Clinical Trials /

Azacitidine, Venetoclax, and Pevonedistat in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

NCT03862157

Description:

This phase I/II trial studies the best dose of venetoclax when given together with azacitidine and pevonedistat and to see how well it works in treating patients with newly diagnosed acute myeloid leukemia. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax and pevonedistat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving azacitidine, venetoclax, and pevonedistat may work better in treating patients with acute myeloid leukemia.

Related Conditions:
  • Acute Myeloid Leukemia
  • Secondary Acute Myeloid Leukemia
  • Therapy-Related Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Azacitidine, Venetoclax, and Pevonedistat in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
  • Official Title: A Phase I/II Study of Azacitidine, Venetoclax and Pevonedistat in Adults With Newly Diagnosed Secondary or Therapy-Related AML

Clinical Trial IDs

  • ORG STUDY ID: 2018-0724
  • SECONDARY ID: NCI-2018-03465
  • SECONDARY ID: 2018-0724
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03862157

Conditions

  • Acute Myeloid Leukemia
  • Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative
  • Chronic Eosinophilic Leukemia, Not Otherwise Specified
  • Chronic Myelomonocytic Leukemia
  • Chronic Neutrophilic Leukemia
  • Dysplasia
  • Essential Thrombocythemia
  • FGFR1 Gene Rearrangement
  • Myelodysplastic Syndrome
  • Myelodysplastic/Myeloproliferative Neoplasm With Ring Sideroblasts and Thrombocytosis
  • Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
  • Myeloid Neoplasm
  • Myeloproliferative Neoplasm
  • Myeloproliferative Neoplasm, Unclassifiable
  • Overt Primary Myelofibrosis
  • PDGFRA Gene Rearrangement
  • PDGFRB Gene Rearrangement
  • Polycythemia Vera
  • Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase
  • Prefibrotic/Early Primary Myelofibrosis

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaTreatment (venetoclax, azacitidine, pevonedistat)
PevonedistatMLN4924, Nedd8-Activating Enzyme Inhibitor MLN4924Treatment (venetoclax, azacitidine, pevonedistat)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, VenclextaTreatment (venetoclax, azacitidine, pevonedistat)

Purpose

This phase I/II trial studies the best dose of venetoclax when given together with azacitidine and pevonedistat and to see how well it works in treating patients with newly diagnosed acute myeloid leukemia. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. venetoclax and pevonedistat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving azacitidine, venetoclax, and pevonedistat may work better in treating patients with acute myeloid leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum-tolerated dose (MTD) of venetoclax in combination with
      azacitidine and pevonedistat in patients with previously untreated secondary acute myeloid
      leukemia (AML). (Phase I) II. To determine the efficacy of the combination regimen, as
      defined by the rate of complete response (CR) plus complete response with incomplete bone
      marrow recovery (CRi) within 6 cycles of treatment. (Phase II)

      SECONDARY OBJECTIVES:

      I. To determine efficacy outcomes, including leukemia response rate (CR + CRi + partial
      response [PR] + morphologic leukemia free state [MLFS]), minimal residual disease (MRD)
      negativity by flow cytometry, duration of response, relapse-free survival (RFS), event-free
      survival (EFS) and overall survival (OS).

      II. To determine the safety of the combination regimen.

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

      Patients receive venetoclax orally (PO) once daily (QD) on days 1-28, azacitidine
      intravenously (IV) or subcutaneously (SC) on days 1-7, and pevonedistat IV over 60 minutes on
      days 1, 3, and 5. Treatment repeats every 28 days for up to 24 cycles in the absence of
      disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 30 days and then every 6
      months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (venetoclax, azacitidine, pevonedistat)ExperimentalPatients receive venetoclax by mouth every day on days 1-28, azacitidine (IV)Intravenous or (SC) subcutaneous on days 1-7, and pevonedistat (IV) Intravenous over 60 minutes on days 1, 3, and 5. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
  • Azacitidine
  • Pevonedistat
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Deemed by the treating physician not to be eligible for intensive chemotherapy

          -  Patients must have a new diagnosis (i.e., no prior therapy for AML) of AML per World
             Health Organization (WHO) 2016 criteria and any one of the following: a) A history of
             myelodysplastic syndrome (MDS); b) A history of a myeloproliferative neoplasm (MPN)
             including polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF,
             whether primary [pre-fibrotic or overt] or post-polycythemia vera [PV]/essential [E]),
             chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia (CEL),
             MPN-unclassifiable (MPN-U) or myeloid neoplasm with a rearrangement of PDGFRA, PDGFRB
             or FGFR1; c) A history of MDS/MPN such as chronic myelomonocytic leukemia (CMML),
             MDS/MPN-unclassifiable (MDS/MPN-U), MDS/MPN with ringed sideroblasts and
             thrombocytosis (MDS/MPN-RS-T) or atypical chronic myeloid leukemia (aCML), BCR-ABL
             negative; d) An MDS-related cytogenetic abnormality other than del9q; e) The presence
             of dysplasia in >= 50% cells in >= 2 myeloid lineages, unless accompanied by mutant
             NPM1 or biallelic CEBPA mutations; f) Exposure to prior chemotherapy or radiation
             therapy for another malignancy

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

          -  Total bilirubin =< upper limit of normal (ULN) except in patients with Gilbert's
             syndrome or if elevation is attributed to underlying leukemia. Patients with Gilbert's
             syndrome or with elevated bilirubin attributed to underlying leukemia may enroll if
             direct bilirubin =< 1.5 x ULN of the direct bilirubin (repeat if more than 3 days
             before the first dose)

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
             (repeat if more than 3 days before the first dose)

          -  Creatinine clearance >= 40 mL/min (repeat if more than 3 days before the first dose)

          -  White blood cell (WBC) count < 50,000/MuL before administration of pevonedistat on
             cycle 1 day 1. Note: Hydroxyurea may be used to control leukocytosis for the first 28
             days of study treatment (i.e., cycle 1). Use of hydroxyurea beyond this point may be
             permitted as clinically indicated, on a case-by-case basis and after discussion with
             the principal investigator (PI). (repeat if more than 3 days before the first dose)

          -  Albumin > 2.7 g/dL (repeat if more than 3 days before the first dose)

          -  Hemoglobin > 8 g/dL. Patients may be transfused to achieve this value. Elevated
             indirect bilirubin due to post-transfusion hemolysis is allowed (repeat if more than 3
             days before the first dose)

          -  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: a) Agree
             to practice 1 highly effective method and 1 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 b) 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 postvasectomy), who: a)
             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 b) 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.)

          -  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

        Exclusion Criteria:

          -  Treatment with any investigational products within 2 weeks before the first dose of
             any study drug (cycle 1 day 1 [C1D1])

          -  Patients whose only site of disease is extramedullary

          -  Acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow,
             by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone
             marrow, or by other accepted analysis

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

          -  Active uncontrolled infection or severe infectious disease, such as severe pneumonia,
             meningitis, or septicemia

          -  Major surgery within 14 days before the first dose of any study drug

          -  Diagnosed or treated for another malignancy within 2 years 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, leading to expected life expectancy
             (unrelated to leukemia) < 1 year

          -  Patients with uncontrolled coagulopathy or bleeding disorder not related to leukemia

          -  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
             (i.e., 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 hepatitis C antibody may be included if they have an undetectable hepatitis C
             viral load

          -  Known hepatic cirrhosis or severe pre-existing hepatic impairment

          -  Known cardiopulmonary disease defined as: a) Unstable angina; b) Congestive heart
             failure (New York Heart Association [NYHA] class III or IV); c) Myocardial infarction
             (MI) within 6 months prior to first dose (patients who had ischemic heart disease such
             as an acute coronary syndrome [ACS], MI, and/or revascularization greater than 6
             months before screening and who are without cardiac symptoms may enroll); d)
             Symptomatic cardiomyopathy; e) Clinically significant arrhythmia: f) History of
             polymorphic ventricular fibrillation or torsade de pointes; g) Persistent atrial
             fibrillation (a fib) requiring cardioversion in the 4 weeks before screening; h) Grade
             3 a fib defined as symptomatic and incompletely controlled medically, or controlled
             with device (e.g. pacemaker), or ablation and i) Implantable cardioverter
             defibrillator; j) Moderate to severe aortic and/or mitral stenosis or other
             valvulopathy (ongoing); k) Symptomatic pulmonary hypertension

          -  Uncontrolled high blood pressure (i.e., systolic blood pressure > 180 mm Hg, diastolic
             blood pressure > 100 mm Hg)

          -  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, interstitial lung
             disease, and pulmonary fibrosis

          -  Known central nervous system (CNS) involvement

          -  Treatment with strong CYP3A4 inducers within 14 days before the first dose of the
             study drug. Strong CYP3A4 inducers are not permitted during this study

          -  Systemic antineoplastic therapy or radiotherapy for other malignant conditions within
             14 days (or 3 half-lives, whichever is shorter) before the first dose of any study
             drug, except for hydroxyurea or up to 2 total grams of intravenous cytarabine for
             cytoreduction. Prior hypomethylating agent (HMA) therapy is allowed, unless given for
             AML

          -  Female patients who are either lactating and/or 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

          -  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)

          -  Known hypersensitivity to azacitidine, mannitol or pevonedistat, any of their
             components, or compounds of similar chemical composition
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of dose-limiting toxicities (DLTs) (Phase I)
Time Frame:Cycle 1( each cycle is 28 days)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Leukemia response rate (CR + CRi + partial response [PR] + morphologic leukemia-free state [MLFS])
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Minimal residual disease negativity rate
Time Frame:Up to 5 years
Safety Issue:
Description:Measured by flow cytometry.
Measure:Duration of response
Time Frame:Time from response to relapse, assessed up to 5 years
Safety Issue:
Description:
Measure:Relapse-free survival (RFS)
Time Frame:Time from response to relapse, death, or last follow-up, assessed up to 5 years
Safety Issue:
Description:
Measure:Event-free survival (EFS)
Time Frame:Time from initiation of treatment to relapse, death or last follow-up, assessed up to 5 years
Safety Issue:
Description:
Measure:Overall survival (OS)
Time Frame:Time from initiation of treatment to death or last follow-up, assessed up to 5 years
Safety Issue:
Description:
Measure:Incidence of adverse events
Time Frame:Up to 30 days after last dose of study drugs
Safety Issue:
Description:Will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.03.

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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