Clinical Trials /

Azacitidine, Venetoclax, and Gilteritinib in Treating Patients With Recurrent/Refractory FLT3-Mutated Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

NCT04140487

Description:

This phase I/II trial studies the side effects and best dose of gilteritinib and to see how well it works in combination with azacitidine and venetoclax in treating patients with FLT3-mutation positive acute myeloid leukemia or high-risk myelodysplastic syndrome that has come back (recurrent) or has not responded to treatment (refractory). Drugs used in chemotherapy, such as azacitidine and venetoclax, 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. Gilteritinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine, venetoclax, and gilteritinib may work better compared to azacitidine and venetoclax alone in treating patients with acute myeloid leukemia or myelodysplastic syndrome.

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

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Azacitidine, Venetoclax, and Gilteritinib in Treating Patients With Recurrent/Refractory FLT3-Mutated Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome
  • Official Title: A Phase I/II Study of Azacitidine, Venetoclax, and Gilteritinib for Patients With Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome With an Activating FLT3 Mutation

Clinical Trial IDs

  • ORG STUDY ID: 2019-0366
  • SECONDARY ID: NCI-2019-04959
  • SECONDARY ID: 2019-0366
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04140487

Conditions

  • FLT3 Internal Tandem Duplication
  • FLT3 Tyrosine Kinase Domain Point Mutation
  • Recurrent Acute Myeloid Leukemia
  • Recurrent High Risk Myelodysplastic Syndrome
  • Refractory Acute Myeloid Leukemia
  • Refractory High Risk Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaTreatment (azacitidine, venetoclax, gilteritinib)
GilteritinibASP-2215, ASP2215, XospataTreatment (azacitidine, venetoclax, gilteritinib)
Gilteritinib FumarateASP-2215 Hemifumarate, ASP2215 Hemifumarate, Gilteritinib Hemifumarate, XospataTreatment (azacitidine, venetoclax, gilteritinib)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, VenclyxtoTreatment (azacitidine, venetoclax, gilteritinib)

Purpose

This phase I/II trial studies the side effects and best dose of gilteritinib and to see how well it works in combination with azacitidine and venetoclax in treating patients with FLT3-mutation positive acute myeloid leukemia or high-risk myelodysplastic syndrome that has come back (recurrent) or has not responded to treatment (refractory). Drugs used in chemotherapy, such as azacitidine and venetoclax, 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. Gilteritinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine, venetoclax, and gilteritinib may work better compared to azacitidine and venetoclax alone in treating patients with acute myeloid leukemia or myelodysplastic syndrome.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To establish the maximum tolerated dose (MTD) of the combination of azacitidine,
      venetoclax and gilteritinib in patients with relapsed/refractory FLT3-mutated acute myeloid
      leukemia (AML) or high-risk myelodysplastic syndrome (MDS). (Phase I) II. To determine the
      complete remission/complete remission with incomplete count recovery (CR/CRi) rate of the
      regimen in patients with newly diagnosed or relapsed/refractory fms-like tyrosine kinase 3
      (FLT3)-mutated AML or high-risk MDS. (Phase II)

      SECONDARY OBJECTIVES:

      I. To assess other efficacy endpoints (CR rate, minimal residual disease negativity by flow
      cytometry, relapse-free survival, 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 determine the impact of baseline FLT3 allelic ratio on response and survival.

      III. To assess minimal residual disease negativity rates by digital droplet polymerase chain
      reaction (PCR) at the time of remission.

      IV. To evaluate leukemia stem cell populations over the course of treatment with the
      combination regimen.

      V. To determine the impact of baseline apoptotic protein levels as assessed by mass cytometry
      (CyTOF) on response and resistance to the regimen.

      OUTLINE: This is phase I, dose-escalation study of gilteritinib followed by a phase II study.

      Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over 30-60 minutes on
      days 1-7, venetoclax orally (PO) once daily (QD) on days 2-28 of cycle 1 and on days 1-21 of
      subsequent cycles, and gilteritinib PO QD on days 1-28. Treatment of azacytidine and
      venetoclax repeats every 28 days for up to 24 cycles in the absence of disease progression or
      unacceptable toxicity. Cycles of gilteritinib repeat every 28 days 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, gilteritinib)ExperimentalPatients receive azacitidine SC or IV over 30-60 minutes on days 1-7, venetoclax PO QD on days 2-28 of cycle 1 and on days 1-21 of subsequent cycles, and gilteritinib PO QD on days 1-28. Treatment of azacytidine and venetoclax repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Cycles of gilteritinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Azacitidine
  • Gilteritinib
  • Gilteritinib Fumarate
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis:

               -  Phase I cohort: Adults >= 18 with relapsed/refractory FLT3-mutated AML or
                  myelodysplastic syndrome (MDS) that is intermediate - 2 or high-risk by the
                  International Prognostic Scoring System

               -  Phase II cohort A: Adults with newly diagnosed FLT3-mutated AML

               -  Phase II cohort B: Adults >= 18 with relapsed/refractory FLT3-mutated AML or MDS
                  that is intermediate-2 or high-risk by the International Prognostic Scoring
                  System who have received 1-2 prior therapies

               -  For all cohorts, patients with either FLT3-internal tandem duplication (FLT3-ITD)
                  or FLT3 tyrosine kinase domain mutations will be eligible

          -  Performance status =< 3 (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 principal investigator
             (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:

          -  Prior therapies:

               -  Phase I cohort: No restriction based on prior therapies

               -  Phase II cohort A: Patients with prior therapy for AML are not eligible. Prior
                  therapy for antecedent hematologic disorder is allowed. Prior hydroxyurea or
                  cytarabine given for purposes of cytoreduction is also allowed. Prior all
                  trans-retinoic acid given for presumed acute promyelocytic leukemia is also
                  allowed

               -  Phase II cohort B: Patients with >= 3 prior lines of therapy are not eligible.
                  Stem cell transplantation, treatment given only for cytoreductive purposes (e.g.
                  hydroxyurea), and growth factors do not count as lines of therapy for this
                  purpose

          -  Prior treatment with gilteritinib

          -  Patients suitable for and willing to receive intensive induction chemotherapy (for
             Phase II cohort A only)

          -  Congenital long QT syndrome or corrected QT interval by Fridericia (QTcF) > 450 msec.
             Repeat electrocardiograms (EKGs) after correction of electrolytes or discontinuation
             of QT prolonging medications are allowed to meet entry criteria

          -  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 cytochrome P450, family 3, subfamily A (CYP3A) within 3
             days of study enrollment. Agents include but are not limited to: carbamazepine,
             phenytoin, rifampin, and St. John's wort

          -  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 and lactating 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 3
             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 3 months after the last dose of study
             drugs
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum-tolerated dose (MTD) of gilteritinib (Phase I)
Time Frame:Up to 28 days
Safety Issue:
Description:The MTD is the highest dose level in which < 2 patients of 6 develop first cycle dose-limiting toxicity.

Secondary Outcome Measures

Measure:Complete response rate
Time Frame:Up to 3 years
Safety Issue:
Description:Will be estimated along with 95% credible interval.
Measure:Minimal residual disease negativity
Time Frame:Up to 3 years
Safety Issue:
Description:Will be assessed by flow cytometry and estimated along with 95% credible interval.
Measure:Relapse-free survival
Time Frame:The number of days from the date of response to the date of documented relapses from CR or death from any cause, whichever occurs first, assessed up to 3 years
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier.
Measure:Overall survival
Time Frame:From the start of treatment until death or last follow-up, assessed for up to 3 years
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier.
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 interval.
Measure:Incidence of adverse events
Time Frame:Up to 3 years
Safety Issue:
Description:Will be summarized using descriptive statistics such as mean, standard deviation, median and range.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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