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A Study of Pevonedistat in Adult East Asian Participants

Primary Purpose

Leukemia, Myeloid, Acute, Myelodysplastic Syndromes

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

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

About this trial

This is an interventional treatment trial for Leukemia, Myeloid, Acute focused on measuring Drug Therapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria include, in part:

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

Exclusion Criteria include, in part:

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.
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.

Sites / Locations

Chonnam National University Hwasun Hospital
Severance Hospital Yonsei University Health System - PPDS
The Catholic University of Korea, Seoul St. Mary's Hospital
National Taiwan University Hospital
Taipei Veterans General Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Arm 1, Cohort 1: Pevonedistat 25 mg/m^2

Arm 1, Cohort 2: Pevonedistat 44 mg/m^2

Arm 2, Cohort 1: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2

Arm 2, Cohort 2: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

• Number of Participants Reporting one or More Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Number of Participants With Dose Limiting Toxicities (DLTs) During Cycle

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.

Number of Participants With Markedly Abnormal Laboratory Values

Cmax: Maximum Observed Plasma Concentration for Pevonedistat

AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time tau Over the Dosing Interval for Pevonedistat

CL: Clearance

Secondary Outcome Measures

Percentage of Participants With Overall Response

Percentage of Participants With CR

Full Information

NCT ID

NCT02782468

First Posted

May 20, 2016

Last Updated

June 23, 2022

Sponsor

Millennium Pharmaceuticals, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT02782468

Brief Title

A Study of Pevonedistat in Adult East Asian Participants

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)

Study Type

Interventional

2. Study Status

Record Verification Date

June 2022

Overall Recruitment Status

Completed

Study Start Date

May 16, 2016 (Actual)

Primary Completion Date

January 25, 2022 (Actual)

Study Completion Date

January 25, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Millennium Pharmaceuticals, Inc.

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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).

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Leukemia, Myeloid, Acute, Myelodysplastic Syndromes

Keywords

Drug Therapy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

23 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm 1, Cohort 1: Pevonedistat 25 mg/m^2

Arm Type

Experimental

Arm Description

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.

Arm Title

Arm 1, Cohort 2: Pevonedistat 44 mg/m^2

Arm Type

Experimental

Arm Description

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.

Arm Title

Arm 2, Cohort 1: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2

Arm Type

Experimental

Arm Description

Arm Title

Arm 2, Cohort 2: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Pevonedistat 25 mg/m^2

Intervention Description

Pevonedistat 25 mg/m^2 intravenous infusion.

Intervention Type

Drug

Intervention Name(s)

Pevonedistat 44 mg/m^2

Intervention Description

Pevonedistat 44 mg/m^2 intravenous infusion.

Intervention Type

Drug

Intervention Name(s)

Pevonedistat 10 mg/m^2

Intervention Description

Pevonedistat 10 mg/m^2 intravenous infusion.

Intervention Type

Drug

Intervention Name(s)

Pevonedistat 20 mg/m^2

Intervention Description

Pevonedistat 20 mg/m^2 intravenous infusion.

Intervention Type

Drug

Intervention Name(s)

Azacitidine 75 mg/m^2

Intervention Description

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

Primary Outcome Measure Information:

Title

• 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

Title

Number of Participants With Dose Limiting Toxicities (DLTs) During Cycle

Description

Time Frame

Cycle 1 Day 1 up to end of Cycle 1 (Day 21 for single-agent groups and Day 28 for combination groups)

Title

Number of Participants With Markedly Abnormal Laboratory Values

Time Frame

Baseline and up to 30 days after the last dose of study drug

Title

Cmax: Maximum Observed Plasma Concentration for Pevonedistat

Time Frame

Day 1: Pre-infusion and at multiple time points (up to 48 hours) post-infusion

Title

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

Title

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 Measure Information:

Title

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

Title

Percentage of Participants With CR

Time Frame

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria include, in part: 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% Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Able to undergo bone marrow aspiration and biopsy at Screening. Exclusion Criteria include, in part: 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. 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Director

Organizational Affiliation

Takeda

Official's Role

Study Director

Facility Information:

City

Maebashi City

Country

Japan

City

Nagoya

Country

Japan

City

Sendai City

Country

Japan

City

Tokyo

Country

Japan

Facility Name

Chonnam National University Hwasun Hospital

City

Jeonnam

ZIP/Postal Code

519-763

Country

Korea, Republic of

Facility Name

Severance Hospital Yonsei University Health System - PPDS

City

Seoul

ZIP/Postal Code

120-752

Country

Korea, Republic of

Facility Name

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

City

Seoul

ZIP/Postal Code

137701

Country

Korea, Republic of

Facility Name

National Taiwan University Hospital

City

Taipei

ZIP/Postal Code

10048

Country

Taiwan

Facility Name

Taipei Veterans General Hospital

City

Taipei

ZIP/Postal Code

112

Country

Taiwan

12. IPD Sharing Statement

Citations:

PubMed Identifier

35545778

Citation

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.

Results Reference

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A Study of Pevonedistat in Adult East Asian Participants

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