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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

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ClinicalTrials.gov Identifier: NCT03814005
Recruitment Status : Recruiting
First Posted : January 23, 2019
Last Update Posted : December 6, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

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

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes Leukemia, Myelomonocytic, Chronic Leukemia, Myeloid, Acute Renal Insufficiency Hepatic Impairment Drug: Azacitidine Drug: Pevonedistat Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Other
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
Actual Study Start Date : July 10, 2019
Estimated Primary Completion Date : October 5, 2020
Estimated Study Completion Date : April 6, 2021


Arm Intervention/treatment
Experimental: Part A: Control Arm (Normal Renal and Hepatic Function)
Pevonedistat 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.
Drug: Azacitidine
Azacitidine subcutaneous injection.

Drug: Pevonedistat
Pevonedistat intravenous infusion.
Other Name: TAK-924 and MLN4924

Experimental: Part A: Renal Arm (Severe Renal Impairment)
Pevonedistat 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.
Drug: Azacitidine
Azacitidine subcutaneous injection.

Drug: Pevonedistat
Pevonedistat intravenous infusion.
Other Name: TAK-924 and MLN4924

Experimental: Part A: Hepatic Arm (Mild Hepatic Impairment)
Pevonedistat 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.
Drug: Azacitidine
Azacitidine subcutaneous injection.

Drug: Pevonedistat
Pevonedistat intravenous infusion.
Other Name: TAK-924 and MLN4924

Experimental: Part B
Azacitidine, 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.
Drug: Azacitidine
Azacitidine subcutaneous injection.

Drug: Pevonedistat
Pevonedistat intravenous infusion.
Other Name: TAK-924 and MLN4924




Primary Outcome Measures :
  1. 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 ]
  2. Part A: AUClast: Area Under the Plasma Concentration-time Curve from Time Zero to the Time of the Last Quantifiable Concentration for Pevonedistat Following a Single Dose [ Time Frame: Day -7 pre-dose and at multiple time points (up to 72 hours) post-dose ]
  3. Part A: Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following a Single Dose [ Time Frame: Day -7 pre-dose and at multiple time points (up to 72 hours) post-dose ]

Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. 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 ]
  4. 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 ]
  5. 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 ]
  6. 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 ]
  7. 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 ]
  8. 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 ]
  9. 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 ]
  10. 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 ]
  11. Part A: CLR: Renal Clearance for Azacitidine [ Time Frame: Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose ]
  12. 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 ]
  13. 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 ]
  14. Part A: Number of Participants Who Experienced Any Dose Limiting Toxicity (DLT) [ Time Frame: Baseline up to 28 days ]
    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.

  15. 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) ]
    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.

  16. 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) ]
    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.

  17. 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) ]
    Overall response is CR, PR, or HI and will be determined by using the revised IWG response criteria.

  18. Part B: Duration of CR or PR [ Time Frame: From first documentation of response up to disease progression ( up to 2.5 years) ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03814005


Contacts
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Contact: Takeda Study Registration Call Center +1-877-825-3327 medicalinformation@tpna.com

Locations
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United States, California
Compassionate Cancer Care Medical Group Inc Recruiting
Fountain Valley, California, United States, 92708
United States, Connecticut
Smilow Cancer Center at Yale New Haven Hospital Recruiting
New Haven, Connecticut, United States, 06510
United States, New York
Icahn School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029
United States, North Carolina
University of North Carolina at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27514
Spain
Hospital Universitario Germans Trias i Pujol Recruiting
Badalona, Barcelona, Spain, 8916
ICO lHospitalet Hospital Duran i Reynals Recruiting
LHospitalet de Llobregat, Barcelona, Spain, 8908
Hospital Universitario Vall d'Hebron - PPDS Recruiting
Barcelona, Spain, 8035
Hospital de San Pedro de Alcantara Recruiting
Caceres, Spain, 10003
C.H. Regional Reina Sofia Recruiting
Cordoba, Spain, 14004
Complejo Asistencial Universitario de Salamanca H. Clinico Recruiting
Salamanca, Spain, 37007
Hospital Universitario Virgen del Rocio - PPDS Recruiting
Sevilla, Spain, 41013
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
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Study Director: Medical Director Millennium Pharmaceuticals, Inc.

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Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03814005    
Other Study ID Numbers: Pevonedistat-1016
U1111-1220-1396 ( Other Identifier: WHO )
2018-004049-17 ( EudraCT Number )
First Posted: January 23, 2019    Key Record Dates
Last Update Posted: December 6, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Drug therapy
Additional relevant MeSH terms:
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Leukemia
Preleukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Liver Diseases
Renal Insufficiency
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Kidney Diseases
Urologic Diseases
Digestive System Diseases
Myelodysplastic-Myeloproliferative Diseases
Azacitidine
Pevonedistat
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors