Clinical Trials /

CPX-351 and Enasidenib in Treating Patients With Relapsed Acute Myeloid Leukemia Characterized by IDH2 Mutation

NCT03825796

Description:

This phase II trial studies how well CPX-351 and enasidenib work in treating patients with acute myeloid leukemia characterized by IHD2 mutation that has come back. Drugs used in chemotherapy, such as CPX-351, 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. Enasidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving CPX-351 and enasidenib may work better in treating patients with acute myeloid leukemia.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: CPX-351 and Enasidenib in Treating Patients With Relapsed Acute Myeloid Leukemia Characterized by IDH2 Mutation
  • Official Title: CPX-351 Plus Enasidenib for Relapsed Acute Myelogenous Leukemia Characterized by the IDH2 Mutation

Clinical Trial IDs

  • ORG STUDY ID: 18-001416
  • SECONDARY ID: NCI-2018-02998
  • SECONDARY ID: 18-001416
  • SECONDARY ID: P30CA016042
  • NCT ID: NCT03825796

Conditions

  • Blasts 5 Percent or More of Bone Marrow Nucleated Cells
  • IDH2 Gene Mutation
  • Recurrent Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Enasidenib Mesylate2-Methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol Methanesulfonate, 2-Propanol, 2-Methyl-1-((4-(6-(trifluoromethyl)-2-pyridinyl)-6-((2-(trifluoromethyl)-4-pyridinyl)amino)-1,3,5-triazin-2-yl)amino)-, Methanesulfonate (1:1), AG-221 Mesylate, CC-90007, Enasidenib Methanesulfonate, IdhifaTreatment (CPX-351, enasidenib mesylate)
Liposome-encapsulated Daunorubicin-CytarabineCPX-351, Cytarabine-Daunorubicin Liposome for Injection, Liposomal AraC-Daunorubicin CPX-351, Liposomal Cytarabine-Daunorubicin, Liposome-encapsulated Combination of Daunorubicin and Cytarabine, VyxeosTreatment (CPX-351, enasidenib mesylate)

Purpose

This phase II trial studies how well CPX-351 and enasidenib work in treating patients with acute myeloid leukemia characterized by IHD2 mutation that has come back. Drugs used in chemotherapy, such as CPX-351, 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. Enasidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving CPX-351 and enasidenib may work better in treating patients with acute myeloid leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To estimate the remission rate (defined as complete remission [CR]/ CR with incomplete
      hematologic recovery [CRi]) of the combination of liposome-encapsulated
      daunorubicin-cytarabine (CPX-351) plus enasidenib mesylate (enasidenib) in adults with
      relapsed acute myeloid leukemia (AML) characterized by a 2-hydroxyglutarate (2-HG) producing
      IDH2 mutations that include IDH2^R172 and IDH2^R140.

      SECONDARY OBJECTIVES:

      I. To evaluate persistent severe hematologic toxicity at induction day 60 in patients with a
      morphologic leukemia-free state (bone marrow blasts < 5%).

      II. To evaluate delayed CR/CRi with enasidenib maintenance in participants with stable
      disease after induction with CPX-351.

      IV. To evaluate 30- and 60-day survival. V. To evaluate CPX-351 plus enasidenib as a bridge
      to allogeneic hematopoietic stem cell transplantation (HSCT).

      EXPLORATORY OBJECTIVES:

      I. To determine the co-existing mutations that are present with the IDH2 mutation and
      describe those that are present in patients who achieve CR/CRi.

      II. To determine the depth of molecular response to induction by minimal residual disease
      (MRD) using next generation sequencing.

      III. To estimate the subclinical cardiotoxicity of CPX-351 as measured by troponin I,
      electrocardiography (ECG), and echocardiography.

      OUTLINE:

      INDUCTION: Patients receive liposome-encapsulated daunorubicin-cytarabine intravenously (IV)
      over 90 minutes on days 1, 3, and 5, and enasidenib mesylate orally (PO) on days 10-60 in the
      absence of disease progression or unacceptable toxicity. Patients whose bone marrow is not
      hypoplastic with no excess blasts receive re-induction including liposome-encapsulated
      daunorubicin-cytarabine IV on days 1 and 3, and enasidenib mesylate PO on days 8-60 in the
      absence of disease progression or unacceptable toxicity.

      CONSOLIDATION: Patients < 60 years receive cytarabine twice daily (BID) on days 1, 3, and 5,
      and patients >= 60 years receive cytarabine IV once daily on days 1-5. Patients also receive
      enasidenib mesylate PO on days 6-55. Treatment repeats every 28-55 days for up to 4 cycles in
      the absence of disease progression or unacceptable toxicity. Patients who maintain CR/CRi
      after completion of consolidation therapy undergo allogeneic HSCT at the discretion of the
      treating physician.

      MAINTENANCE: Patients receive enasidenib mesylate PO daily in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 28 days, then periodically
      thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (CPX-351, enasidenib mesylate)ExperimentalSee detailed description
  • Enasidenib Mesylate
  • Liposome-encapsulated Daunorubicin-Cytarabine

Eligibility Criteria

        Inclusion Criteria:

          -  Bone marrow blasts >= 5% that develops after CR/CRi in patient with prior history of
             AML, no restriction on prior number of relapses or regimens

          -  AML characterized by the IDH2 gene mutation, without requirement for a particular
             allelic frequency

          -  Patients previously treated with IDH2 inhibitor can be enrolled

          -  At least a 3-month duration of CR/CRi prior to relapse

          -  Relapses after allogeneic HSCT are included with a minimum of 3 from the date of
             allogeneic HSCT

          -  Up to 1 cycle of hypomethylating agent monotherapy at time of relapse is allowed, must
             be discontinued at least 14 days prior to start of salvage induction

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2

          -  Serum total bilirubin < 2.0 mg/dL, unless considered due to Gilbert?s disease or
             leukemic involvement

          -  Aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 3 times the upper
             limit of normal, unless considered due to leukemic involvement

          -  Alkaline phosphatase < 3 times the upper limit of normal, unless considered due to
             leukemic involvement

          -  Serum creatinine =< 2.0 mg/dL, or creatinine clearance > 40 mL/min based on
             Cockcroft-Gault glomerular filtration rate (GFR)

          -  Females of reproductive potential as well as fertile men and their partners who are
             female of reproductive potential must agree to abstain from sexual intercourse or to
             use two highly effective forms of contraception from the time of giving informed
             consent, during the study, and for four months (females and males) following the last
             dose of IDH inhibitor. A highly effective form of contraception is defined as hormonal
             oral contraceptives, injectables, patches, intrauterine devices, double-barrier method
             (eg, synthetic condoms, diaphragm or cervical cap with spermicidal foam, cream, or
             gel) or male partner sterilization

        Exclusion Criteria:

          -  Concurrent FLT3 mutation that the treating physician deems necessary to treat with
             FLT3-targeted therapy; whereas, patients with FLT3-mutated AML not treated with
             FLT3-targeted therapy can be enrolled

          -  Inability to swallow medications or history of gastrointestinal (GI) malabsorptive
             disease

          -  Active malignancy that would limit survival by less than two years

          -  New York Heart Association class III or VI

          -  Left ventricular ejection fraction < 40%

          -  History of coronary stent placement that require mandatory continuation of
             dual-antiplatelet therapy

          -  Baseline QT corrected interval based on Fridericia?s formula (QTcF) interval > 450 ms

          -  History of Wilson?s disease or other copper handling disorders

          -  Hypersensitivity to cytarabine, daunorubicin, or liposomal products

          -  Active hepatitis B with surface antibody positivity (participants with hepatitis B
             core antibody positivity can be enrolled if given concurrent entecavir)

          -  Hepatitis C immnuoglobulin (Ig)G antibody positivity, unless received curative
             hepatitis C therapy and now with hepatitis C ribonucleic acid (RNA) undetectable

          -  Active invasive fungal infection

          -  Active bacterial or viral infection manifesting as fevers or hemodynamic instability
             within the past 72 hours

          -  Lifetime cumulative daunorubicin-equivalent anthracycline dose > 368 mg/m^2

          -  Pregnant or breast feeding
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete remission (CR)/CR with incomplete hematologic recovery (CRi) after induction therapy
Time Frame:Up to day 60
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Proportion of patients with persistent grade 4 hematologic toxicity per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
Time Frame:At day 60
Safety Issue:
Description:The proportion along with the exact 95% confidence interval will reported.
Measure:Proportion of patients who achieve CR/CRi during maintenance therapy
Time Frame:Up to 2 years
Safety Issue:
Description:This is calculated only among patients who had stable disease after induction therapy and have received maintenance enasidenib monotherapy.
Measure:Time to return of normal hematopoiesis
Time Frame:From day 1 of induction assessed up to 2 years
Safety Issue:
Description:Defined as time from day 1 of induction to absolute neutrophil count (ANC) >= 1000/uL and platelet count >= 100,000/uL. The median time to return of normal hematopoiesis will be reported along with the corresponding range.
Measure:Overall survival
Time Frame:From day 1 of induction therapy, assessed at day 30 and 60
Safety Issue:
Description:Will be estimated using Kaplan-Meier methods. The survival estimate at these two time points will be reported along with a 95% confidence interval.
Measure:Proportion of patients who go on to receive allogeneic hematopoietic stem cell transplantation (HSCT) after achieving CR/CRi
Time Frame:Up to 2 years
Safety Issue:
Description:Will be reported along with an exact 95% confidence interval.
Measure:Proportion of echocardiogram findings with left ventricular ejection fraction reduction by >= 25%
Time Frame:Up to 2 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Jonsson Comprehensive Cancer Center

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