints (CR rate, minimal residual disease negativity by flow cytometry, relapse-free survival, event-free survival, and overall survival).

II. To assess proportion of patients proceeding to hematopoietic stem cell transplantation (HSCT).

III. To determine the safety of the combination regimen.

EXPLORATORY OBJECTIVES:

I. To evaluate the impact of baseline genomic alterations on response and survival of the combination regimen.

II. To evaluate clonal evolution from diagnosis to relapse.

OUTLINE:

INDUCTION (CYCLE 1): Patients receive azacitidine intravenously (IV) over 30-60 minutes or subcutaneously (SC) on days 1-7, venetoclax orally (PO) once daily (QD) on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, and then every 6 months thereafter.

Arms: arm 1: INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. arm 2: INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Azacitidine intervention 2: Trametinib intervention 3: Venetoclax
Intervention descriptions: intervention 1: Given IV or SC intervention 2: Given PO intervention 3: Given PO

Protocol documents:
Prot_SAP_001.pdf: 
 
                Protocol 2020-0506 
 
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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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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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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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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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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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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 
1. 
Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care 
regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015;126:291-9. 
2. 
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 
journal of the American Society of Clinical Oncology 2012;30:2670-7. 
3. 
DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or 
azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, 
phase 1b study. The Lancet Oncology 2018;19:216-28. 
4. 
DiNardo CD, Pollyea DA, Jonas BA, et al. Updated Safety and Efficacy of Venetoclax with Decitabine or 
Azacitidine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia. Blood 2017;130:2628-. 
5. 
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. 
American journal of hematology 2018;93:401-7. 
6. 
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-. 
8. 
Short NJ, Ravandi F. Acute Myeloid Leukemia: Past, Present, and Prospects for the Future. Clinical 
lymphoma, myeloma & leukemia 2016;16 Suppl:S25-9. 
9. 
Short NJ, Rytting ME, Cortes JE. Acute myeloid leukaemia. Lancet 2018;392:593-606. 


 
                Protocol 2020-0506 
 
February 8, 2021 
 
Page 22 
 
22 
10. 
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. 
11. 
Chyla B, Daver N, Doyle K, et al. Genetic Biomarkers Of Sensitivity and Resistance to Venetoclax 
Monotherapy in Patients With Relapsed Acute Myeloid Leukemia. American journal of hematology 2018. 
12. 
Han L, Zhang Q, Dail M, et al. Concomitant targeting of BCL2 with venetoclax and MAPK signaling with 
cobimetinib in acute myeloid leukemia models. Haematologica 2019. 
13. 
Borthakur G, Popplewell L, Boyiadzis M, et al. Activity of the oral mitogen-activated protein kinase kinase 
inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies. Cancer 2016;122:1871-9. 
14. 
DiNardo CD, Tiong IS, Quaglieri A, et al. Molecular patterns of response and treatment failure after 
frontline venetoclax combinations in older patients with AML. Blood 2020;135:791-803. 
15. 
Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN 
recommendations from an international expert panel. Blood 2016. 
 

ICF_002.pdf: 
Protocol 2020-0506 
June 4, 2020 
Page 1 of 14 
 
Informed Consent 
 
INFORMED CONSENT/AUTHORIZATION FOR PARTICIPATION IN 
RESEARCH 
 
A phase II Study of Azacitidine, Venetoclax and Trametinib for Patients 
with Acute Myeloid Leukemia or Higher-Risk Myelodysplastic Syndrome 
2020-0506 
 
Subtitle: Astellas Pharma-MDACC Alliance 
 
Study Chair:  Nicholas Short 
 
_________________________ 
_____________________ 
Participant’s Name 
 
 
Medical Record Number  
 
This is an informed consent and authorization form for a research study. It includes 
a summary about the study. A more detailed description of procedures and risks is 
provided after the summary.  
 
STUDY SUMMARY 
 
The goal of this clinical research study is learn if the combination of azacitidine, 
venetoclax, and trametinib can help to control acute myeloid leukemia (AML) or 
myelodysplastic syndrome (MDS). The safety the study drug combination will also be 
studied. 
 
This is an investigational study. Azacitidine is FDA approved and commercially 
available for the treatment of MDS. Venetoclax is FDA approved and commercially 
available for the treatment of chronic lymphocytic leukemia (CLL) and AML. 
Trametinib is FDA approved and commercially available for the treatment of certain 
types of lung cancer, melanoma, and thyroid cancer. It is considered investigational 
to give azacytidine, venetoclax, and trametinib together to patients with AML or MDS. 
 
The study drugs may help to control the disease. Future patients may benefit from 
what is learned. There may be no benefits for you in this study. 
 
Your participation is completely voluntary. Before choosing to take part in this study, 
you should discuss with the study team any concerns you may have, including side 
effects, potential expenses, and time commitment. If you take part in this study, you 
may experience challenges related to the cost of staying in Houston, traveling to the 
clinic for study visits, and not being eligible for other studies or therapies. 
 


Protocol 2020-0506 
June 4, 2020 
Page 2 of 14 
You can read a full list of potential side effects below in the Possible Risks section of 
this consent. 
 
You may receive up to 24 cycles of azacitidine, venetoclax, and trametinib.  
 
You and/or your insurance provider will be responsible for the cost of azacitidine, 
venetoclax, and trametinib. 
 
You may choose not to take part in this study. You may choose to receive standard 
treatment for AML that includes cytarabine in combination with idarubicin or 
daunorubicin, or a combination of commercially available drugs that may include 
venetoclax. You may choose to receive azacitidine and venetoclax alone. You may 
choose to receive other drugs or supportive care alone (including transfusions). 
There are approved treatments that have been shown to be effective in treating the 
disease. You may choose to receive other investigational therapy, if available. You 
may choose not to have treatment for cancer at all. In all cases, you will receive 
appropriate medical care, including treatment for pain and other symptoms of 
cancer. 
 
1. STUDY DETAILS 
 
Screening Tests 
Signing this consent form does not mean that you will be able to take part in this 
study. The following screening tests will be done within 2-4 weeks before your first 
dose of the study drugs to help the doctor decide if you are eligible: 
• You will have a physical exam. 
 
• You will have either an echocardiogram (ECHO) or a MUGA scan to check 
your heart function.  
• Blood (about 5-6 teaspoons) will be drawn for routine tests and biomarker 
testing. Biomarkers are found in the blood and may be related to your reaction 
to the study drugs. 
• You will have a bone marrow aspirate to check the status of the disease and 
for genetic testing and biomarker testing. Genetic testing in this study tests for 
genetic mutations (changes) in DNA found in the bone marrow. To collect a 
bone marrow aspirate, an area of the hip or other site is numbed with 
anesthetic, and a small amount of bone marrow is withdrawn through a large 
needle. 
• If you can become pregnant, blood (about 1 teaspoon) or urine will be 
collected for a pregnancy test  
The study doctor will discuss the screening test results with you. If the screening 
tests show that you are not eligible to take part in the study, you will not be enrolled. 
Other treatment options will be discussed with you. 
 
Up to 40 participants will be enrolled in this study. All will take part at MD Anderson. 
 
Study Drug Administration 


Protocol 2020-0506 
June 4, 2020 
Page 3 of 14 
Each study cycle is 28 days. If you are found to be eligible to take part in this study, 
you may receive the study drugs for up to 24 cycles. 
 
You will receive azacitidine by vein (IV) over about 30-60 minutes on Days 1-7 of 
each cycle. If you prefer, you may instead receive azacitidine as an injection under 
the skin, which is generally quicker to give compared to an IV. If you are receiving 
azacitidine at a clinic that closes over the weekend, alternate dosing schedules (such 
as receiving azacitidine on Days 1-5 and 8-9 of each cycle) are possible. 
 
You will take trametinib by mouth 1 time each day on Days 1-28 of each cycle. You 
should fast (not eat or drink anything except water) for at least 1 hour before the 
dose and then at last 2 hours after the dose. 
 
 
You will take venetoclax by mouth 1 time each day on Days 1-28 of Cycle 1 and then 
on Days 1-21 of following cycles. Venetoclax should be taken with food.  
 
During Cycle 1, your dose of venetoclax will be slowly increased over Days 1-3. After 
that, you will receive the same dose for the rest of the study cycles. For all 24 cycles, 
you will receive the same dose of azacytidine and trametinib. 
 
You may be hospitalized for Days 1-3 of Cycle 1 while the venetoclax dose is 
increased or for all of Cycle 1 to monitor your health. This will be discussed with you. 
 
You may be given standard drugs to help decrease the risk of side effects. You may 
ask the study staff for information about how the drugs are given and their risks. 
 
If you experience side effects from azacytidine, trametinib, and/or venetoclax, dosing 
for the drug(s) that caused the side effects may be paused, and the dose level may 
be lowered. You may also continue to receive the remaining study drug(s) that are 
not causing side effects. The study doctor will discuss this with you.  
 
You will no longer be able to receive the study drugs if the disease gets worse, if 
intolerable side effects occur, or if you are unable to follow study directions.  
 
Study Visits 
 
On Day 1 of each cycle: 
• You will have a physical exam. 
• Blood (about 2-3 teaspoons) will be drawn for routine tests.  
At least 1-2 times each week during Cycle 1, blood (about 2-3 teaspoons) will be 
drawn for routine tests.  
 
On Day 21 of Cycle 1, Day 28 of Cycle 4, every 2-4 cycles after that, and if the 
doctor thinks it is needed, you will have a bone marrow aspiration to check the 
status of the disease and for genetic testing (only during Cycles 1-4 and if the 


Protocol 2020-0506 
June 4, 2020 
Page 4 of 14 
disease comes back). If the disease does not get better by around Day 21 of Cycle 1, 
you may also have a bone marrow aspiration on Day 28 of Cycle 1 and/or Cycle 2.  
 
Every 2-3 cycles, if you are continuing to take trametinib, you will have either an 
ECHO or a MUGA scan. 
 
End-of-Dosing Visit 
As soon as possible after your last dose of the study drugs, you will be called by the 
study staff and asked how you are doing. The call should last about 5-10 minutes. 
 
Long-Term Follow-up 
About 30 days after your last dose of the study drugs and then about every 6 
months after that, you will be called by the study staff and asked how you are 
doing. This call should last about 5-10 minutes. 
 
Other Information 
• Within 3 days before your first dose of the study drugs and while taking 
venetoclax, avoid grapefruit, Seville (sour) oranges, star fruit, and 
pomegranate, including juices and products containing these fruits. 
• Tell the study doctor/staff about all medications you are taking or may take 
during this study. Some medications are not allowed during this study or may 
change how your body processes the study drugs. The dose level of 
venetrolax you receive may need to be lowered because of the medications 
you are taking. This will be explained to you in more detail.  
• If you take part in this study, you will not be able to receive any other 
investigational, anticancer drugs or treatments outside of this study.  
 
2. POSSIBLE RISKS 
 
While on this study, you are at risk for side effects. You should discuss these with the 
study doctor. The more commonly occurring side effects are listed in this form, as are 
rare but serious side effects. You may also want to ask about uncommon side effects 
that have been observed in small numbers of patients but are not listed in this form. 
Many side effects go away shortly after treatment is stopped, but in some cases side 
effects may be serious, long-lasting or permanent, and may even result in 
hospitalization and/or death. 
 
Side effects will vary from person to person, and some may occur after you have 
stopped receiving treatment. Tell the study staff about any side effects you may 
have, even if you do not think they are related to the study drugs/procedures. 
 
Venetoclax, azacitidine, and trametinib may each cause low blood cell counts (red 
blood cells, platelets, and/or white blood cells):  
• A low red blood cell count (anemia) may cause difficulty breathing and/or 
fatigue. You may need a blood transfusion.  


Protocol 2020-0506 
June 4, 2020 
Page 5 of 14 
• A low platelet count increases your risk of bleeding (such as nosebleeds, 
bruising, stroke, and/or digestive system bleeding). You may need a platelet 
transfusion.  
• A low white blood cell count increases your risk of infection (such as 
pneumonia and/or severe blood infection). Infections may occur anywhere and 
become life-threatening. Symptoms of infection may include fever, pain, 
redness, and difficulty breathing. 
Venetoclax Side Effects  
 
Common (occurring in more than 20% of patients) 
 
 
Occasional (occurring in 3-20% of patients) 
 
 
  
 
TLS is a problem that can occur when cancer cells break down rapidly and the body 
has to get rid of the broken up cell parts. Sometimes your body, especially the 
kidneys, cannot remove the cell parts quickly enough, so the level of some of these 
cell products in your blood, such as salts and acids, can rise. This can happen 
especially in participants with large tumors or a high number of cancerous white cells 
in the blood. TLS can lead to serious problems, such as effects on your kidneys and 
heart (including abnormal heart rhythms), seizures, or even death. 
 
If you develop TLS, your urine may look dark, thick, or cloudy. You may have fever, 
chills, nausea/vomiting, diarrhea, confusion, shortness of breath, irregular heartbeat, 
fatigue, muscle pain, joint discomfort, and/or seizure. If you notice any of these, tell 
• fatigue 
• 
diarrhea 
• nausea 
• 
low blood counts 
(red, platelets, white) 
• 
upper respiratory 
tract infection 
• swelling (arm/leg) 
• fever 
• headache 
• abnormal salts, 
minerals, and/or acids 
in the blood (possible 
weakness, swelling, 
fatigue, low blood 
pressure, organ failure, 
heart problems, 
changes in mental 
status, and/or seizure) 
• vomiting 
• constipation 
• back pain 
• high blood levels of 
uric acid (possible 
painful joints and/or 
kidney failure) 
• pneumonia 
• cough 
• tumor lysis syndrome 
(TLS)--breakdown 
products of the cancer 
cells entering the blood 
stream (possible 
weakness, low blood 
pressure, muscle 
cramps, kidney 
damage, and/or other 
organ damage) 
• severe life-threatening 
infection (possible low 
blood pressure, kidney 
failure, and/or heart 
failure) 


Protocol 2020-0506 
June 4, 2020 
Page 6 of 14 
your doctor or nurse right away. Your study doctor will closely watch and treat you as 
needed to lower the risk of any serious changes in your blood or other complications 
of TLS. You may need to have extra blood tests or EKGs to check for signs of TLS. 
 
You should wear ear plugs or other hearing protection when involved in a loud 
activity. 
 
If you notice any rash, hives, itching, or other signs of an allergic reaction such as 
swelling, wheezing, or you are having a hard time breathing, tell your doctor right 
away. 
 
At this time, there are no known serious side effects that occur in fewer than 3% 
of patients. 
 
Azacitidine Side Effects 
 
The following side effects have been reported when azacitidine is given either by 
vein or as an injection under the skin: 
 
Common (occurring in more than 20% of patients)  
 
 
 
 
Occasional (occurring in 5-20% of patients) 
 
• fever  
• fatigue/lack of energy 
• headache 
• nausea 
• vomiting 
• diarrhea 
• constipation 
• loss of appetite  
• low blood cell counts 
(red, white, platelets)  
• weakness 
• pain 
• shivering  
• cough  
• difficulty breathing 
• injection site redness 
and/or pain 
• chest pain  
• pale skin 
• swelling (arm/leg) 
• abnormal heart sound  
• fast heartbeat  
• low blood pressure 
(possible dizziness/ 
fainting)  
• high blood pressure 
• fainting  
• dizziness  
• anxiety  
• depression  
• difficulty sleeping 
• numbness  
• low blood levels of 
potassium (possible 
weakness /or muscle 
cramps)  
• weight loss  
• abdominal pain, 
tenderness, and/or 
swelling 
• bleeding gums 
• tongue sores 
• bleeding in the mouth 
• mouth blisters and/or 
sores (possible 
difficulty swallowing) 
• upset stomach  
• hemorrhoids 
• muscle cramps 
• nosebleed 
• stuffy and/or runny 
nose 
• abnormal breath 
sounds 
• wheezing  
• build-up of fluid around 
the lungs  
• lymph node swelling  
• infection 
• hardened 
tissue/inflammation/ski
n discoloration at the 
injection site 


Protocol 2020-0506 
June 4, 2020 
Page 7 of 14 
 
 
 
Rare but serious (occurring in fewer than 5% of patients) 
 
 
Azacitidine may cause you to develop another type of cancer (such as leukemia, a 
type of blood cancer). 
 
Trametinib Side Effects 
 
Common (occurring in more than 20% of patients)  
 
• hives and/or skin 
redness 
• skin bump/sores/rash 
• dry skin and/or itching 
• sweating 
• difficulty swallowing  
• difficult and/or painful 
urination  
• blood in the urine 
• sore throat 
• injection site swelling, 
itching, and/or rash 
• increased risk of 
bleeding after a 
procedure/surgery 
• reaction to a blood 
transfusion 
 
• irregular heartbeat  
• heart failure 
• bleeding in and/or 
around the brain 
• seizures 
• skin condition with 
fever and skin lesions 
• decay of body tissue 
• lesions due to skin 
infection 
• abnormal blood 
acid/base balance 
(possible organ 
damage) 
• dehydration 
• gallbladder 
inflammation (possible 
abdominal pain) 
• digestive system 
bleeding 
• tarry stool 
• enlarged spleen  
• bone marrow failure 
• liver failure 
• kidney failure 
• build-up of bodily 
waste products in the 
blood (possible kidney 
problems) 
• coughing up blood 
• lung inflammation 
(possible difficulty 
breathing) 
• tissue death at the 
injection site caused 
by drug leakage 
• bleeding in the eye 
• catheter site bleeding 
• infection at the 
injection site 
• allergic reaction, which 
may be life-threatening 
(such as difficulty 
breathing, low blood 
pressure, and/or organ 
failure) 
• severe life-threatening 
infection (possible low 
blood pressure, kidney 
failure, and/or heart 
failure) 
• breakdown products of 
the cancer cells 
entering the blood 
stream (possible 
weakness, low blood 
pressure, muscle 
cramps, kidney 
damage, and/or other 
organ damage) 
• skin rash/redness  
• acne-like skin rash 
• hand-foot syndrome 
(palms of 
hands/soles of feet 
having pain, 
• low blood levels of 
albumin (possible 
swelling, weakness, 
and/or fatigue) 
• diarrhea 
• low red blood cell 
counts 
• lymphedema 
(swelling of 
arms/legs/torso)  
• abnormal liver test 
(possible liver 
damage) 


Protocol 2020-0506 
June 4, 2020 
Page 8 of 14 
 
Occasional (occurring in 3-20% of patients)  
 
 
The drug may cause an increased risk of infection, such as pneumonia. This 
infection may occur anywhere, such as the skin (including the nails and/or hair 
follicles) or lungs. It may become life-threatening. Symptoms of infection may include 
fever, pain, redness, and difficulty breathing. 
 
Frequency Unknown but occurring between 1 and 10% of patients: 
 
 
Rare but serious (occurring in fewer than 3% of patients) 
 
 
Trametinib may cause eye problems, such as bleeding or blood clots in the eye.  This 
may lead to blindness or other visual damage. If you have any vision changes, you 
should not drive a car or work with machinery. 
 
Tell your doctor about glaucoma, diabetes, any pre-existing lung problems, if you 
have high blood pressure, or are on drugs to treat high blood pressure. 
 
swelling, and 
blistering) 
• high blood pressure 
• enlarged heart 
• heart failure 
• severe heart 
problems 
• itching 
• dry skin 
• mouth blisters/sores 
(possible difficulty 
swallowing) 
• abdominal pain 
• bright red, tarry or 
coffee ground-like 
blood in the stool 
• bleeding (gums, 
uterus, vagina, 
hemorrhoids, nose, 
and/or eye)  
• blood in the urine 
• slow heartbeat 
• dizziness 
• blistering skin rash 
• abnormal taste 
• dry mouth 
• breakdown of 
muscle tissue 
(possible kidney 
failure) 
• blurry vision 
• dry eyes 
• detachment of part 
of the retina 
(possible blurry 
vision, vision 
changes, and/or 
vision loss)  
• blood clot in the eye 
(possible vision loss) 
• lung inflammation 
(possible difficulty 
breathing) 


Protocol 2020-0506 
June 4, 2020 
Page 9 of 14 
Using the study drugs together may cause side effects that are not seen when 
each is given alone. The study drug combination may also increase the frequency 
and/or severity of the side effects listed above. 
 
Other Risks 
 
Blood draws may cause pain, bleeding, and/or bruising. You may faint and/or 
develop an infection with redness and irritation of the vein at the site where blood is 
drawn. Frequent blood collection may cause anemia (low red blood cell count), which 
may create a need for blood transfusions. 
 
Having bone marrow aspirations performed may cause pain, bruising, bleeding, 
redness, low blood pressure, swelling, and/or infection at the site of the aspiration. 
An allergic reaction to the anesthetic may occur. A scar may form at the aspiration 
site. 
 
This study may involve unpredictable risks to the participants. 
 
Pregnancy Related Risks 
 
Taking part in this study can result in risks to an unborn or breastfeeding baby, so 
you should not become pregnant, breastfeed a baby, or father a child while on this 
study. You must use effective birth control methods during the study and for at least 
4 months (for males) or 6 months (for females) after your last dose of study drugs, if 
you are sexually active. 
 
Birth Control Specifications: The study doctor or staff will discuss effective birth 
control methods with you.  
 
Males: Do not donate sperm while on study and for 4 months after your last dose of 
study drug. Tell the doctor right away if your partner becomes pregnant or suspects 
pregnancy. 
 
Females: If you are pregnant, you will not be enrolled on this study. If you become 
pregnant or suspect that you are pregnant, you must tell your doctor right away. 
 
Getting pregnant will result in your removal from this study.  
 
3. COSTS AND COMPENSATION  
 
If you suffer injury as a direct result of taking part in this study, MD Anderson health 
providers will provide medical care. However, this medical care will be billed to your 
insurance provider or you in the ordinary manner. You will not be reimbursed for 
expenses or compensated financially by MD Anderson for this injury. You may also 
contact the Chair of MD Anderson’s IRB at 713-792-6477 with questions about 
study-related injuries. By signing this consent form, you are not giving up any of your 
legal rights. 


Protocol 2020-0506 
June 4, 2020 
Page 10 of 14 
 
Certain tests, procedures, and/or drugs that you may receive as part of this study 
may be without cost to you because they are for research purposes only. However, 
your insurance provider and/or you may be financially responsible for the cost of 
care and treatment of any complications resulting from the research tests, 
procedures, and/or drugs. Standard medical care that you receive under this 
research study will be billed to your insurance provider and/or you in the ordinary 
manner. Before taking part in this study, you may ask about which parts of the 
research-related care may be provided without charge, which costs your insurance 
provider may pay for, and which costs may be your responsibility. You may ask that 
a financial counselor be made available to you to talk about the costs of this study. 
 
Samples that are collected from you in this study may be used for the development 
of treatments, devices, new drugs, or patentable procedures that may result in 
commercial profit. 
 
There are no plans to compensate you for any patents or discoveries that may result 
from your participation in this research.  
 
You will receive no compensation for taking part in this study.  
 
Additional Information  
 
4. You may ask the study chair (Dr. Nicholas Short, at 713-563-4485) any questions 
you have about this study. You may also contact the Chair of MD Anderson's 
Institutional Review Board (IRB - a committee that reviews research studies) at 713-
792-6477 with any questions that have to do with this study or your rights as a study 
participant. 
 
5. You may choose not to take part in this study without any penalty or loss of benefits 
to which you are otherwise entitled. You may also withdraw from participation in this 
study at any time without any penalty or loss of benefits. If you decide you want to 
stop taking part in the study, it is recommended for your safety that you first talk to 
your doctor. If you withdraw from this study, you can still choose to be treated at MD 
Anderson. 
 
6. This study or your participation in it may be changed or stopped without your 
consent at any time by the study chair, the U.S. Food and Drug Administration 
(FDA), the Office for Human Research Protections (OHRP), or the IRB of MD 
Anderson. 
 
7. You will be informed of any new findings or information that might affect your 
willingness to continue taking part in the study and you may be asked to sign 
another informed consent and authorization form stating your continued willingness 
to participate in this study. 
 
8. MD Anderson may benefit from your participation and/or what is learned in this 


Protocol 2020-0506 
June 4, 2020 
Page 11 of 14 
study. 
 
Future Research 
 
Data 
Your personal information is being collected as part of this study. These data may be 
used by researchers at MD Anderson and/or shared with other researchers and/or 
institutions for use in future research. 
 
Samples  
Samples (such as blood and/or tissue) are being collected from you as part of this 
study. Researchers at MD Anderson may use any leftover samples that are stored at 
MD Anderson in future research.  
 
Before being used or shared for future research, every effort will be made to remove 
your identifying information from any data and/or research samples. If all identifying 
information is removed, you will not be asked for additional permission before future 
research is performed. 
 
In some cases, all of your identifying information may not be removed before your 
data or research samples are used for future research. If future research is 
performed at MD Anderson, the researchers must get approval from the 
Institutional Review Board (IRB) of MD Anderson before your data and/or research 
samples can be used. At that time, the IRB will decide whether or not further 
permission from you is required. The IRB is a committee of doctors, researchers, 
and community members that is responsible for protecting study participants and 
making sure all research is safe and ethical. 
 
If this research is not performed at MD Anderson, MD Anderson will not have 
oversight of any data and/or samples. 
 
Genetic Research 
Research samples collected from you as part of this study will be used for genetic 
research, which may include whole genome sequencing. Whole genome sequencing 
is a type of testing in which researchers study your entire genetic makeup (DNA). 
This may help researchers learn how changes in the ordering of genes may affect a 
disease or response to treatment. If genetic research is done with your samples, 
those who have access to those samples may be able to identify you. The results of 
this research may also be able to be linked to you. 
 
Outside Care 
 


Protocol 2020-0506 
June 4, 2020 
Page 12 of 14 
Part of your care may be provided outside of MD Anderson by your home doctor(s). 
Your home doctor(s) will be given a copy of the informed consent as well as 
information about the study drug dosing and study tests. If your home doctor thinks 
the dose of the study drug(s) you are receiving or the dosing schedule you are 
following during a study cycle should be changed, the study doctor will make the 
final decision. If any study tests are performed by your home doctor, the results will 
be sent to the study doctor for review.  
 
Authorization for Use and Disclosure of Protected Health Information (PHI): 
 
A. During the course of this study, MD Anderson will be collecting and using your PHI, 
including identifying information, information from your medical record, and study 
results. For legal, ethical, research, and safety-related reasons, your doctor and the 
research team may share your PHI with: 
• Federal agencies that require reporting of clinical study data (such as the FDA, 
National Cancer Institute [NCI], and OHRP) 
• The IRB and officials of MD Anderson 
• Study monitors and auditors who verify the accuracy of the information 
• Individuals who put all the study information together in report form 
 
Study sponsors and/or supporters receive limited amounts of PHI. They may also 
view additional PHI in study records during the monitoring process. MD Anderson’s 
contracts require sponsors/supporters to protect this information and limit how they 
may use it.  
 
B. Signing this consent and authorization form is optional but you cannot take part in 
this study or receive study-related treatment if you do not agree and sign. 
 
C. MD Anderson will keep your PHI confidential when possible (according to state and 
federal law). However, in some situations, the FDA could be required to reveal the 
names of participants. 
 
Once disclosed outside of MD Anderson, federal privacy laws may no longer protect 
your PHI. 
 
D.  The permission to use your PHI will continue indefinitely unless you withdraw your 
authorization in writing. Instructions on how to do this can be found in the MD 
Anderson Notice of Privacy Practices (NPP) or you may contact the Chief Privacy 
Officer at 713-745-6636. If you withdraw your authorization, you will be removed 
from the study and the data collected about you up to that point can be used and 
included in data analysis. However, no further information about you will be 
collected. 
 
E. A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. 
At most, the Web site will include a summary of the results. You can search this 
Web site at any time. 
 


Protocol 2020-0506 
June 4, 2020 
Page 13 of 14 
CONSENT/AUTHORIZATION 
 
I understand the information in this consent form.  I have had a chance to read the 
consent form for this study, or have had it read to me. I have had a chance to think 
about it, ask questions, and talk about it with others as needed. I give the study chair 
permission to enroll me on this study.  By signing this consent form, I am not giving up 
any of my legal rights. I will be given a signed copy of this consent document. 
 
________________________________________ 
_______ 
SIGNATURE OF PARTICIPANT 
DATE 
 
_________________________________         
PRINTED NAME OF PARTICIPANT                 
 
LEGALLY AUTHORIZED REPRESENTATIVE (LAR) 
The following signature line should only be filled out when the participant does not have 
the capacity to legally consent to take part in the study and/or sign this document on his 
or her own behalf. 
 
_____________________________________________________ 
_________ 
SIGNATURE OF LAR 
DATE 
 
 
 
PRINTED NAME and RELATIONSHIP TO PARTICIPANT 
 
WITNESS TO CONSENT 
I was present during the explanation of the research to be performed under Protocol 
2020-0506. 
 
_____________________________________________________  
_________ 
SIGNATURE OF WITNESS TO THE VERBAL CONSENT  
  
DATE  
PRESENTATION (OTHER THAN PHYSICIAN OR STUDY CHAIR) 
A witness signature is only required for vulnerable adult participants. If witnessing the assent of a pediatric 
participant, leave this line blank and sign on the witness to assent page instead. 
 
 
 
PRINTED NAME OF WITNESS TO THE VERBAL CONSENT 
 
PERSON OBTAINING CONSENT 
I have discussed this research study with the participant and/or his or her authorized 
representative, using language that is understandable and appropriate.  I believe that I 
have fully informed this participant of the nature of this study and its possible benefits 
and risks and that the participant understood this explanation. 
 
______________________________________________ 
  
_________ 
PERSON OBTAINING CONSENT  
 
 
 
 
 
DATE 
 
______________________________________________ 
PRINTED NAME OF PERSON OBTAINING CONSENT 


Protocol 2020-0506 
June 4, 2020 
Page 14 of 14 
TRANSLATOR 
I have translated the above informed consent as written (without additions or 
subtractions) into 
and assisted the people 
(Name of Language) 
obtaining and providing consent by translating all questions and responses during the 
consent process for this participant. 
 
 
_____________________       _______________________________   ___________ 
NAME OF TRANSLATOR       SIGNATURE OF TRANSLATOR 
DATE 
 
   Please check here if the translator was a member of the research team.  (If checked, 
a witness, other than the translator, must sign the witness line below.) 
 
____________________________________________________  ___________ 
SIGNATURE OF WITNESS TO THE VERBAL TRANSLATION  
 DATE  
(OTHER THAN TRANSLATOR, PARENT/GUARDIAN,  
OR STUDY CHAIR) 
 
_____________________________________________________ 
PRINTED NAME OF WITNESS TO THE VERBAL TRANSLATION