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Leukemia, Myeloid, AcutePhase 1NCT02782468

A Study of Pevonedistat in Adult East Asian Participants

A Phase 1 study testing Pevonedistat 25 mg/m^2, Pevonedistat 44 mg/m^2 and Pevonedistat 10 mg/m^2 in people with Leukemia, Myeloid, Acute and Myelodysplastic Syndromes, run by Millennium Pharmaceuticals, Inc. at 9 sites in 3 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Pevonedistat 25 mg/m^2, Pevonedistat 44 mg/m^2 and Pevonedistat 10 mg/m^2
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
23 participants
Where
9 sitesin 3 countries
Study dates
16 May 2016to 25 Jan 2022
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

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

Who cannot join

  • 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.
  • More than 3 prior lines of therapy (Combination Arm only).
  • Prior therapy with hypomethylating agents (example, azacitidine, decitabine). (Combination Arm only).
  • Is eligible for a hematopoietic stem cell transplant.
  • 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.
  • Had treatment with any investigational products within 14 days before the first dose of any study drug.
Show all 9Show fewer
  • Has known hypersensitivity to azacitidine or mannitol (Combination Arm only).
  • Has known central nervous system involvement.
  • Had systemic antineoplastic therapy or radiotherapy within 14 days before the first dose of any study drug, except for hydroxyurea.

Trial locations and contacts

9 sites in 3 countries.

9 sites in 3 countries

Japan4 sites

  • Study site

    Maebashi

  • Study site

    Nagoya

  • Study site

    Sendai

  • Study site

    Tokyo

Other trials in Japan

South Korea3 sites

  • Chonnam National University Hwasun Hospital

    Jeonnam, 519-763

  • Severance Hospital Yonsei University Health System - PPDS

    Seoul, 120-752

  • The Catholic University of Korea, Seoul St. Mary's Hospital

    Seoul, 137701

Other trials in South Korea

Taiwan2 sites

  • National Taiwan University Hospital

    Taipei, 10048

  • Taipei Veterans General Hospital

    Taipei, 112

Other trials in Taiwan

About this study

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)

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).

Read the 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).

Being tested
Pevonedistat 25 mg/m^2, Pevonedistat 44 mg/m^2, Pevonedistat 10 mg/m^2, Pevonedistat 20 mg/m^2, Azacitidine 75 mg/m^2
Keywords
Drug Therapy
Medical subject headings
Leukemia, Myeloid, Acute, Myelodysplastic Syndromes

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Pevonedistat 25 mg/m^2Drug

    Pevonedistat 25 mg/m^2 intravenous infusion.

  • Pevonedistat 44 mg/m^2Drug

    Pevonedistat 44 mg/m^2 intravenous infusion.

  • Pevonedistat 10 mg/m^2Drug

    Pevonedistat 10 mg/m^2 intravenous infusion.

  • Pevonedistat 20 mg/m^2Drug

    Pevonedistat 20 mg/m^2 intravenous infusion.

  • Azacitidine 75 mg/m^2Drug

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

Study groups in NCT02782468
Study groupRoleWhat they receive
Arm 1, Cohort 1: Pevonedistat 25 mg/m^2ExperimentalPevonedistat, 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.
Receives: Drug: Pevonedistat 25 mg/m^2
Arm 1, Cohort 2: Pevonedistat 44 mg/m^2ExperimentalPevonedistat, 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.
Receives: Drug: Pevonedistat 44 mg/m^2
Arm 2, Cohort 1: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2ExperimentalPevonedistat 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.
Receives: Drug: Pevonedistat 10 mg/m^2; Drug: Azacitidine 75 mg/m^2
Arm 2, Cohort 2: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2ExperimentalPevonedistat 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.
Receives: Drug: Pevonedistat 20 mg/m^2; Drug: Azacitidine 75 mg/m^2

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

    Measured: From first dose through 30 days after the last dose of study drug: single agent arms (up to Cycle 19 [up to Day 429]) (Cycle=21 days); combination arms (up to Cycle 65 [up to Day 1850]) (Cycle=28 days)

  2. Number of Participants With Dose Limiting Toxicities (DLTs) Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 During Cycle 1

    DLT: Any of following events considered possibly related to study drug(s) by investigator: Grade (G) 3 or greater nausea and/or emesis despite use of optimal antiemetic prophylaxis; G3 diarrhea occurred despite maximal supportive therapy; G3 arthralgia/myalgia despite use of optimal analgesia; G3 nonhematologic toxicity with exceptions: 1) Brief fatigue, 2) hypophosphatemia; Persistent elevations of transaminases/bilirubin above G2 beyond 2 days between doses; Other study drug-related nonhematologic toxicities G2 or greater, required a dose reduction/discontinuation of pevonedistat. G3 or greater hematologic toxicities, including G3 or 4 febrile neutropenia, considered DLTs if: A delay in initiation of Cycle 2 due to lack of adequate recovery from treatment-related toxicity: 1) Of more than (>) 4 weeks due to hematologic toxicity believed not related to leukemic infiltration. Bone marrow (BM) evaluation may have been required. 2) Of >2 weeks due to nonhematologic toxicities.

    Measured: Cycle 1 (Cycle length = 21 days [single agent arms]; 28 days [combination arms])

  3. Number of Participants With Clinically Significant Abnormal Laboratory Values

    Measured: Baseline up to Cycle 19 (up to Day 399) in single agent arms (Cycle=21days) and Cycle 65 (up to Day 1820) in combination arms (Cycle=28 days)

  4. Cmax: Maximum Observed Plasma Concentration for Pevonedistat When Administered Alone and in Combination With Azacitidine on Cycle 1 Day 1

    Measured: Cycle 1 Day 1: pre-infusion and at multiple time points (up to 48 hours) post-infusion (Cycle length = 21 days [single agent arms]; 28 days [combination arms])

  5. Cmax: Maximum Observed Plasma Concentration for Pevonedistat When Administered Alone and in Combination With Azacitidine on Cycle 1 Day 5

    Measured: Cycle 1 Day 5: pre-infusion and at multiple time points (up to 48 hours) post-infusion (Cycle length = 21 days [single agent arms]; 28 days [combination arms])

  6. AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Pevonedistat When Administered Alone and in Combination With Azacitidine on Cycle 1 Day 5

    Measured: Cycle 1 Day 5: pre-infusion and at multiple time points (up to 48 hours) post-infusion (Cycle length = 21 days [single agent arms]; 28 days [combination arms])

  7. CL: Total Clearance for Pevonedistat When Administered Alone and in Combination With Azacitidine on Cycle 1 Day 1

    Measured: Cycle 1 Day 1: pre-infusion and at multiple time points (up to 48 hours) post-infusion (Cycle length = 21 days [single agent arms]; 28 days [combination arms])

  8. CL: Total Clearance for Pevonedistat When Administered Alone and in Combination With Azacitidine on Cycle 1 Day 5

    Measured: Cycle 1 Day 5: pre-infusion and at multiple time points (up to 48 hours) post-infusion (Cycle length = 21 days [single agent arms]; 28 days [combination arms])

Secondary outcomes (4)

  1. Overall Response Rate (ORR) for Participants With AML

    ORR for AML was defined as the percentage of participants with a complete remission (CR), CR with incomplete blood count recovery (CRi), or partial remission (PR) based on Modified International Working Group (IWG) Response Criteria for AML. CR was defined as participant achieved the morphologic leukemia-free state and had an absolute neutrophil count (ANC) of more than 1,000 per microliter (/mcL) and platelets of greater than or equal to (>=) 100,000/mcL. A morphologic leukemia-free state requires less than (<) 5 percent (%) blasts in an aspirate sample with marrow spicules and with a count of at least 200 nucleated cells. CRi was, after chemotherapy, some participants who fulfilled all of the criteria for CR except for residual neutropenia (<1,000/mcL) or thrombocytopenia (<100,000/mcL). PR designation required all the hematologic values for a CR but with a decrease of at least 50% in the percentage of blasts to between 5% and 25% in the bone marrow aspirate.

    Measured: From first dose up to 30 days after last dose of study drug or before start of subsequent antineoplastic therapy, whichever comes earlier up to Cycle 19 (up to Day 429, single agent)(Cycle=21 days) and Cycle 65 (up to Day 1850, combination)(Cycle=28 days)

  2. ORR for Participants With MDS

    ORR for MDS: Percentage of participants with CR,PR or hematologic improvement(HI) based on IWG Response Criteria. CR: BM:<=5% myeloblasts with normal maturation of all cell lines; persistent dysplasia noted peripheral blood: hemoglobin (Hgb)>=11 gram per deciliter (g/dL),platelets>=100*10^9/L,neutrophils >=1.0*10^9/L, blasts 0%. PR:CR criteria if abnormal before treatment except: BM blasts decreased by >=50% from pretreatment but still>5%; cellularity, morphology not relevant. HI criteria: Erythroid response:Hgb up by >=1.5 g/dL; transfused RBC reduced by at least 4 red blood cell (RBC) transfusions/8 weeks comparatively last 8 weeks; Platelet response: Increase of >=30*10^9/L for participants starting with >20*10^9/L platelets; increase from <20*10^9/L to >20*10^9/L and by 100%; Neutrophil response: At least 100% and absolute increase >0.5*10^9/L; Progression/relapse after HI: Granulocytes/platelets decreased by 50% from maximum; Hgb reduced by >=1.5 g/dL; transfusion dependence.

    Measured: From first dose up to 30 days after last dose of study drug or before start of subsequent antineoplastic therapy, whichever comes earlier up to Cycle 19 (up to Day 429, single agent)(Cycle=21 days) and Cycle 65 (up to Day 1850, combination)(Cycle=28 days)

  3. Percentage of Participants With CR for Participants With AML

    CR was defined as participant achieved the morphologic leukemia-free state and had an ANC of more than 1,000/mcL and platelets of >=100,000/mcL. A morphologic leukemia-free state requires <5% blasts in an aspirate sample with marrow spicules and with a count of at least 200 nucleated cells. CR assessment was based on IWG Response Criteria.

    Measured: From first dose up to 30 days after last dose of study drug or before start of subsequent antineoplastic therapy, whichever comes earlier up to Cycle 19 (up to Day 429, single agent)(Cycle=21 days) and Cycle 65 (up to Day 1850, combination)(Cycle=28 days)

  4. Percentage of Participants With CR for Participants With MDS

    CR was defined as participant with bone marrow: less than or equal to (<=) 5% myeloblasts with normal maturation of all cell lines; persistent dysplasia was noted peripheral blood: Hgb >=11 g/dL, platelets >=100*10^9/L, neutrophils >=1.0*10^9 per liter (/L), blasts 0%. CR assessment was based on IWG Response Criteria.

    Measured: From first dose up to 30 days after last dose of study drug or before start of subsequent antineoplastic therapy, whichever comes earlier up to Cycle 19 (up to Day 429, single agent)(Cycle=21 days) and Cycle 65 (up to Day 1850, combination)(Cycle=28 days)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 May 2016 (estimated)
  2. Study start16 May 2016
  3. Primary completion25 Jan 2022
  4. Study completion25 Jan 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
23 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02782468
Sponsor's protocol ID
Pevonedistat-1012
Other IDs
U1111-1166-8630
Status last verified
Jan 2023
First submitted
20 May 2016
Last updated
3 Nov 2023
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Publications

  • Handa H, Cheong JW, Onishi Y, Iida H, Kobayashi Y, Kim HJ, Chiou TJ, Izutsu K, Tsukurov O, Zhou X, Faessel H, Yuan Y, Sedarati F, Faller DV, Kimura A, Wu SJ. Pevonedistat in East Asian patients with acute myeloid leukemia or myelodysplastic syndromes: a phase 1/1b study to evaluate safety, pharmacokinetics and activity as a single agent and in combination with azacitidine. J Hematol Oncol. 2022 May 11;15(1):56. doi: 10.1186/s13045-022-01264-w.

    PubMed 35545778

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Pevonedistat 25 mg/m^2, Pevonedistat 44 mg/m^2 and Pevonedistat 10 mg/m^2 in people with Leukemia, Myeloid, Acute and Myelodysplastic Syndromes, run by Millennium Pharmaceuticals, Inc. at 9 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 3 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 9 sites in Japan, South Korea, Taiwan. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 3 Nov 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) (time frame: From first dose through 30 days after the last dose of study drug: single agent arms (up to Cycle 19 [up to Day 429]) (Cycle=21 days); combination arms (up to Cycle 65 [up to Day 1850]) (Cycle=28 days)). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02782468, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Nov 2023.

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