Clinical Trials /

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

NCT04487106

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Azacitidine, Venetoclax, and Trametinib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Higher-Risk Myelodysplastic Syndrome
  • Official Title: A Phase II Study of Azacitidine, Venetoclax and Trametinib for Patients With Acute Myeloid Leukemia or Higher-Risk Myelodysplastic Syndrome

Clinical Trial IDs

  • ORG STUDY ID: 2020-0506
  • SECONDARY ID: NCI-2020-05350
  • SECONDARY ID: 2020-0506
  • NCT ID: NCT04487106

Conditions

  • Recurrent Acute Myeloid Leukemia
  • Recurrent Chronic Myelomonocytic Leukemia
  • Recurrent Myelodysplastic Syndrome
  • Refractory Acute Myeloid Leukemia
  • Refractory Chronic Myelomonocytic Leukemia
  • Refractory Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaTreatment (azacitidine, venetoclax, trametinib)
TrametinibGSK1120212, JTP-74057, MEK Inhibitor GSK1120212, MekinistTreatment (azacitidine, venetoclax, trametinib)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, VenclyxtoTreatment (azacitidine, venetoclax, trametinib)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (azacitidine, venetoclax, trametinib)ExperimentalINDUCTION (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
  • Trametinib
  • Venetoclax

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival (Cohort A)
Time Frame:From the first day of treatment to time of death from any cause, assessed at 1 year
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Complete response rate
Time Frame:Up to 3 years
Safety Issue:
Description:Will be estimated along with 95% credible intervals.
Measure:Minimal residual disease negativity
Time Frame:Up to time of relapse, assessed up to 3 years
Safety Issue:
Description:Will be assessed by flow cytometry and estimated along with 95% credible intervals.
Measure:Relapse-free survival
Time Frame:From documented CR/CRi until relapse or death, assessed up to 3 years
Safety Issue:
Description: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.
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 up to 3 years
Safety Issue:
Description: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.
Measure:Overall survival
Time Frame:From the first day of treatment to time of death from any cause, assessed up to 3 years
Safety Issue:
Description: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.
Measure:Proportion of patients proceeding to hematopoietic stem cell transplantation
Time Frame:Up to 3 years
Safety Issue:
Description:Will be estimated along with 95% credible intervals.
Measure:Incidence of adverse events
Time Frame:Up to 30 days after last dose of treatment
Safety Issue:
Description:Will be graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Event Reporting Version 5.0.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

July 22, 2020