A Study of Pevonedistat in Adult East Asian Participants

Sponsor
Millennium Pharmaceuticals, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT02782468
Collaborator
(none)
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Study Details

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).

Condition or Disease Intervention/Treatment Phase
  • 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/m2). If this dose is tolerable, participants will be enrolled in parallel at single-agent higher dose level (44 mg/m2) and in combination treatment cohorts.

  • Pevonedistat 25 mg/m^2

  • Pevonedistat 44 mg/m^2

  • Pevonedistat 10 mg/m2 and azacitidine 75 mg/m2 combination

  • Pevonedistat 20 mg/m2 and azacitidine 75 mg/m2 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).

Study Design

Study Type:
Interventional
Actual Enrollment :
23 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
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 16, 2016
Actual Primary Completion Date :
Jan 25, 2022
Actual Study Completion Date :
Jan 25, 2022

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

  1. • Number of Participants Reporting one or More Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [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 [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 [Baseline and up to 30 days after the last dose of study drug]

  4. Cmax: Maximum Observed Plasma Concentration for Pevonedistat [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 [Day 1: Pre-infusion and at multiple time points (up to 48 hours) post-infusion]

  6. CL: Clearance [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 [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 [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]

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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):
  1. 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%
  1. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

  2. 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.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Maebashi City Japan
2 Nagoya Japan
3 Sendai City Japan
4 Tokyo Japan
5 Chonnam National University Hwasun Hospital Jeonnam Korea, Republic of 519-763
6 Severance Hospital Yonsei University Health System - PPDS Seoul Korea, Republic of 120-752
7 The Catholic University of Korea, Seoul St. Mary's Hospital Seoul Korea, Republic of 137701
8 National Taiwan University Hospital Taipei Taiwan 10048
9 Taipei Veterans General Hospital Taipei Taiwan 112

Sponsors and Collaborators

  • Millennium Pharmaceuticals, Inc.

Investigators

  • Study Director: Medical Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT02782468
Other Study ID Numbers:
  • Pevonedistat-1012
  • U1111-1166-8630
First Posted:
May 25, 2016
Last Update Posted:
Jun 24, 2022
Last Verified:
Jun 1, 2022
Keywords provided by Millennium Pharmaceuticals, Inc.
Additional relevant MeSH terms:

Study Results

No Results Posted as of Jun 24, 2022