- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04487106
Azacitidine, Venetoclax, and Trametinib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Higher-Risk Myelodysplastic Syndrome
A Phase II Study of Azacitidine, Venetoclax and Trametinib for Patients With Acute Myeloid Leukemia or Higher-Risk Myelodysplastic Syndrome
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Texas
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Houston, Texas, United States, 77030
- M D Anderson Cancer Center
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / 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. |
Given IV or SC
Other Names:
Given PO
Other Names:
Given PO
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
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)
Time Frame: Up to 6 cycles of treatment (each cycle = 28 days)
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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
Time Frame: Up to 3 years
|
Will be estimated along with 95% credible intervals.
|
Up to 3 years
|
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.
|
Up to time of relapse, assessed up to 3 years
|
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.
|
From documented CR/CRi until relapse or death, assessed up to 3 years
|
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.
|
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
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.
|
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
Time Frame: Up to 3 years
|
Will be estimated along with 95% credible intervals.
|
Up to 3 years
|
Collaborators and Investigators
Sponsor
Collaborators
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Neoplasms by Histologic Type
- Neoplasms
- Disease Attributes
- Disease
- Bone Marrow Diseases
- Hematologic Diseases
- Precancerous Conditions
- Myelodysplastic-Myeloproliferative Diseases
- Syndrome
- Myelodysplastic Syndromes
- Leukemia
- Leukemia, Myeloid
- Leukemia, Myeloid, Acute
- Recurrence
- Preleukemia
- Leukemia, Myelomonocytic, Acute
- Leukemia, Myelomonocytic, Chronic
- Leukemia, Myelomonocytic, Juvenile
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Protein Kinase Inhibitors
- Venetoclax
- Azacitidine
- Trametinib
Other Study ID Numbers
- 2020-0506 (Other Identifier: M D Anderson Cancer Center)
- NCI-2020-05350 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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