Recurrent Acute Myeloid Leukemia, Recurrent Chronic Myelomonocytic Leukemia, Recurrent Myelodysplastic Syndrome, Refractory Acute Myeloid Leukemia, Refractory Chronic Myelomonocytic Leukemia, Refractory Myelodysplastic Syndrome
Conditions
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.
Interventions
DRUGAzacitidine
Given IV or SC
DRUGTrametinib
Given PO
DRUGVenetoclax
Given PO
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With a Response | Up to 2.5 years | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Minimal Residual Disease Negativity | Up to time of relapse, assessed up to 2.5 years | Will be assessed by flow cytometry and estimated along with 95% credible intervals. |
| Relapse-free Survival | From documented CR/CRi until relapse or death, assessed until study completion | Relapse-free survival is the time from documented CR/CRi until relapse or death. |
| Event-free Survival | 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 | 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). |
| Overall Survival | From the first day of treatment to time of death from any cause, assessed until study completion | Overall survival is defined as the time from the first day of treatment to time of death from any cause. |
| Number of Participants Proceeding to Hematopoietic Stem Cell Transplantation | Up to 2.5 years | Will be totaled based on the number of participants who continue with hematopoietic stem cell transplantation post treatment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 5 |
| 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 | 16 |
| Total | 21 |
Baseline characteristics
| Characteristic | Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) | Total | Cohort A (Newly Diagnosed AML Patients) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 13 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 8 Participants | 1 Participants |
| Age, Continuous | 67 years | 69 years | 75 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 17 Participants | 4 Participants |
| Region of Enrollment United States | 16 participants | 21 participants | 5 participants |
| Sex: Female, Male Female | 5 Participants | 6 Participants | 1 Participants |
| Sex: Female, Male Male | 11 Participants | 15 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 5 | 1 / 16 |
| other Total, other adverse events | 3 / 5 | 15 / 16 |
| serious Total, serious adverse events | 2 / 5 | 4 / 16 |
Outcome results
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 \</= 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).
Time frame: Up to 2.5 years
Population: Of the five participants registered on Cohort A, three were evaluable. Of the sixteen participants registered on Cohort B, thirteen were evaluable.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A (Newly Diagnosed AML Patients) | Participants With a Response | 2 Participants |
| Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) | Participants With a Response | 2 Participants |
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).
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A (Newly Diagnosed AML Patients) | Event-free Survival | 1.8 Months |
| Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) | Event-free Survival | 2.1 Months |
Secondary
Minimal Residual Disease Negativity
Will be assessed by flow cytometry and estimated along with 95% credible intervals.
Time frame: Up to time of relapse, assessed up to 2.5 years
Population: Of the five participants in Cohort A, three were evaluable for response. Of the 16 participants in Cohort B, 13 were evaluable for response.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A (Newly Diagnosed AML Patients) | Minimal Residual Disease Negativity | 1 Participants |
| Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) | Minimal Residual Disease Negativity | 1 Participants |
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.
Time frame: Up to 2.5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A (Newly Diagnosed AML Patients) | Number of Participants Proceeding to Hematopoietic Stem Cell Transplantation | 0 Participants |
| Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) | Number of Participants Proceeding to Hematopoietic Stem Cell Transplantation | 1 Participants |
Secondary
Overall Survival
Overall survival is defined as the time from the first day of treatment to time of death from any cause.
Time frame: From the first day of treatment to time of death from any cause, assessed until study completion
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A (Newly Diagnosed AML Patients) | Overall Survival | 2.5 Months |
| Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) | Overall Survival | 2.4 Months |
Secondary
Relapse-free Survival
Relapse-free survival is the time from documented CR/CRi until relapse or death.
Time frame: From documented CR/CRi until relapse or death, assessed until study completion
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A (Newly Diagnosed AML Patients) | Relapse-free Survival | 19 Months |
| Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) | Relapse-free Survival | NA Months |