Clinical Trials /

Pevonedistat, Cytarabine, and Idarubicin in Treating Patients With Acute Myeloid Leukemia

NCT03330821

Description:

This phase Ib/II trial studies the side effects and best dose of pevonedistat and to see how well it works in combination with cytarabine and idarubicin in treating patients with acute myeloid leukemia. Pevonedistat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine and idarubicin, 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. Given pevonedistat, cytarabine, and idarubicin may work better in treating patients with acute myeloid leukemia.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pevonedistat, Cytarabine, and Idarubicin in Treating Patients With Acute Myeloid Leukemia
  • Official Title: Phase 1B/II Study of Escalating Doses of Pevonedistat (TAK-924, Formerly MLN4924) Administered in Combination With Standard Induction Chemotherapy (Cytarabine and Idarubicin) in Newly Diagnosed High Risk Acute Myelogenous Leukemia (AML)

Clinical Trial IDs

  • ORG STUDY ID: 9L-17-6
  • SECONDARY ID: NCI-2017-01710
  • SECONDARY ID: 9L-17-6
  • SECONDARY ID: P30CA014089
  • NCT ID: NCT03330821

Conditions

  • Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
  • Acute Myeloid Leukemia With Myelodysplasia-Related Changes
  • Therapy-Related Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Cytarabine.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosar-U, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Treatment (idarubicin, cytarabine, pevonedistat)
Idarubicin4-Demethoxydaunomycin, 4-demethoxydaunorubicin, 4-DMDRTreatment (idarubicin, cytarabine, pevonedistat)
PevonedistatMLN4924, Nedd8-Activating Enzyme Inhibitor MLN4924Treatment (idarubicin, cytarabine, pevonedistat)

Purpose

This phase Ib/II trial studies the side effects and best dose of pevonedistat and to see how well it works in combination with cytarabine and idarubicin in treating patients with acute myeloid leukemia. Pevonedistat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine and idarubicin, 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. Given pevonedistat, cytarabine, and idarubicin may work better in treating patients with acute myeloid leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of
      pevonedistat in combination with cytarabine and idarubicin in newly diagnosed high-risk acute
      myeloid leukemia. (Phase Ib) II. To determine the composite complete response rate (complete
      remission [CR] or complete remission with incomplete blood count recovery [CRi]) of
      pevonedistat in combination with cytarabine and idarubicin in newly diagnosed high-risk acute
      myeloid leukemia. (Phase II)

      SECONDARY OBJECTIVES:

      I. To evaluate plasma pharmacokinetic (PK) profiles of pevonedistat when used in combination
      with cytarabine and idarubicin in the phase Ib part of the study.

      II. To evaluate the relapse free (RFS), overall survival (OS), safety and tolerability of
      pevonedistat in combination with cytarabine and idarubicin in the phase II part of the study.

      TERTIARY OBJECTIVES:

      I. To evaluate the pharmacodynamics (PD) effects of pevonedistat in combination with
      cytarabine and idarubicin in acute myelogenous leukemia (AML) blasts.

      II. To evaluate potential predictive biomarkers of response to pevonedistat in combination
      with cytarabine and idarubicin in AML.

      III. To determine the CR without minimal residual disease rate (CR MRD-) of pevonedistat in
      combination with cytarabine and idarubicin in newly diagnosed acute myeloid leukemia.

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

      INDUCTION: Patients receive idarubicin intravenously (IV) over 10-15 minutes on days 1-3,
      cytarabine IV over 1-3 hours on days 1-7, and pevonedistat IV over 60 minutes on days 1, 3,
      and 5. Patients with gross residual disease on day 14 bone marrow may receive a second course
      of induction chemotherapy.

      CONSOLIDATION: Patients who achieve CR and will not undergo bone marrow transplant receive
      cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats every 28-35
      days for 4 courses in the absence of disease progression or unaccepted toxicity.

      After completion of study treatment, patients are followed up for at least 30 days, and then
      every 3 months for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (idarubicin, cytarabine, pevonedistat)ExperimentalINDUCTION: Patients receive idarubicin IV over 10-15 minutes on days 1-3, cytarabine IV over 1-3 hours on days 1-7, and pevonedistat IV over 60 minutes on days 1, 3, and 5. Patients with gross residual disease on day 14 bone marrow may receive a second course of induction chemotherapy. CONSOLIDATION: Patients who achieve CR and will not undergo bone marrow transplant receive cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats every 28-35 days for 4 courses in the absence of disease progression or unaccepted toxicity.
  • Cytarabine
  • Idarubicin
  • Pevonedistat

Eligibility Criteria

        Inclusion Criteria:

          -  Voluntary written consent must be given before performance of any study related
             procedure not part of standard medical care, with the understanding that consent may
             be withdrawn by the patient at any time without prejudice to future medical care

          -  Female patients who:

               -  Are postmenopausal for at least 1 year before the screening visit, OR

               -  Are surgically sterile, OR

               -  If they are of childbearing potential, agree to practice 1 highly effective
                  method and 1 additional (barrier) of contraception, at the same time, from the
                  time of signing the informed consent through 4 months after the last dose of
                  study drug (female and male condoms should not be used together), or

               -  Agree to practice true abstinence, when this is in line with the preferred and
                  usual lifestyle of the subject; (periodic abstinence [eg, calendar, ovulation,
                  symptothermal, postovulation methods] withdrawal, spermicides only and
                  lactational amenorrhea are not acceptable methods of contraception)

          -  Male patients, even if surgically sterilized (ie, status postvasectomy), who:

               -  Agree to practice effective barrier contraception during the entire study
                  treatment period and through 4 months after the last dose of study drug (female
                  and male condoms should not be used together), or

               -  Agree to practice true abstinence, when this is in line with the preferred and
                  usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation,
                  symptothermal, postovulation methods for the female partner] withdrawal,
                  spermicides only and lactational amenorrhea are not acceptable methods of
                  contraception)

          -  Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance
             status 0-2

          -  Expected survival > 3 months from study enrollment

          -  Within 3 days before the first dose of study drug: albumin > 2.7 g/dL

          -  Within 3 days before the first dose of study drug: total bilirubin < upper limit of
             normal (ULN)

          -  Within 3 days before the first dose of study drug: alanine aminotransferase (ALT) and
             aspartate aminotransferase (AST) < 2.5 x ULN

          -  Within 3 days before the first dose of study drug: creatinine clearance > 50 mL/min

          -  Within 3 days before the first dose of study drug: hemoglobin > 8 g/dL (prior red
             blood cell [RBC] transfusion allowed); patients may be transfused to achieve this
             value; elevated indirect bilirubin due to post-transfusion hemolysis is allowed

          -  Patients with previously untreated AML (except acute promyelocytic leukemia [APL]) who
             have at least one of the following:

               -  Adverse genetic features as per the European Leukemia Net guidelines

               -  Treatment related AML or AML with antecedent myelodysplastic syndrome (MDS);
                  (patient who have received treatment with hypomethylating agents for MDS and have
                  now transformed to AML are eligible)

               -  Are over the age of 55 years and considered fit for chemotherapy

               -  Patients with AML with MDS-related changes

          -  Patients must be considered candidates for intensive chemotherapy treatment with
             standard doses of cytarabine and anthracycline regimen (?7+3 regimen?)

          -  White blood cell (WBC) count < 50,000/uL before administration of pevonedistat on
             cycle 1 day 1; Note: hydroxyurea may be used to control the level of circulating
             leukemic blast cell counts to not lower than 10,000/uL during the study

        Exclusion Criteria:

          -  Known cardiopulmonary disease defined as one of the following:

               -  Uncontrolled high blood pressure (ie, systolic blood pressure > 180 mm Hg,
                  diastolic blood pressure > 95 mm Hg)

               -  Cardiomyopathy or history of ischemic heart disease

               -  Arrhythmia (eg, history of polymorphic ventricular fibrillation or torsade de
                  pointes); however, patients with < grade 3 atrial fibrillation (a fib) for a
                  period of at least 6 months may enroll; grade 3 a fib is symptomatic and
                  incompletely controlled medically, or controlled with device (e.g., pacemaker),
                  or ablation; patients with paroxysmal a fib are permitted to enroll

               -  Implantable cardioverter defibrillator

               -  Congestive heart failure (New York Heart Association [NYHA] class III or IV; or
                  class II with a recent decompensation requiring hospitalization or referral to a
                  heart failure clinic within 4 weeks before screening), myocardial infarction
                  and/or revascularization (eg, coronary artery bypass graft, stent) within 6
                  months of first dose of study drug

               -  Patients who had ischemic heart disease who have had acute coronary syndrome
                  (ACS), myocardial infarction (MI), and/or revascularization greater than 6 months
                  before screening and who are without cardiac symptoms may enroll

               -  Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing)

               -  Pulmonary hypertension

          -  Prolonged rate corrected QT (QTc) interval >= 500 msec, calculated according to
             institutional guidelines

          -  Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or
             radionuclide angiography

          -  Known moderate to severe chronic obstructive pulmonary disease (COPD), interstitial
             lung disease, and pulmonary fibrosis

          -  Any serious medical or psychiatric illness that could, in the investigator?s opinion,
             potentially interfere with the completion of study procedures

          -  Treatment with any investigational products within 14 days before the first dose of
             any study drug

          -  Patients receiving any other investigational or commercial agents or therapies
             administered with the intention to treat their malignancy within 14 days of first
             receipt of study drug with the exception of: hydroxyurea (HU) in patients who need to
             continue this agent to maintain WBC count =< 50,000/mm^3

          -  Active uncontrolled infection or severe infectious disease, such as severe pneumonia,
             meningitis, septicemia, or methicillin resistant staphylococcus aureus infection

          -  Major surgery within 14 days before the first dose of any study drug or a scheduled
             surgery during study period

          -  Diagnosed or treated for another malignancy within 2 years before randomization or
             previously diagnosed with another malignancy and have any evidence of residual
             disease; patients with nonmelanoma skin cancer or carcinoma in situ of any type are
             not excluded if they have undergone resection

          -  Life-threatening illness unrelated to cancer

          -  Patients with uncontrolled coagulopathy or bleeding disorder

          -  Known central nervous system (CNS) involvement

          -  Known human immunodeficiency virus (HIV) seropositive

          -  Known hepatitis B surface antigen seropositive or known or suspected active hepatitis
             C infection

               -  Note: patients who have isolated positive hepatitis B core antibody (ie, in the
                  setting of negative hepatitis B surface antigen and negative hepatitis B surface
                  antibody) must have an undetectable hepatitis B viral load

          -  Known hepatic cirrhosis or severe pre-existing hepatic impairment

          -  Systemic antineoplastic therapy or radiotherapy within 14 days before the first dose
             of any study drug, except for hydroxyurea

          -  Treatment with clinically significant metabolic enzyme inducers within 14 days before
             the first dose of the study drug; clinically significant metabolic enzyme inducers are
             not permitted during this study

          -  Patients who refuse to potentially receive blood products and/or have a
             hypersensitivity to blood products

          -  Patients with history of allergic or toxic reactions attributed to cytarabine or a
             history of allergic reactions to components of the formulated product

          -  Patients with history of allergic or toxic reactions attributed to anthracyclines or a
             history of allergic reactions to components of the formulated product

          -  Patients who have had prior chemotherapy for AML

          -  Female patients who intend to donate eggs (ova) during the course of this study or 4
             months after receiving their last dose of study drug(s)

          -  Female patients who are both lactating and breastfeeding or have a positive serum
             pregnancy test during the screening period or a positive urine pregnancy test on day 1
             before first dose of study drug (if applicable)

          -  Male patients who intend to donate sperm during the course of this study or 4 months
             after receiving their last dose of study drug(s)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Composite complete response rate
Time Frame:Up to 2 years
Safety Issue:
Description:Response will be assessed according to the 2017 European Leukemia Net Guidelines. The composite complete response rate will be calculated as the percentage of patients who have CR or CRi. Wilson 95% confidence interval will be provided.

Secondary Outcome Measures

Measure:Relapse-free survival (RFS)
Time Frame:From the date of achievement of a remission until the date of relapse or death from any cause, assessed up to 2 years
Safety Issue:
Description:RFS will be calculated as the date of achievement of a remission (CR or CRi) until the date of relapse (documented morphological recurrence (≥ 5% blasts on in the bone marrow, reappearance of blasts in the blood or development of extramedullary disease after CR) or death - whichever comes first; patients who are alive and have not progressed or recurred at the time of their last disease assessment, will be censored at that time. Survival curves will be plotted by the Kaplan-Meier (KM) method. Median RFS and their 95% confidence intervals, 1-year and 2- year survival rates and corresponding standard errors will be derived from the KM curves.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Southern California

Last Updated

June 21, 2019