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A Study of Pevonedistat in Adult East Asian Participants

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ClinicalTrials.gov Identifier: NCT02782468
Recruitment Status : Active, not recruiting
First Posted : May 25, 2016
Last Update Posted : September 22, 2020
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Brief Summary:
The purpose of this study is to evaluate the safety and tolerability of pevonedistat administered as a single agent and in combination with azacitidine in adult east Asian participants with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS).

Condition or disease Intervention/treatment Phase
Leukemia, Myeloid, Acute Myelodysplastic Syndromes Drug: Pevonedistat 25 mg/m^2 Drug: Pevonedistat 44 mg/m^2 Drug: Pevonedistat 10 mg/m^2 Drug: Pevonedistat 20 mg/m^2 Drug: Azacitidine 75 mg/m^2 Phase 1

Detailed Description:

The drug being tested in this study is called Pevonedistat. Pevonedistat is being tested to treat people with myelodysplastic syndromes MDS (including nonproliferative chronic myelomonocytic leukemia [CMML]) and AML (acute myeloid leukaemia) as a single-agent and in combination treatment with azacitidine. This study will look at the safety and tolerability, the recommended phase 2/phase 3 dose of pevonedistat administered in combination with azacitidine, pharmacokinetics and response to treatment in participants who take single agent pevonedistat compared to participants who take pevonedistat and azacitidine.

The study will enroll approximately 37 participants. Participants will be assigned into one of the four treatment groups which will remain disclosed to the patient and study doctor during the study. Participants will be first enrolled at single-agent low dose level (25 mg/m^2). If this dose is tolerable, participants will be enrolled in parallel at single-agent higher dose level (44 mg/m^2) and in combination treatment cohorts.

  • Pevonedistat 25 mg/m^2
  • Pevonedistat 44 mg/m^2
  • Pevonedistat 10 mg/m^2 and azacitidine 75 mg/m^2 combination
  • Pevonedistat 20 mg/m^2 and azacitidine 75 mg/m^2 combination Participants will receive pevonedistat infusion intravenously and azacitidine via intravenous or subcutaneous route.

This multi-center trial will be conducted in Japan, Korea and Taiwan. The overall time to participate in this study is approximately 24 months. Participants will attend the End of Study (EOS) visit for safety, 30 days after receiving their last dose of study drug or before the start of subsequent antineoplastic therapy (other than hydroxyurea).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 1/1b, Open-label Study of Pevonedistat (MLN4924, TAK-924) as Single Agent and in Combination With Azacitidine in Adult East Asian Patients With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS)
Actual Study Start Date : May 30, 2016
Estimated Primary Completion Date : September 1, 2021
Estimated Study Completion Date : September 1, 2021


Arm Intervention/treatment
Experimental: Arm 1, Cohort 1: Pevonedistat 25 mg/m^2
Pevonedistat, 25 milligram per square meter (mg/m^2), 60-minute infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in 21-day treatment cycles.
Drug: Pevonedistat 25 mg/m^2
Pevonedistat 25 mg/m^2 intravenous infusion.

Experimental: Arm 1, Cohort 2: Pevonedistat 44 mg/m^2
Pevonedistat, 44 mg/m^2, 60-minute infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in 21-day treatment cycles.
Drug: Pevonedistat 44 mg/m^2
Pevonedistat 44 mg/m^2 intravenous infusion.

Experimental: Arm 2, Cohort 1: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2
Pevonedistat 10 mg/m^2, 60-minute infusion, intravenously, on Days 1, 3, and 5 and azacitidine 75 mg/m^2, on Days 1 to 5, and Days 8 and 9, intravenously or subcutaneously, followed by a rest period of 19 days, in 28-day treatment cycles.
Drug: Pevonedistat 10 mg/m^2
Pevonedistat 10 mg/m^2 intravenous infusion.

Drug: Azacitidine 75 mg/m^2
Azacitidine 75 mg/m^2 intravenous or subcutaneous formulation.

Experimental: Arm 2, Cohort 2: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2
Pevonedistat 20 mg/m^2, 60-minute infusion, intravenously, on Days 1, 3, and 5 and azacitidine 75 mg/m^2, on Days 1 to 5, and Days 8 and 9, intravenously or subcutaneously, followed by a rest period of 19 days, in 28-day treatment cycles.
Drug: Pevonedistat 20 mg/m^2
Pevonedistat 20 mg/m^2 intravenous infusion.

Drug: Azacitidine 75 mg/m^2
Azacitidine 75 mg/m^2 intravenous or subcutaneous formulation.




Primary Outcome Measures :
  1. • Number of Participants Reporting one or More Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Throughout study from Baseline up to 30 days after the last dose of study drug ]
  2. Number of Participants With Dose Limiting Toxicities (DLTs) During Cycle [ Time Frame: Cycle 1 Day 1 up to end of Cycle 1 (Day 21 for single-agent groups and Day 28 for combination groups) ]
    Toxicity will be evaluated according to NCI CTCAE, Version4.03. DLT will be defined as any of the events specified in the protocol that are considered by the investigator to be at least possibly related to therapy with study medications.

  3. Number of Participants With Markedly Abnormal Laboratory Values [ Time Frame: Baseline and up to 30 days after the last dose of study drug ]
  4. Cmax: Maximum Observed Plasma Concentration for Pevonedistat [ Time Frame: Day 1: Pre-infusion and at multiple time points (up to 48 hours) post-infusion ]
  5. AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time tau Over the Dosing Interval for Pevonedistat [ Time Frame: Day 1: Pre-infusion and at multiple time points (up to 48 hours) post-infusion ]
  6. CL: Clearance [ Time Frame: Days 1 and 5: Day 1: Pre-infusion and at multiple time points (up to 48 hours) post-infusion ]

Secondary Outcome Measures :
  1. Percentage of Participants With Overall Response [ Time Frame: Screening until CR or PR, assessed within 6 days before Day 21 for single-agent groups and Day 20 to 28 for combination groups of Cycle 2, 4 and every 3 cycles thereafter up to Day 35 for single-agent groups and Day 39 for combination groups ]
  2. Percentage of Participants With CR [ Time Frame: Screening until CR or PR, assessed within 6 days before Day 21 for single-agent groups and Day 20 to 28 for combination groups of Cycle 2, 4 and every 3 cycles thereafter up to Day 35 for single-agent groups and Day 39 for combination groups ]


Information from the National Library of Medicine

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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 include, in part:

  1. East Asian patients aged 18 years or older (or minimum age of legal consent consistent with local regulations) when written study informed consent is obtained must meet 1 of the following diagnosis criteria for either the Single-Agent Arm or the Combination Arm (additional restrictions apply to the Single Agent Arm):

    a. Are male and female participants with WHO-defined AML, including leukemia secondary to prior chemotherapy or resulting from an antecedent hematologic disorder, who have failed to achieve CR or who have relapsed after prior therapy (R/R) and are not candidates for potentially curative treatment, or ii. Are male and female participants aged 60 years or older with previously untreated AML who have bone marrow blasts <30% and who are not candidates for standard induction chemotherapy, or iii. Are male and female participants with WHO-defined MDS that meets the IPSS-R criteria for the very high, high, or intermediate risk group, for whom standard curative, life-prolonging treatment does not exist or is no longer effective (R/R), or iv. Are male and female participants with previously untreated MDS that meets the IPSS-R criteria for the very high, high, or intermediate risk group, or vi. Are male and female participants with WHO-defined CMML-2 or CMML-1 that meets the IPSS-R criteria for the very high, high, or intermediate risk group CMML-1 participants must have bone marrow blasts >=5%

  2. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
  3. Able to undergo bone marrow aspiration and biopsy at Screening.

Exclusion Criteria include, in part:

  1. Acute promyelocytic leukemia (as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics [t (15:17)] of peripheral blood or bone marrow, or by other accepted analysis) or AML associated with t (9;22) karyotypes or molecular.
  2. More than 3 prior lines of therapy (Combination Arm only).
  3. Prior therapy with hypomethylating agents (example, azacitidine, decitabine). (Combination Arm only).
  4. Is eligible for a hematopoietic stem cell transplant.
  5. Is a female participant who is 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.
  6. Had treatment with any investigational products within 14 days before the first dose of any study drug.
  7. Has known hypersensitivity to azacitidine or mannitol (Combination Arm only).
  8. Has known central nervous system involvement.
  9. Had systemic antineoplastic therapy or radiotherapy within 14 days before the first dose of any study drug, except for hydroxyurea.

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): NCT02782468


Locations
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Japan
Maebashi City, Japan
Nagoya, Japan
Sendai City, Japan
Tokyo, Japan
Korea, Republic of
Chonnam National University Hwasun Hospital
Jeonnam, Korea, Republic of, 519-763
Severance Hospital Yonsei University Health System - PPDS
Seoul, Korea, Republic of, 120-752
The Catholic University of Korea, Seoul St. Mary's Hospital
Seoul, Korea, Republic of, 137701
Taiwan
National Taiwan University Hospital
Taipei, Taiwan, 10048
Taipei Veterans General Hospital
Taipei, Taiwan, 112
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
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Study Director: Medical Director Takeda
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Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02782468    
Other Study ID Numbers: Pevonedistat-1012
U1111-1166-8630 ( Other Identifier: WHO )
First Posted: May 25, 2016    Key Record Dates
Last Update Posted: September 22, 2020
Last Verified: September 2020
Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Drug Therapy
Additional relevant MeSH terms:
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Leukemia
Preleukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Azacitidine
Pevonedistat
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors