Clinical Trials /

Pevonedistat and Decitabine in Treating Patients With High Risk Acute Myeloid Leukemia

NCT03009240

Description:

This phase I trial studies the side effects and best dose of pevonedistat when given together with decitabine in treating patients with high risk acute myeloid leukemia. Pevonedistat and decitabine may stop the growth of cancer cells by blocking some of the enzymes need for cell growth.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pevonedistat and Decitabine in Treating Patients With High Risk Acute Myeloid Leukemia
  • Official Title: A Phase I Study of Pevonedistat (TAK-924) and Decitabine Combination Therapy in High Risk Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 16270
  • SECONDARY ID: NCI-2016-02044
  • SECONDARY ID: 16270
  • NCT ID: NCT03009240

Conditions

  • Recurrent Adult Acute Myeloid Leukemia
  • Recurrent Childhood Acute Myeloid Leukemia
  • Secondary Acute Myeloid Leukemia
  • Therapy-Related Acute Myeloid Leukemia
  • Untreated Adult Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Decitabine5-Aza-2'-deoxycytidine, Dacogen, Decitabine for Injection, Deoxyazacytidine, DezocitidineTreatment (pevonedistat, decitabine)
PevonedistatMLN4924, Nedd8-Activating Enzyme Inhibitor MLN4924Treatment (pevonedistat, decitabine)

Purpose

This phase I trial studies the side effects and best dose of pevonedistat when given together with decitabine in treating patients with high risk acute myeloid leukemia. Pevonedistat and decitabine may stop the growth of cancer cells by blocking some of the enzymes need for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine if the addition of pevonedistat to standard dose decitabine is safe and
      tolerable by the evaluation of toxicities including: type, frequency, severity, attribution,
      time course, reversibility and duration.

      II. Determine the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) of
      pevonedistat when given in combination with standard dose decitabine.

      SECONDARY OBJECTIVES:

      I. Obtain preliminary estimates of complete remission (CR) rate, overall response rate (ORR:
      CR+CRi [incomplete CR]), duration of response, and survival probabilities: overall survival
      (OS) and event-free survival (EFS) at 1-year and 2-years.

      II. Demonstrate down-modulation of micro ribonucleic acid (miR)-155 and increased expression
      of miR-155 targets (SHIP1 and PU.1) in vivo.

      III. Examine the impact of the combination on leukemia stem cells (LSCs); enriched blast cell
      subpopulations.

      IV. Evaluate possible associations between changes in levels of miR-155, miR-155 gene targets
      (PU.1, SHIP1) and toxicity and/or clinical response.

      OUTLINE: This is a dose-escalation study of pevonedistat.

      Patients receive pevonedistat intravenously (IV) over 1 hour on days 1, 3, and 5 and
      decitabine IV over 1 hour on days 1-5 and 8-12. Treatment repeats every 28 days for up to 24
      courses in the absence of disease progression or unexpected toxicity.

      After completion of study treatment, patients are follow up for 30 days, monthly for 1 year,
      and bi-monthly for another year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pevonedistat, decitabine)ExperimentalPatients receive pevonedistat IV over 1 hour on days 1, 3, and 5 and decitabine IV over 1 hour on days 1-5 and 8-12. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unexpected toxicity.
  • Decitabine
  • Pevonedistat

Eligibility Criteria

        Inclusion Criteria:

          -  Patients diagnosed with acute myeloid leukemia (AML) by World Health Organization
             (WHO) classification, meeting one of following criteria:

               -  Age 60 or older, newly diagnosed, untreated, who are unwilling to undergo or not
                  candidates for conventional induction chemotherapy with cytarabine/anthracyclines

               -  Age 60 or older with relapsed or refractory disease

               -  Younger adult patients with previously untreated high-risk disease (complex
                  karyotype, inv[3] or t[3;3], t[6;9], monosomal karyotype, therapy-related and
                  secondary disease) that are unwilling to undergo or not candidates for
                  conventional induction chemotherapy with cytarabine/anthracyclines and/or
                  allogeneic stem cell transplantation

               -  Younger patients with refractory/relapsed AML who are otherwise not candidates
                  for allogeneic stem cell transplantation

               -  Patients with extramedullary disease who meet one of the above criteria may be
                  included

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Patients with co-morbid medical illness, life expectancy attributed to this must be
             greater than 6 months

          -  Women of child-bearing potential and men must agree to use effective contraception
             (hormonal or barrier method of birth control or abstinence) prior to study entry and
             for 4 months following duration of study participation; should a woman become pregnant
             or suspect that she is pregnant while participating on the trial, she should inform
             her treating physician immediately

          -  Female patients must be:

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

               -  Surgically sterile, OR

               -  If they are of childbearing potential

                  ** Agree to practice 1 highly effective method and one additional effective
                  (barrier) method 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 [e.g., calendar, ovulation,
                  symptothermal, postovulation methods] withdrawal, spermicides only, and
                  lactational amenorrhea are not acceptable methods of contraception)

          -  Male patients, even if surgically sterilized (i.e., status post-vasectomy) must:

               -  Agree to practice effective barrier contraception during the entire study
                  treatment period and through 6 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 [e.g., calendar, ovulation,
                  symptothermal, postovulation methods for the female partner] withdrawal,
                  spermicides only, and lactational amenorrhea are not acceptable methods of
                  contraception)

          -  Creatinine < 1.5 X institutional upper limit of normal

          -  OR creatinine clearance >= 60 mL/min for patients with creatinine levels above 1.5 X
             institutional upper limit of normal

          -  Cardiac ejection fraction >= 50%

          -  Albumin > 2.7 g/dL

          -  Total bilirubin =< institutional upper limit of normal (ULN) (except in patients with
             Gilbert's syndrome; patients with Gilbert's syndrome may enroll if direct bilirubin is
             =< 1.5 x ULN

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 ULN unless
             higher levels are related to leukemic infiltration

          -  Hemoglobin > 8 g/dL; patients may be transfused to receive this value; elevated
             indirect bilirubin due to post-transfusion hemolysis is allowed

          -  All subjects must have the ability to understand and the willingness to sign a written
             informed consent

          -  The following patients are allowed:

               -  Patients may have been treated for AML or antecedent hematologic disorder with
                  myeloid growth factors, recombinant erythropoietin, thalidomide, lenalidomide,
                  5-azacitidine or decitabine

               -  Any prior chemo therapy must have been completed >= 2 weeks prior to day 1 of
                  study treatment and the participant must have recovered to eligibility levels
                  from prior toxicity

               -  There is no limit for prior chemo regimens

               -  Patients may have received hematopoietic stem cell transplantation for AML or
                  other diseases

               -  Hydroxyurea is allowed prior to day 1 of study treatment for count control and
                  during cycle 1; the use of hydroxyurea is not allowed beyond completion of cycle
                  1

        Exclusion Criteria:

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to pevonedistat or decitabine

          -  Patients have received prior chemotherapy or radiation for AML < two weeks before
             study enrollment, or those who have not recovered from the adverse events due to
             agents administered

          -  Females who are both lactating and breastfeeding or who 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

          -  Patients with additional (other than AML) active malignancies, other than curatively
             treated carcinoma in situ (CIS) of the cervix, or basal or squamous cell carcinoma of
             the skin; patients are not considered to have a "currently active" malignancy if they
             have completed therapy for a prior malignancy and disease free from prior malignancies
             for > 2 years

          -  Life-threatening illness unrelated to cancer

          -  Known cardiopulmonary disease defined as one of the following:

               -  Unstable angina

               -  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); permanent atrial fibrillation (a fib) defined as continuous a fib >= 6
                  months; persistent a fib defined as sustained a fib lasting > 7 days and/or
                  requiring cardioversion in the 4 weeks before screening; 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 ACS, 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

          -  Patients with uncontrolled coagulopathy or bleeding disorder

          -  Prolonged rate corrected QT (QTc) interval of >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

          -  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

          -  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; patients who have
             positive hepatitic C antibody may be included if they have an undetectable hepatitis C
             viral load

          -  Known hepatic cirrhosis or severe pre-existing hepatic impairment

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

          -  White blood cell (WBC) > 50,000/mcL

          -  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 (CYP3A4/5 inducers)

          -  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)

          -  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)

          -  Subjects, who in the opinion of the investigator, may not be able to comply with the
             safety monitoring requirements of the study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:DLT defined as any toxicities that are at least possibly related to pevonedistat that occur during cycle 1 assessed by NCI CTCAE version 4.03
Time Frame:Up to 28 days
Safety Issue:
Description:Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.

Secondary Outcome Measures

Measure:CR rate assessed by International Working Group criteria
Time Frame:Up to 2 years
Safety Issue:
Description:Will be calculated as the percent of evaluable patients that have confirmed CR.
Measure:Duration of response
Time Frame:Time interval from the date of first documented response (CR or CRi) to documented disease relapse or death whichever occurs first, assessed up to 2 years
Safety Issue:
Description:
Measure:EFS
Time Frame:Time from start of study therapy until death, relapse/progression, receipt of anti-leukemia therapy, or last contact, whichever comes first, assessed up to 2 years
Safety Issue:
Description:
Measure:ORR (CR + incomplete CR [CRi]) assessed by International Working Group criteria
Time Frame:Up to 2 years
Safety Issue:
Description:Will be calculated as the percent of evaluable patients that have confirmed CR or CRi.
Measure:OS
Time Frame:Time from start of study therapy until death, or last contact, whichever comes first, assessed up to 2 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

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