NCT04487106 · REGISTRY CONDITION SEARCH

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

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase: PHASE2
Status at capture: COMPLETED
Registry last update: 2025-04-22

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Participants With a Response

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outcome · POSTED

Minimal Residual Disease Negativity

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outcome · POSTED

Relapse-free Survival

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outcome · POSTED

Event-free Survival

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outcome · POSTED

Overall Survival

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outcome · POSTED

Number of Participants Proceeding to Hematopoietic Stem Cell Transplantation

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: 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
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
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.
intervention Names
Drug: Azacitidine
Drug: Trametinib
Drug: Venetoclax
label
Cohort A (Newly Diagnosed AML Patients)
type
EXPERIMENTAL
description
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.
intervention Names
Drug: Azacitidine
Drug: Trametinib
Drug: Venetoclax
label
Cohort B (Relapsed/Refractory AML or higher-risk MDS or CMML Patients)
type
EXPERIMENTAL

interventions

arm Group Labels
Cohort A (Newly Diagnosed AML Patients)
Cohort B (Relapsed/Refractory AML or higher-risk MDS or CMML Patients)
description
Given IV or SC
name
Azacitidine
other Names
5 AZC
5-AC
5-Azacytidine
5-AZC
Azacytidine
Azacytidine, 5-
Ladakamycin
Mylosar
U-18496
Vidaza
type
DRUG
arm Group Labels
Cohort A (Newly Diagnosed AML Patients)
Cohort B (Relapsed/Refractory AML or higher-risk MDS or CMML Patients)
description
Given PO
name
Trametinib
other Names
GSK1120212
JTP-74057
MEK Inhibitor GSK1120212
Mekinist
type
DRUG
arm Group Labels
Cohort A (Newly Diagnosed AML Patients)
Cohort B (Relapsed/Refractory AML or higher-risk MDS or CMML Patients)
description
Given PO
name
Venetoclax
other Names
ABT-0199
ABT-199
ABT199
GDC-0199
RG7601
Venclexta
Venclyxto
type
DRUG

Study design

allocation

NON_RANDOMIZED

intervention Model

SINGLE_GROUP

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 21
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
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 \</= to 5 % blasts with a granulocyte count of 1 x 10\^9/L or greater and a platelet count of 100 x 10\^9/L and complete resolution of all extramedullary disease. CRi is Peripheral blood and marrow results as for CR, but with incomplete recover of counts (platelets \< 100 x 10\^9/L or neutrophils \< 1 x 10\^9/L).
measure
Participants With a Response
time Frame
Up to 2.5 years

secondary Outcomes

description
Will be assessed by flow cytometry and estimated along with 95% credible intervals.
measure
Minimal Residual Disease Negativity
time Frame
Up to time of relapse, assessed up to 2.5 years
description
Relapse-free survival is the time from documented CR/CRi until relapse or death.
measure
Relapse-free Survival
time Frame
From documented CR/CRi until relapse or death, assessed until study completion
description
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).
measure
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 until study completion
description
Overall survival is defined as the time from the first day of treatment to time of death from any cause.
measure
Overall Survival
time Frame
From the first day of treatment to time of death from any cause, assessed until study completion
description
Will be totaled based on the number of participants who continue with hematopoietic stem cell transplantation post treatment.
measure
Number of Participants Proceeding to Hematopoietic Stem Cell Transplantation
time Frame
Up to 2.5 years

Full study description

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.

Source references