A Study of Pevonedistat in Adult East Asian Participants

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).

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes; Leukemia, Myeloid, Acute
• Intervention / Treatment: Drug: Pevonedistat 25 mg/m^2; Drug: Pevonedistat 44 mg/m^2; Drug: Pevonedistat 10 mg/m^2; Drug: Azacitidine 75 mg/m^2; Drug: Pevonedistat 20 mg/m^2

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).

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Maebashi City, Japan
  • Nagoya, Japan
  • Sendai City, Japan
  • Tokyo, Japan
• Korea, Republic of
  • Jeonnam, Korea, Republic of, 519-763
    • Chonnam National University Hwasun Hospital
  • Seoul, Korea, Republic of, 120-752
    • Severance Hospital Yonsei University Health System - PPDS
  • Seoul, Korea, Republic of, 137701
    • The Catholic University of Korea, Seoul St. Mary's Hospital
• Taiwan
  • Taipei, Taiwan, 112
    • Taipei Veterans General Hospital
  • Taipei, Taiwan, 10048
    • National Taiwan University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / 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: Azacitidine 75 mg/m^2; Azacitidine 75 mg/m^2 intravenous or subcutaneous formulation.; Drug: Pevonedistat 20 mg/m^2; Pevonedistat 20 mg/m^2 intravenous infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)		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)
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.	Cycle 1 (Cycle length = 21 days [single agent arms]; 28 days [combination arms])
Number of Participants With Clinically Significant Abnormal Laboratory Values		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)
Cmax: Maximum Observed Plasma Concentration for Pevonedistat When Administered Alone and in Combination With Azacitidine on Cycle 1 Day 1		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])
Cmax: Maximum Observed Plasma Concentration for Pevonedistat When Administered Alone and in Combination With Azacitidine on Cycle 1 Day 5		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])
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		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])
CL: Total Clearance for Pevonedistat When Administered Alone and in Combination With Azacitidine on Cycle 1 Day 1		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])
CL: Total Clearance for Pevonedistat When Administered Alone and in Combination With Azacitidine on Cycle 1 Day 5		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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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)
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.	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)
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.	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)
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.	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)

Collaborators and Investigators

• Sponsor: Millennium Pharmaceuticals, Inc.
• Investigators: Study Director: Study Director, Takeda

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 16, 2016
• Primary Completion (Actual): January 25, 2022
• Study Completion (Actual): January 25, 2022

Study Registration Dates

• First Submitted: May 20, 2016
• First Submitted That Met QC Criteria: May 20, 2016
• First Posted (Estimated): May 25, 2016

Study Record Updates

• Last Update Posted (Estimated): November 3, 2023
• Last Update Submitted That Met QC Criteria: January 12, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Drug Therapy
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine; Pevonedistat
• Other Study ID Numbers: Pevonedistat-1012; U1111-1166-8630 (Other Identifier: WHO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No