Clinical Trials /

Pinometostat and 5-Azacitidine in Treating Patients With Relapsed, Refractory, or Newly Diagnosed Acute Myeloid Leukemia With 11q23 Rearrangement

NCT03701295

Description:

This phase Ib/II trial studies the side effects and best dose of pinometostat when given together with azacitidine (5-azacitidine) and to see how well it works in treating patients with acute myeloid leukemia that has come back, does not respond to treatment, or is newly diagnosed, with an 11q23 rearrangement. Pinometostat and 5-azacitidine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pinometostat and 5-Azacitidine in Treating Patients With Relapsed, Refractory, or Newly Diagnosed Acute Myeloid Leukemia With 11q23 Rearrangement
  • Official Title: Combination Pinometostat and 5-Azacitidine for the Treatment of Patients With Relapsed / Refractory Acute Myeloid Leukemia, or Newly Diagnosed Patients Who Are Ineligible for or Unwilling to Undergo Intensive Therapy, Who Harbor an 11q23 Rearrangement

Clinical Trial IDs

  • ORG STUDY ID: NCI-2018-02128
  • SECONDARY ID: NCI-2018-02128
  • SECONDARY ID: 10200
  • SECONDARY ID: 10200
  • SECONDARY ID: UM1CA186691
  • NCT ID: NCT03701295

Conditions

  • Acute Myeloid Leukemia With t(9;11)(p21.3;q23.3); MLLT3-KMT2A
  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaTreatment (pinometostat, azacitidine)
Enzyme Inhibitor TherapyTreatment (pinometostat, azacitidine)

Purpose

This phase Ib/II trial studies the side effects and best dose of pinometostat when given together with azacitidine (5-azacitidine) and to see how well it works in treating patients with acute myeloid leukemia that has come back, does not respond to treatment, or is newly diagnosed, with an 11q23 rearrangement. Pinometostat and 5-azacitidine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine if the combination of pinometostat, at a dose of 54 or 90 mg/m^2/day, and
      azacitidine, at a dose of 75 mg/m2 daily for 7 days, is safe and tolerable in patients >= 12
      years old (yo) with MLL-rearranged acute myeloid leukemia, either in the relapsed /
      refractory setting or in those who choose not to undergo standard induction therapy in the
      previously untreated setting. (Phase Ib) II. To determine the preliminary efficacy, as
      determined by overall response rate (complete response [CR], complete response with
      incomplete bone marrow recovery [CRi], partial response [PR], and morphologic leukemia-free
      state [MLFS]), of pinometostat administered at the maximum tolerated dose from the phase 1b,
      combined with azacitidine administered at 75 mg/m^2 daily for 7 days, in patients with
      MLL-rearranged acute myeloid leukemia, either in the relapsed / refractory setting or in
      those who choose not to undergo standard induction therapy in the previously untreated
      setting. (Phase II)

      SECONDARY OBJECTIVES:

      I. Perform correlative studies to evaluate for on-target effects, cellular differentiation,
      and decreased leukemia cell proliferation in these patients. (Phase Ib and II) II. To observe
      and record anti-tumor activity. (Phase Ib)

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

      Patients receive pinometostat intravenously (IV) continuously on days 1-28 and azacitidine IV
      over 10-40 minutes or subcutaneously (SC) for 7 of the first 10 days of the course. Treatment
      repeats every 28 days for up to 6 courses in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up for 1 month.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pinometostat, azacitidine)ExperimentalPatients receive pinometostat IV continuously on days 1-28 and azacitidine IV over 10-40 minutes or SC for 7 of the first 10 days of the course. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
  • Azacitidine
  • Enzyme Inhibitor Therapy

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed acute myeloid leukemia

          -  Patients must have an 11q23 translocation or partial tandem duplication, confirmed by
             cytogenetics, fluorescence in situ hybridization (FISH), or myeloid panel

          -  Patients may not have any other targetable mutations (including, but not limited to
             PML/RARa, FLT3, IDH1/2, and JAK2) identified on myeloid mutational panel testing

          -  Eastern Cooperative Oncology Group (ECOG) performance status < 3 (Karnofsky > 60%)

          -  Prothrombin time (PT) and activated partial thromboplastin time (aPTT) =< 1.5 x upper
             limit of normal (ULN)

          -  Total bilirubin < 2 times the upper limit of institutional normal (ULN) unless due to
             Gilbert's disease

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =<
             2.5 x institutional upper limit of normal

          -  Creatinine =< 2 times the upper limit of institutional normal (ULN) OR creatinine
             clearance glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2

          -  Patients treated in the up-front setting must decline standard-of-care therapy

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Patients must have measurable disease, defined as abnormal blasts detectable in the
             peripheral blood or bone marrow

          -  Patients may have had previous treatment with standard-of-care or experimental agents.
             Patients who have previously undergone bone marrow transplantation may also be
             included

          -  Patients who are human immunodeficiency virus (HIV)+, hepatitis B virus (HBV)+, and /
             or hepatitis C virus (HCV)+ may be eligible as follows:

               -  Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral
                  therapy with undetectable viral load within 6 months are eligible for this trial.
                  The antiretroviral therapy should not strongly induce or inhibit CYP3A4

               -  If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be
                  undetectable on suppressive therapy if indicated

               -  If history of hepatitis C virus (HCV) infection, must be treated with
                  undetectable HCV viral load

          -  The effects of pinometostat on the developing human fetus are unknown. For this reason
             and because histone methyltransferase inhibitors as well as hypomethylating agents are
             known to be teratogenic, women of child-bearing potential and men must agree to use
             adequate contraception (hormonal or barrier method of birth control; abstinence) prior
             to study entry, and for the duration of study participation and for 4 weeks after the
             last dose of study treatment. Should a woman become pregnant or suspect she is
             pregnant while she or her partner is participating in this study, she should inform
             her treating physician immediately. Men treated or enrolled on this protocol must also
             agree to use adequate contraception prior to the study, for the duration of study
             participation, and 90 days after completion of pinometostat and azacitidine
             administration

        Exclusion Criteria:

          -  Patients who are receiving any other investigational agents

          -  Patients with active central nervous system (CNS) disease are excluded from this
             clinical trial because they may develop progressive neurologic dysfunction that would
             confound the evaluation of neurologic and other adverse events. Patients with a prior
             history of CNS disease will not be excluded

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to pinometostat or azacitidine

          -  Patients receiving any medications or substances that are inhibitors or inducers of
             the CYP3A4 or CYP450 system should have their medications reviewed and adjusted for
             interactions as appropriate for local institutional practice. Because the lists of
             these agents are constantly changing, it is important to regularly consult a
             frequently-updated medical reference. As part of the enrollment/informed consent
             procedures, the patient will be counseled on the risk of interactions with other
             agents, and what to do if new medications need to be prescribed or if the patient is
             considering a new over-the-counter medicine or herbal product

          -  Patients receiving any medications or substances that are inhibitors or inducers of
             MATE1 and MATE2-K transporters should have their medications reviewed and adjusted for
             interactions as appropriate for local institutional practice. Pinometostat has been
             demonstrated to be an inhibitor of MATE1 and MATE2-K transporters in vitro, although
             the clinical significance of this is unclear. Drug interactions may occur between
             pinometostat and other therapies that are MATE substrates, including metformin.
             Consultation with a frequently updated medical reference and / or pharmacist should be
             sought to guide necessary changes in the patient's other medications

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris,
             uncontrolled or clinically significant cardiac arrhythmia, or psychiatric
             illness/social situations that would limit compliance with study requirements.
             Patients with these conditions that are medically well controlled may be considered
             for enrollment

          -  Pregnant women are excluded from this study because pinometostat is an agent with the
             potential for teratogenic or abortifacient effects. Because there is an unknown but
             potential risk for adverse events in nursing infants secondary to treatment of the
             mother with pinometostat, breastfeeding should be discontinued if the mother is
             treated with pinometostat. These potential risks may also apply to other agents used
             in this study

          -  HIV-positive patients on combination antiretroviral therapy should have their regimen
             reviewed for potential pharmacokinetic interactions with pinometostat and azacitidine.
             In the event of a potential interaction, alternative therapies may be considered in
             consultation with the patient's primary HIV physician

          -  Absence of an 11q23 rearrangement or absence of an 11q23 partial tandem duplication

          -  Patients with an active bleeding diathesis
      
Maximum Eligible Age:N/A
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of dose-limiting toxicities (DLTs) (Phase Ib)
Time Frame:Up to day 42
Safety Issue:
Description:Safety and tolerability will be assessed by evaluating the number of patients out of 6 who experience a DLT defined as a significant suspected adverse reaction or clinically significant abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications.

Secondary Outcome Measures

Measure:Number of patients who experience a DLT (Phase Ib)
Time Frame:Up to day 42
Safety Issue:
Description:
Measure:Change in H3K79 methylation (Phase Ib)
Time Frame:Baseline up to day 28
Safety Issue:
Description:Will compare quantitative methylation and methylation valence (e.g. if H3K27 has been methylated once, twice, or three times) from baseline and subsequent bone marrow samples using descriptive statistics and graphical displays. A Wilcoxon signed rank test will be used to assess post-treatment differences as compared to baseline.
Measure:Change in expression levels of HOXA9 and Meis1 (Phase Ib)
Time Frame:Baseline up to day 28
Safety Issue:
Description:Will compare expression level by quantitative polymerase chain reaction (qPCR) of HOXA9 and Meis1 levels from baseline and subsequent bone marrow samples using descriptive statistics and graphical displays. A Wilcoxon signed rank test will be used to assess post-treatment differences as compared to baseline.
Measure:Fraction of cells with 11q23 rearrangements (Phase Ib)
Time Frame:Up to day 28
Safety Issue:
Description:Samples will be banked, and cytogenetic and fluorescence in situ hybridization (FISH) analysis of these cells will be performed to evaluate for the presence of MLL-rearrangement in patients who respond to therapy.
Measure:Change in absolute neutrophil / absolute monocyte count (Phase Ib)
Time Frame:Baseline up to day 28
Safety Issue:
Description:Will evaluate differentiation by performing a differential on the bone marrow biopsy and peripheral blood samples at baseline and from subsequent time points and assessing percentage of monocytes / neutrophils, bands, and myeloid forms present.
Measure:Number of patients who experience a DLT (Phase II)
Time Frame:Up to 1 month post-treatment
Safety Issue:
Description:
Measure:Response rate based on relapsed / refractory or previously untreated status (Phase II)
Time Frame:Up to 1 month post-treatment
Safety Issue:
Description:Patients will be stratified based on treatment for relapsed / refractory or previously untreated disease. The response of each stratum to combination therapy, defined as CR, CRi, MLFS, or PR, with or without MRD, on bone marrow biopsy as defined by the 2017 European Leukemia Network guidelines, will be described. Kaplan-Meier estimates will be calculated and compared for each stratum. A report will be generated to look at all patients, all eligible patients who were enrolled, and all evaluable patients.
Measure:Change in H3K79 methylation (Phase II)
Time Frame:Baseline up to 1 month post-treatment
Safety Issue:
Description:Will compare quantitative methylation and methylation valence (e.g. if H3K27 has been methylated once, twice, or three times) from baseline and subsequent bone marrow samples using descriptive statistics and graphical displays. A Wilcoxon signed rank test will be used to assess post-treatment differences as compared to baseline.
Measure:Change in expression levels of HOXA9 and Meis1 (Phase II)
Time Frame:Baseline up to 1 month post-treatment
Safety Issue:
Description:Will compare expression level by qPCR of HOXA9 and Meis1 levels from baseline and subsequent bone marrow samples using descriptive statistics and graphical displays. A Wilcoxon signed rank test will be used to assess post-treatment differences as compared to baseline.
Measure:Fraction of cells with 11q23 rearrangements (Phase II)
Time Frame:Up to 1 month post-treatment
Safety Issue:
Description:Samples will be banked, and cytogenetic and FISH analysis of these cells will be performed to evaluate for the presence of MLL-rearrangement in patients who respond to therapy.
Measure:Change in absolute neutrophil / absolute monocyte count (Phase II)
Time Frame:Baseline up to the end of course 1
Safety Issue:
Description:Will evaluate differentiation by performing a differential on the bone marrow biopsy and peripheral blood samples at baseline and from subsequent time points and assessing percentage of monocytes / neutrophils, bands, and myeloid forms present.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

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