Pevonedistat and Belinostat in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

NCT03772925 | Terminated Phase 1 Results FDA Drug

• 3 other identifiers: NCI-2018-0322710246UM1CA186644
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 6

Brief Summary

This phase I trial studies side effects and best dose of pevonedistat and belinostat in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has come back (relapsed) or does not respond to treatment (refractory). Chemotherapy drugs, such as pevonedistat and belinostat, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Conditions

Recurrent Acute Myeloid Leukemia; Recurrent Myelodysplastic Syndrome; Refractory Acute Myeloid Leukemia; Refractory Myelodysplastic Syndrome

Outcome Measures

Primary Outcomes (1)

• Recommended Phase 2 Dose (RP2D) for the Combination of MLN4924 (Pevonedistat) and Belinostat

  Determined by the number of patients with treatment dosing level toxicities (DLT's). DLT's will be defined in cycle 1 as pre-specified adverse events that are considered by the investigator to be related to therapy with MLN4924 (pevonedistat) and/or belinostat.

  Up to the end of cycle 1, 21 days.

Secondary Outcomes (7)

• Incidence of Adverse Events (AEs)

  Adverse Events (AE's) were collected starting Cycle 1 Day 1 through 30 days following treatment up to 1 year, 6 months.

• Treatment Response

  From day 1 until final response measured, up to 188 days.

• Duration of Stable and Complete Response

  From documentation of tumor response to disease progression or death assessed up to 188 days.

• Time to Response

  From Day 1 of protocol treatment to the time of documentation of tumor response, assessed up to 188 days.

• Change in MLN4924 Belinostat Plasma Concentrations

  Baseline up to cycle 1 day 1

Other Outcomes (12)

• Determine What Relationship, if Any, Exists Between Such Responses and TP53/FLT3 Mutational Status.

  Screening

• Change in Candidate Biomarker Levels in Bone Marrow and/or Blood Samples gH2A.X

  Baseline up to 24 hours post-treatment with the first doses of study drugs

• Change in Candidate Biomarker Levels in Bone Marrow and/or Blood Samples Phosphorylated Checkpoint Kinase 1 (p-Chk1)

  Baseline up to 24 hours post-treatment with the first doses of study drugs

Study Arms (1)

Treatment (belinostat, pevonedistat)

EXPERIMENTAL

Patients receive belinostat IV daily over 30 minutes on days 1-5 and pevonedistat IV QD over 60 minutes on days 1, 3, and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: Belinostat; Drug: Pevonedistat

Interventions

Belinostat DRUG

Given IV

Also known as: Beleodaq, PXD 101, PXD-101, PXD101

Treatment (belinostat, pevonedistat)

Pevonedistat DRUG

Given IV

Also known as: MLN4924, Nedd8-Activating Enzyme Inhibitor MLN4924

Treatment (belinostat, pevonedistat)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have one of the following, histologically or cytologically confirmed:
• AML (non- acute promyelocytic leukemia \[APL\] AML)
• AML that is relapsed or refractory to at least one prior line of therapy
• MDS, must meet all of the following at the time of enrollment:
• Higher risk MDS (intermediate-2 or high risk by the original International Prognostic Scoring System \[IPSS\]), and
• Relapsed, refractory, or intolerant to at least one prior line of therapy containing a hypomethylating agent (deoxyribonucleic acid \[DNA\] methyltransferase inhibitor)
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
• Total bilirubin =\< upper limit of normal (ULN) for the laboratory except in patients with Gilbert's syndrome. Patients with Gilbert's syndrome may enroll if direct bilirubin =\< 1.5 x ULN for the laboratory of the direct bilirubin
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 x institutional ULN
• Creatinine clearance within normal limits for the laboratory OR estimated glomerular filtration rate (GFR) \>= 60 mL/min/1.73 m\^2 appropriate to race for patients with creatinine levels above institutional normal
• Known human immunodeficiency virus (HIV) positive patients who meet the following criteria will be considered eligible:
• CD4 count \> 350 cells/mm\^3
• Undetectable viral load
• Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents
• No history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections

You may not qualify if:

• Clinical picture indicative of leukostasis or evidence of disseminated intravascular coagulopathy
• Patients with uncontrolled coagulopathy or bleeding disorder
• Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 14 days before the first dose of any study drug, except for hydroxyurea
• Uncontrolled high blood pressure (i.e., systolic blood pressure \> 180 mm Hg, diastolic blood pressure \> 95 mm Hg)
• Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s)
• Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s)
• Ongoing toxicities \>= grade 2 from prior therapy, except those related to hydroxyurea (which is permitted through the first 5 days of study treatment)
• APL (M3)
• Active central nervous system (CNS) leukemia
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to MLN4924 (pevonedistat) or belinostat
• Stem cell transplant within previous 3 months prior to initiation of study therapy
• Major surgical procedures =\< 28 days before beginning study treatment or minor surgical procedures =\< 7 days before beginning study treatment. No waiting required after placement of a vascular access device
• Uncontrolled intercurrent illness or infection
• Circulating blast count \> 50,000 mm\^3 within 7 days preceding enrollment
• Current candidacy for a potentially curative allogeneic stem cell transplant, unless declined

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (6)

Moffitt Cancer Center-International Plaza

Tampa, Florida, 33607, United States

Location

Moffitt Cancer Center - McKinley Campus

Tampa, Florida, 33612, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, 08903, United States

Location

UT Southwestern/Simmons Cancer Center-Dallas

Dallas, Texas, 75390, United States

Location

Virginia Commonwealth University/Massey Cancer Center

Richmond, Virginia, 23298, United States

Location

Related Publications (1)

• Maher KR, Shafer D, Schaar D, Bandyopadhyay D, Deng X, Wright J, Piekarz R, Rudek MA, Harvey RD, Grant S. A phase I study of MLN4924 and belinostat in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome. Cancer Chemother Pharmacol. 2025 Jan 17;95(1):24. doi: 10.1007/s00280-024-04742-9.

  PMID: 39821392 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

belinostat; pevonedistat

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Limitations and Caveats

Takeda stopped producing Pevonedistat

Results Point of Contact

• Title: Massey IIT Research Operations
• Organization: Virginia Commonwealth University Massey Comprehensive Cancer Center

masseyepd@vcu.edu

804-628-6430

Study Officials

• Keri R Maher

  University Health Network Princess Margaret Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 11, 2018
• First Posted: December 12, 2018
• Study Start: June 20, 2019
• Primary Completion: September 6, 2022
• Study Completion: May 8, 2025
• Last Updated: March 3, 2026
• Results First Posted: March 3, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share

Locations

US (6)