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| ID | Type | Description | Link |
|---|---|---|---|
| NCI-2020-05350 | Registry Identifier | CTRP (Clinical Trial Reporting Program) | |
| 2020-0506 | Other Identifier | M D Anderson Cancer Center |
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| Name | Class |
|---|---|
| National Cancer Institute (NCI) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort A (Newly Diagnosed AML Patients) | Experimental | 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. |
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| Cohort B (Relapsed/Refractory AML or higher-risk MDS or CMML Patients) | Experimental | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Azacitidine | Drug | Given IV or SC |
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| Measure | Description | Time Frame |
|---|---|---|
| Participants With a Response | Overall response is defined as the number of participants achieving Complete Remission (CR) or Complete Remission without recovery of counts (CRi) CR is Normalization of the peripheral blood and bone marrow with \ | Up to 2.5 years |
| Measure | Description | Time Frame |
|---|---|---|
| Minimal Residual Disease Negativity | Will be assessed by flow cytometry and estimated along with 95% credible intervals. | Up to time of relapse, assessed up to 2.5 years |
| Relapse-free Survival |
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Inclusion Criteria:
Diagnosis:
Performance status =< 2 (Eastern Cooperative Oncology Group [ECOG] scale)
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
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =< 3 x ULN, unless due to the underlying leukemia approved by the PI
Creatinine clearance >= 30 mL/min
Ability to swallow
Signed informed consent
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Nicholas Short | M.D. Anderson Cancer Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| M D Anderson Cancer Center | Houston | Texas | 77030 | United States |
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| Label | URL |
|---|---|
| M D Anderson Cancer Center | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Cohort A (Newly Diagnosed AML Patients) | 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. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 8, 2021 |
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| Trametinib | Drug | Given PO |
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| Venetoclax | Drug | Given PO |
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Relapse-free survival is the time from documented CR/CRi until relapse or death.
| From documented CR/CRi until relapse or death, assessed until study completion |
| Event-free Survival | 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). | From the first day of treatment until any treatment failure (lack of response within 6 cycles of treatment, relapse, or death), assessed until study completion |
| Overall Survival | Overall survival is defined as the time from the first day of treatment to time of death from any cause. | From the first day of treatment to time of death from any cause, assessed until study completion |
| Number of Participants Proceeding to Hematopoietic Stem Cell Transplantation | Will be totaled based on the number of participants who continue with hematopoietic stem cell transplantation post treatment. | Up to 2.5 years |
| FG001 | Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) | 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. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Cohort A (Newly Diagnosed AML Patients) | 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. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO |
| BG001 | Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) | 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. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Median | Full Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Participants With a Response | Overall response is defined as the number of participants achieving Complete Remission (CR) or Complete Remission without recovery of counts (CRi) CR is Normalization of the peripheral blood and bone marrow with \ | Of the five participants registered on Cohort A, three were evaluable. Of the sixteen participants registered on Cohort B, thirteen were evaluable. | Posted | Count of Participants | Participants | Up to 2.5 years |
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| Secondary | Minimal Residual Disease Negativity | Will be assessed by flow cytometry and estimated along with 95% credible intervals. | Of the five participants in Cohort A, three were evaluable for response. Of the 16 participants in Cohort B, 13 were evaluable for response. | Posted | Count of Participants | Participants | Up to time of relapse, assessed up to 2.5 years |
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| Secondary | Relapse-free Survival | Relapse-free survival is the time from documented CR/CRi until relapse or death. | Posted | Median | Full Range | Months | From documented CR/CRi until relapse or death, assessed until study completion |
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| Secondary | Event-free Survival | 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). | Posted | Median | Full Range | Months | From the first day of treatment until any treatment failure (lack of response within 6 cycles of treatment, relapse, or death), assessed until study completion |
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| Secondary | Overall Survival | Overall survival is defined as the time from the first day of treatment to time of death from any cause. | Posted | Median | Full Range | Months | From the first day of treatment to time of death from any cause, assessed until study completion |
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| Secondary | Number of Participants Proceeding to Hematopoietic Stem Cell Transplantation | Will be totaled based on the number of participants who continue with hematopoietic stem cell transplantation post treatment. | Posted | Count of Participants | Participants | Up to 2.5 years |
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All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cohort A (Newly Diagnosed AML Patients) | 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. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO | 1 | 5 | 2 | 5 | 3 | 5 |
| EG001 | Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) | 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. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO | 1 | 16 | 4 | 16 | 15 | 16 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Catheter related infection | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
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| Febrile neutropenia | Blood and lymphatic system disorders | CTCAE (4.0) | Systematic Assessment |
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| Heart failure | Cardiac disorders | CTCAE (4.0) | Systematic Assessment |
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| Hip pain | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
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| Intracranial hemorrhage | Nervous system disorders | CTCAE (4.0) | Systematic Assessment |
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| Lung infection | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
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| Oral ulcers | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
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| Sepsis | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
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| Skin infection | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
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| Small intestinal obstruction | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
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| Subdural Hemorrhage | General disorders | CTCAE (4.0) | Systematic Assessment |
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| Upper Respiratory Infection | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
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| Urinary tract infection | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| alanine aminotransferase increased | Investigations | CTCAE (4.0) | Systematic Assessment |
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| Anorexia | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
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| Cardiac-General Other | Cardiac disorders | CTCAE (4.0) | Systematic Assessment |
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| Confusion | Psychiatric disorders | CTCAE (4.0) | Systematic Assessment |
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| Constipation | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
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| Creatinine Increased | Investigations | CTCAE (4.0) | Systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
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| Dyspnea (shortness of breath) | Respiratory, thoracic and mediastinal disorders | CTCAE (4.0) | Systematic Assessment |
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| Edema limb | General disorders | CTCAE (4.0) | Systematic Assessment |
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| Fatigue (asthenia, lethargy, malaise) | General disorders | CTCAE (4.0) | Systematic Assessment |
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| Febrile neutropenia | Blood and lymphatic system disorders | CTCAE (4.0) | Systematic Assessment |
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| Hemorrhoids | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
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| Hypertension | Vascular disorders | CTCAE (4.0) | Systematic Assessment |
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| Hypothermia | General disorders | CTCAE (4.0) | Systematic Assessment |
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| Infection-Other | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
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| Mucositis/stomatitis | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
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| Muscle weakness, generalized or specific area | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
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| Pain | General disorders | CTCAE (4.0) | Systematic Assessment |
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| Rash/desquamation | Skin and subcutaneous tissue disorders | CTCAE (4.0) | Systematic Assessment |
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| Retinopathy | Eye disorders | CTCAE (4.0) | Systematic Assessment |
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| Skin ulceration | Skin and subcutaneous tissue disorders | CTCAE (4.0) | Systematic Assessment |
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| Tachycardia | Cardiac disorders | CTCAE (4.0) | Systematic Assessment |
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| Ulceration | Skin and subcutaneous tissue disorders | CTCAE (4.0) | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Nichols Short MD/Associate Professor | The University of Texas MD Anderson Cancer Center | 713-563-4485 | NShort@mdanderson.org |
| Mar 14, 2024 |
| Prot_SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jun 4, 2020 | Nov 22, 2024 | ICF_002.pdf |
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| ID | Term |
|---|---|
| D015470 | Leukemia, Myeloid, Acute |
| D015477 | Leukemia, Myelomonocytic, Chronic |
| D009190 | Myelodysplastic Syndromes |
| ID | Term |
|---|---|
| D007951 | Leukemia, Myeloid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D054437 | Myelodysplastic-Myeloproliferative Diseases |
| D001855 | Bone Marrow Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D001374 | Azacitidine |
| C560077 | trametinib |
| C579720 | venetoclax |
| ID | Term |
|---|---|
| D001372 | Aza Compounds |
| D009930 | Organic Chemicals |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D012263 | Ribonucleosides |
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| >=65 years |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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