Azacitidine, Venetoclax, and Trametinib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Higher-Risk Myelodysplastic Syndrome
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ClinicalTrials.gov Identifier: NCT04487106 |
Recruitment Status :
Recruiting
First Posted : July 27, 2020
Last Update Posted : January 15, 2021
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Condition or disease | Intervention/treatment | Phase |
---|---|---|
Recurrent Acute Myeloid Leukemia Recurrent Chronic Myelomonocytic Leukemia Recurrent Myelodysplastic Syndrome Refractory Acute Myeloid Leukemia Refractory Chronic Myelomonocytic Leukemia Refractory Myelodysplastic Syndrome | Drug: Azacitidine Drug: Trametinib Drug: Venetoclax | Phase 2 |
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.
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 40 participants |
Allocation: | N/A |
Intervention Model: | Single Group Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | A Phase II Study of Azacitidine, Venetoclax and Trametinib for Patients With Acute Myeloid Leukemia or Higher-Risk Myelodysplastic Syndrome |
Actual Study Start Date : | July 21, 2020 |
Estimated Primary Completion Date : | June 1, 2024 |
Estimated Study Completion Date : | June 1, 2024 |

Arm | Intervention/treatment |
---|---|
Experimental: Treatment (azacitidine, venetoclax, trametinib)
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. |
Drug: Azacitidine
Given IV or SC
Other Names:
Drug: Trametinib Given PO
Other Names:
Drug: Venetoclax Given PO
Other Names:
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- Overall survival (Cohort A) [ Time Frame: From the first day of treatment to time of death from any cause, assessed at 1 year ]Will be calculated. The distribution will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups (e.g., baseline genomic alterations) will be made using the log-rank tests.
- Complete remission(CR)/complete remission without recovery of counts (CRi) (Cohort B) [ Time Frame: Up to 6 cycles of treatment (each cycle = 28 days) ]Will estimate the CR/CRi for the combination treatment (defined as the proportion of patients achieving CR or CRi within 6 cycles of treatment), along with the 95% credible interval.
- Complete response rate [ Time Frame: Up to 3 years ]Will be estimated along with 95% credible intervals.
- Minimal residual disease negativity [ Time Frame: Up to time of relapse, assessed up to 3 years ]Will be assessed by flow cytometry and estimated along with 95% credible intervals.
- Relapse-free survival [ Time Frame: From documented CR/CRi until relapse or death, assessed up to 3 years ]Will be calculated. The distribution will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups (e.g., baseline genomic alterations) will be made using the log-rank tests.
- Event-free survival [ Time Frame: From the first day of treatment until any treatment failure (lack of response within 6 cycles of treatment, relapse, or death), assessed up to 3 years ]Will be calculated. The distribution will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups (e.g., baseline genomic alterations) will be made using the log-rank tests.
- Overall survival [ Time Frame: From the first day of treatment to time of death from any cause, assessed up to 3 years ]Will be calculated. The distribution will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups (e.g., baseline genomic alterations) will be made using the log-rank tests.
- Proportion of patients proceeding to hematopoietic stem cell transplantation [ Time Frame: Up to 3 years ]Will be estimated along with 95% credible intervals.

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
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Diagnosis:
- Cohort A (frontline): Newly diagnosed AML
- Cohort B (relapsed/refractory): Relapsed/refractory AML or relapsed/refractory MDS or chronic myelomonocytic leukemia (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 principal investigator (PI)
- 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:
- Patients suitable for and willing to receive intensive induction chemotherapy (cohort A only)
- Active serious infection not controlled by oral or intravenous antibiotics (e.g. persistent fever or lack of improvement despite antimicrobial treatment)
- 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
- 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
- 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. Prior recent treatment with corticosteroids, hydroxyurea and/or cytarabine (given for cytoreduction) permitted
- 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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04487106
United States, Texas | |
M D Anderson Cancer Center | Recruiting |
Houston, Texas, United States, 77030 | |
Contact: Nicholas Short 713-563-4485 nshort@mdanderson.org | |
Principal Investigator: Nicholas Short |
Principal Investigator: | Nicholas Short | M.D. Anderson Cancer Center |
Responsible Party: | M.D. Anderson Cancer Center |
ClinicalTrials.gov Identifier: | NCT04487106 |
Other Study ID Numbers: |
2020-0506 NCI-2020-05350 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) 2020-0506 ( Other Identifier: M D Anderson Cancer Center ) |
First Posted: | July 27, 2020 Key Record Dates |
Last Update Posted: | January 15, 2021 |
Last Verified: | January 2021 |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Preleukemia Leukemia, Myelomonocytic, Acute Leukemia, Myelomonocytic, Chronic Leukemia, Myelomonocytic, Juvenile Myelodysplastic Syndromes Syndrome Recurrence Disease Pathologic Processes Neoplasms by Histologic Type Neoplasms |
Disease Attributes Bone Marrow Diseases Hematologic Diseases Precancerous Conditions Myelodysplastic-Myeloproliferative Diseases Azacitidine Venetoclax Trametinib Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Enzyme Inhibitors Protein Kinase Inhibitors |