Azacitidine, Venetoclax, and Trametinib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Higher-Risk Myelodysplastic Syndrome

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Study of Azacitidine, Venetoclax and Trametinib for Patients With Acute Myeloid Leukemia or Higher-Risk Myelodysplastic Syndrome

Conditions
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Recurrent Acute Myeloid Leukemia, Recurrent Chronic Myelomonocytic Leukemia, Recurrent Myelodysplastic Syndrome, Refractory Acute Myeloid Leukemia, Refractory Chronic Myelomonocytic Leukemia, Refractory Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: Azacitidine
* Drug: Trametinib
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (azacitidine, venetoclax, trametinib)<br>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<br>* Given IV or SC<br>* Other names: Vidaza;Drug: Trametinib<br>* Given PO<br>* Other names: Mekinist;Drug: Venetoclax<br>* Given PO<br>* Other names: Venclyxto;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (Cohort A) | 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. | From the first day of treatment to time of death from any cause, assessed at 1 year | 
| Complete remission(CR)/complete remission without recovery of counts (CRi) (Cohort B) | 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. | Up to 6 cycles of treatment (each cycle = 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate | Will be estimated along with 95% credible intervals. | Up to 3 years | 
| 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 3 years | 
| Relapse-free survival | 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. | From documented CR/CRi until relapse or death, assessed up to 3 years | 
| Event-free survival | 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. | 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 | 
| Overall survival | 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. | From the first day of treatment to time of death from any cause, assessed up to 3 years | 
| Proportion of patients proceeding to hematopoietic stem cell transplantation | Will be estimated along with 95% credible intervals. | Up to 3 years |