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A Study of Pevonedistat in Combination With Azacitidine in Participants With Higher-risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myelogenous Leukemia (AML) With Severe Renal Impairment or Mild Hepatic Impairment

NCT03814005

Description:

The purpose of this study is to characterize the pharmacokinetic (PK) of pevonedistat in participants with severe renal impairment and mild hepatic impairment.

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of Pevonedistat in Combination With Azacitidine in Participants With Higher-risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myelogenous Leukemia (AML) With Severe Renal Impairment or Mild Hepatic Impairment
  • Official Title: A Phase 1/1b Study of Pevonedistat in Combination With Azacitidine in Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myelogenous Leukemia With Severe Renal Impairment or Mild Hepatic Impairment

Clinical Trial IDs

  • ORG STUDY ID: Pevonedistat-1016
  • SECONDARY ID: U1111-1220-1396
  • SECONDARY ID: 2018-004049-17
  • NCT ID: NCT03814005

Conditions

  • Myelodysplastic Syndromes
  • Leukemia, Myelomonocytic, Chronic
  • Leukemia, Myeloid, Acute
  • Renal Insufficiency
  • Hepatic Impairment

Interventions

DrugSynonymsArms
AzacitidinePart A: Control Arm (Normal Renal and Hepatic Function)
PevonedistatTAK-924 and MLN4924Part A: Control Arm (Normal Renal and Hepatic Function)

Purpose

The purpose of this study is to characterize the pharmacokinetic (PK) of pevonedistat in participants with severe renal impairment and mild hepatic impairment.

Detailed Description

      The drug being tested in this study is called pevonedistat. The study will characterize the
      PK of pevonedistat, assess the safety, and determine the dose of pevonedistat, in combination
      with azacitidine, in participants with myelodysplastic syndromes (MDS), CMML and AML who also
      have severe renal impairment or mild hepatic impairment.

      The study will enroll approximately 60 participants. The study will be conducted in 2 parts:
      Part A (PK run-in and dose escalation phase) and Part B. In Part A, participants will be
      assigned to one of the 3 treatment groups on the basis of their renal and hepatic function:

        -  Control Arm (Normal Renal and Hepatic Function)

        -  Renal Arm (Severe Renal Impairment)

        -  Hepatic Arm (Mild Hepatic Impairment)

      Part A will include pevonedistat PK run-in starting on Day -7, followed by a dose-escalation
      phase with the combination of pevonedistat and azacitidine starting on Day 1. Eligible
      participants from Part A will continue treatment in optional Part B with the same treatment
      received in Part A: pevonedistat in combination with azacitidine.

      This multi-center trial will be conducted in the United States and Spain. The overall time to
      participate in this study is approximately 2.5 years. Participants will attend end of the
      study visit 30 days after the last dose of study drug or before the start of subsequent
      therapy, if that occurs sooner for safety follow up.
    

Trial Arms

NameTypeDescriptionInterventions
Part A: Control Arm (Normal Renal and Hepatic Function)ExperimentalPevonedistat 20 milligram per square meter (mg/m^2), infusion, once, intravenously, over 1 hour on Day-7 in PK run-in, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 75 mg/m^2, injection, once, subcutaneously, on Day 1 up to Day 5, and on Days 8 and 9 in combination with pevonedistat 20 mg/m^2, infusion, once, intravenously, over 1 hour on Days 1, 3, and 5 in a 28-day treatment cycle.
  • Azacitidine
  • Pevonedistat
Part A: Renal Arm (Severe Renal Impairment)ExperimentalPevonedistat 20 mg/m^2, infusion, once, intravenously, over 1 hour on Day-7 in PK run-in, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 75 mg/m^2, injection, once, subcutaneously, on Day 1 up to Day 5, and on Days 8 and 9 in combination with pevonedistat 10 mg/m^2, infusion, once, intravenously, over 1 hour on Days 1, 3, and 5 in a 28-day treatment cycle. Dose escalation of pevonedistat will follow a standard 3+3 schema until a maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) is determined. Dose escalation will be based on the available PK and safety data from the single dose pevonedistat PK run-in phase and previous dose groups.
  • Azacitidine
  • Pevonedistat
Part A: Hepatic Arm (Mild Hepatic Impairment)ExperimentalPevonedistat 20 mg/m^2, infusion, once, intravenously, over 1 hour on Day-7 in PK run-in, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 5 mg/m^2, injection, once, subcutaneously, on Day 1 up to Day 5, and on Days 8 and 9 in combination with pevonedistat 10 mg/m^2, infusion, once, intravenously, over 1 hour on Days 1, 3, and 5 in a 28-day treatment cycle. Dose escalation of pevonedistat will follow a standard 3+3 schema until a MTD or RP2D is determined. Dose escalation will be based on the available PK and safety data from the single dose pevonedistat PK run-in phase and previous dose groups.
  • Azacitidine
  • Pevonedistat
Part BExperimentalAzacitidine, injection, once, subcutaneously, on Day 1 up to Day 5, and on Days 8 and 9 in combination with pevonedistat, infusion, once, intravenously, over 1 hour on Days 1, 3, and 5 in each 28-day treatment cycles for up to 12 cycles or symptomatic deterioration, disease progression, discontinuation of treatment for another reason, or until study is stopped. Based on the sponsor's discretion and available PK and safety data from Part A, intrapatient dose escalation may be allowed to start during Cycle 1 or as soon as Part A data is known at that dose level, for participants in the organ impairment arms. Up to a maximal dose of 20 mg/m^2 pevonedistat in combination with 75 mg/m^2 azacitidine, may be allowed during Part B.
  • Azacitidine
  • Pevonedistat

Eligibility Criteria

        Inclusion Criteria:

          1. Has morphologically confirmed diagnosis of MDS or nonproliferative CMML (that is, with
             white blood cell [WBC] <13,000 /mcL].

             French-American-British (FAB) Classifications:

               -  Refractory anemia with excess blasts (RAEB), defined as having 5% to 20%
                  myeloblasts in the bone marrow.

               -  CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in
                  the blood.

             OR world health organization (WHO) Classifications:

               -  RAEB-1, defined as having 5% to 9% myeloblasts in the bone marrow.

               -  RAEB-2, defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to
                  19% blasts in the blood.

               -  CMML-2, defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to
                  19% blasts in the blood.

               -  CMML-1 (although CMML-1 is defined as having <10% myeloblasts in the bone marrow
                  and/or <5% blasts in the blood, these patients may enroll only if bone marrow
                  blasts >=5%).

          2. Has MDS or CMML and must also have one of the following Prognostic Risk Categories,
             based on the Revised International Prognostic Scoring System (IPSS-R):

               -  Very high (>6 points).

               -  High (>4.5-6 points).

               -  Intermediate (>3-4.5 points): a participant determined to be in the Intermediate
                  Prognostic Risk Category is only allowable in the setting of >=5% bone marrow
                  myeloblasts.

          3. Has WHO-defined AML, including leukemia secondary to prior chemotherapy or resulting
             from an antecedent hematologic disorder, have failed to achieve CR or have relapsed
             after prior therapy and are not candidates for potentially curative treatment.

          4. Has relapsed or refractory MDS, have previously been treated with an hypomethylating
             agent.

          5. Eastern Cooperative Oncology Group (ECOG) status of 0, 1, or 2.

          6. Has recovered (that is, Grade <=1 toxicity) from the reversible effects of prior
             anticancer therapy.

          7. Laboratory value requirements per study arms are:

               -  Estimated glomerular filtration rate (eGFR) (milliliter per minute per 1.73
                  square meter [mL/min/1.73^m]) >=90 (Control arm), <30 (Renal arm) and >=60
                  (Hepatic arm).

               -  Total Bilirubin <= upper limit of normal (ULN) (Control arm), <= ULN (Renal arm)
                  and ULN <Bilirubin <=1.5 * ULN (not secondary to transfusions) (Hepatic arm).

               -  Alanine aminotransferase (ALT) <= ULN (Control arm), <=2.5 * ULN (Renal arm) and
                  Any (Hepatic arm).

        Exclusion Criteria:

          1. Has 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.

          2. Has known hepatitis B surface antigen seropositive, or known or suspected active
             hepatitis C infection. Note: Participants who have isolated positive hepatitis B core
             antibody (that is, in the setting of negative hepatitis B surface antigen and negative
             hepatitis B surface antibody) must have an undetectable hepatitis B viral load.

          3. Known hepatic cirrhosis or severe pre-existing hepatic impairment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part A: AUC∞: Area Under the Plasma Concentration-time Curve from Time Zero to Infinity for Pevonedistat Following a Single Dose
Time Frame:Day -7 pre-dose and at multiple time points (up to 72 hours) post-dose
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Part A: t1/2z: Terminal Disposition Phase Half-life for Pevonedistat Following Single and Multiple Dose
Time Frame:Day -7 pre-dose and at multiple time points (up to 72 hours) post-dose; Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose
Safety Issue:
Description:
Measure:Part A: Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following Multiple Dose
Time Frame:Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose
Safety Issue:
Description:
Measure:Part A: fu: Unbound Fraction of Drug in Plasma
Time Frame:Day -7 pre-dose and at multiple time points (up to 48 hours) post-dose
Safety Issue:
Description:
Measure:Part A: Cmax: Maximum Observed Plasma Concentration for Azacitidine Following Multiple Dose
Time Frame:Day 3 pre-dose and at multiple time points (up to 7 hours) post-dose
Safety Issue:
Description:
Measure:Part A: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Azacitidine Following Multiple Dose
Time Frame:Day 3 pre-dose and at multiple time points (up to 7 hours) post-dose
Safety Issue:
Description:
Measure:Part A: t1/2z: Terminal Disposition Phase Half-life for Azacitidine Following Multiple-dose
Time Frame:Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose
Safety Issue:
Description:
Measure:Part A: AUCτ: Area under the Concentration-time Curve from Time Zero to the end of the Dosing Interval for Pevonedistat and Azacitidine Following Multiple Dose
Time Frame:Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose
Safety Issue:
Description:
Measure:Part A: CL: Total Clearance for Pevonedistat
Time Frame:Day -7 pre-dose and at multiple time points (up to 72 hours) post-dose; Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose
Safety Issue:
Description:
Measure:Part A: CL/F: Apparent Clearance for Azacitidine
Time Frame:Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose
Safety Issue:
Description:
Measure:Part A: CLR: Renal Clearance for Pevonedistat
Time Frame:Days -7 and 3 pre-dose and at multiple time points (up to 8 hours) post-dose
Safety Issue:
Description:
Measure:Part A: CLR: Renal Clearance for Azacitidine
Time Frame:Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose
Safety Issue:
Description:
Measure:Part A: Vss: Volume of Distribution at Steady-state of Pevonedistat
Time Frame:Day -7 pre-dose and at multiple time points (up to 72 hours) post-dose; Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose
Safety Issue:
Description:
Measure:Part A: Vss: Apparent Volume of Distribution of Azacitidine
Time Frame:Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose
Safety Issue:
Description:
Measure:Part A: Number of Participants Who Experienced Any Dose Limiting Toxicity (DLT)
Time Frame:Baseline up to 28 days
Safety Issue:
Description:Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE 5.0). DLT will be defined as any of the events that are considered by the investigator to be at least possibly related to therapy with the study medication.
Measure:Part B: Percentage of AML Participants with Complete Response (CR) or Partial Response
Time Frame:Cycle 2 Day 22, Cycles 5, 8, and 11 (between Days 15 and 28), and every 6 cycles or as per the discretion of the investigator (up to 2.5 years) (each cycle=28 days)
Safety Issue:
Description:Disease response in AML are based on international working group (IWG) for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in AML. For AML participants, all CR includes both CR and complete remission with incomplete blood count recovery (Cri). CR: morphologic leukemia-free state with absolute neutrophil count (ANC) of greater than (>) 1000 per microliter (/mcL) and platelets of greater than or equal to (>=) 100,000/mcL, and no residual evidence of extramedullary leukemia. Cri: After chemotherapy, some participants fulfill all criteria for CR except for residual neutropenia (less than [<] 1000/mcL) or thrombocytopenia (<100,000/mcL). PR: requires all hematologic values for a CR but with a decrease of at least 50 percent (%) in the percentage of blasts to 5% to 25% in the bone marrow aspirate. A value of less than or equal to (<=) 5% blasts may also be considered a PR if Auer rods are present.
Measure:Part B: Percentage of MDS/CMML Participants with CR, PR or Hematologic Improvement (HI)
Time Frame:Cycle 2 Day 22, Cycles 5, 8, and 11 (between Days 15 and 28), and every 6 cycles or as per the discretion of the investigator (up to 2.5 years) (each cycle=28 days)
Safety Issue:
Description:Disease response in MDS/CMML will be based on best overall response (CR+PR+HI) as determined by investigator using revised IWG response criteria for MDS/CMML.
Measure:Percentage of AML Participants with Overall Response
Time Frame:Cycle 2 Day 22, Cycles 5, 8, and 11 (between Days 15 and 28), and every 6 cycles or as per the discretion of the investigator (up to 2.5 years) (each cycle=28 days)
Safety Issue:
Description:Overall response is CR, PR, or HI and will be determined by using the revised IWG response criteria.
Measure:Part B: Duration of CR or PR
Time Frame:From first documentation of response up to disease progression ( up to 2.5 years)
Safety Issue:
Description:Duration of response in participants with disease response (CR or PR) is time between first documentation of response and disease progression. Duration of response will be determined by the investigator using the revised IWG response criteria.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Millennium Pharmaceuticals, Inc.

Trial Keywords

  • Drug therapy

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