A Study of Pevonedistat in People With Blood Cancers or Solid Tumors With Kidney or Liver Problems

NCT03814005 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: Pevonedistat-1016U1111-1220-13962018-004049-17
• Study Type: interventional
• Target: 17
• Locations: 2 countries
• Sites: 8

Brief Summary

Pevonedistat is a medicine to treat people with blood cancers or solid tumors. The main aim of the study is to learn about the levels of pevonedistat in the blood of participants with blood cancers or solid tumors, who also have severe kidney problems or mild to moderate liver problems. The information from this study will be used to work out the best dose of pevonedistat to give people with these conditions in future studies. At the first visit, the study doctor will check who can take part in the study. This study is in 2 parts: A and B. Part A Participants will be placed into 1 of 4 treatment groups depending on how severe their kidney and liver problems are. All participants will receive 1 dose of pevonedistat as a slow injection in their vein (infusion). Then, the study doctors will check the levels of pevonedistat in the blood of the participants for 3 days after the infusion. They will also check if the participants have any side effects from pevonedistat. Participants will be asked to continue to Part B. Those who don't want to continue will visit the clinic 30 days later for a final check-up. Part B Participants who agree to participate into Part B will receive an infusion of pevonedistat on specific days during a 21-day or 28-day cycle. The cycle time will depend on what type of cancer the participants have. Participants will also be treated with standard of care medicines for their kidney and liver problems during this time. In the first cycle, the study doctors will also check the levels of pevonedistat in the blood and urine of participants for 3 days after the infusion. Participants will continue with cycles of treatment together with standard of care medicines until their condition gets worse or they have too many side effects from the treatment. When treatment has finished, participants will visit the clinic 10 days later for a final check-up.

Conditions

Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic; Leukemia, Myeloid, Acute; Renal Insufficiency; Liver Disease; Neoplasms

Keywords

Drug therapy

Outcome Measures

Primary Outcomes (3)

• Part A, AUC∞: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Pevonedistat Following a Single Dose

  Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose

• Part A, AUClast: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration for Pevonedistat Following a Single Dose

  Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose

• Part A, Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following a Single Dose

  Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose

Secondary Outcomes (19)

• Parts A and B, t1/2z: Terminal Disposition Phase Half-life for Pevonedistat Following Single and Multiple Dose

  Part A: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Part B: Cycle 1 Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length= 28 days)

• Part B: Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following Multiple Dose

  Cycle 1 Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length= 28 days)

• Parts A, fu: Fraction of Unbound Drug in Plasma for Pevonedistat

  Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose

• Part B, Cmax: Maximum Observed Plasma Concentration for Azacitidine Following Multiple Dose

  Cycle 1 Day 3 pre-dose and at multiple time points (up to 7 hours) post-dose (Cycle length= 28 days)

• Part B, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Azacitidine Following Multiple Dose

  Cycle 1 Day 3 pre-dose and at multiple time points (up to 7 hours) post-dose (Cycle length= 28 days)

Study Arms (3)

Control Arm

EXPERIMENTAL

Pevonedistat 20 milligram per square meter (mg/m\^2), infusion, intravenously, once, on Day 1 of Part A in participants with hematologic malignancies, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 75 mg/m\^2, injection, subcutaneously in Cycle 1 or subcutaneously or intravenously in Cycle 2 and subsequent cycles, once on Day 1 through Day 7 or Day 1 through Day 5, and on Days 8 and 9 in combination with pevonedistat 20 mg/m\^2, infusion, intravenously, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles.

Drug: Azacitidine; Drug: Pevonedistat

Renal Arm

EXPERIMENTAL

Pevonedistat 20 mg/m\^2, infusion, intravenously, once, on Day 1 of Part A in participants with hematologic malignancies, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 75 mg/m\^2, injection, subcutaneously in Cycle 1 or subcutaneously or intravenously in Cycle 2 and subsequent cycles, once on Day 1 through Day 7 or Day 1 through Day 5, and on Days 8-9 in combination with a starting dose of pevonedistat 10 mg/m\^2 to a maximum dose of pevonedistat 15 mg/m\^2, infusion, intravenously, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles.

Drug: Azacitidine; Drug: Pevonedistat

Mild Hepatic Arm

EXPERIMENTAL

Pevonedistat 20 mg/m\^2, infusion, intravenously, once, on Day 1 of Part A in participants with hematologic malignancies, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 75 mg/m\^2, injection, subcutaneously in Cycle 1 or subcutaneously or intravenously in Cycle 2 and subsequent cycles, once on Day 1 through Day 7 or Day 1 through Day 5, and on Days 8 and 9 in combination with a starting dose of pevonedistat 10 mg/m\^2 to a maximum dose of pevonedistat 20 mg/m\^2, infusion, intravenously, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles.

Drug: Azacitidine; Drug: Pevonedistat

Interventions

Azacitidine DRUG

Azacitidine subcutaneous or intravenous injection.

Control Arm; Mild Hepatic Arm; Renal Arm

Pevonedistat DRUG

Pevonedistat intravenous infusion.

Also known as: TAK-924 and MLN4924

Control Arm; Mild Hepatic Arm; Renal Arm

Eligibility Criteria

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

You may qualify if:

• All participants:
• Has expected survival of at least 3 months from the date of enrollment in the study.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
• Has recovered (that is, Grade \<=1 toxicity) from the reversible effects of prior anticancer therapy.
• Prothrombin time (PT) and activated partial thromboplastin time (aPTT) \<=1.5 \* upper limit of the normal range (ULN) at screening or within 7 days before the first dose of study drug.
• Suitable venous access for the study-required blood sampling (that is, PK sampling).
• For hematologic malignancies:
• Previously untreated hematologic malignancies not suitable for induction therapy.
• Morphologically confirmed diagnosis of MDS or nonproliferative CMML (that is, with white blood cell \[WBC\] \<13,000 /mcL) at the study entry, based on one of the following:
• French-American-British (FAB) Classifications:
• Refractory anemia with excess blasts (RAEB), defined as having 5% to 20% myeloblasts in the bone marrow.
• CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.
• World Health Organization (WHO) Classifications:
• RAEB-1, defined as having 5% to 9% myeloblasts in the bone marrow.
• RAEB-2, defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.

You may not qualify if:

• All participants:-
• With end-stage renal disease requiring hemodialysis.
• Has Gilbert syndrome.
• Has active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia. Prophylactic treatment with antibiotics is allowed.
• Has life-threatening illness unrelated to cancer.
• Known human immunodeficiency virus (HIV) seropositive.
• Treatment with strong cytochrome P450 (CYP)3A inducers within 14 days before the first dose of pevonedistat.
• Has left ventricular ejection fraction (LVEF) \<50% within 6 months prior to study enrollment. If a result within this time frame is unavailable, LVEF must be determined by echocardiography or multigated acquisition scan at screening.
• Has severe symptomatic pulmonary hypertension requiring pharmacologic therapy or participants with chronic respiratory disease that requires continuous oxygen.
• For hematologic malignancies:
• Has acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis.
• With AML with a WBC count \>=50,000/mcL. Participants who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they otherwise meet the eligibility criteria.
• With either clinical evidence of or history of central nervous system (CNS) involvement by AML.
• With hematologic malignancies, PT or aPTT \>1.5 \* ULN or active uncontrolled coagulopathy or bleeding disorder. Participants therapeutically anticoagulated with warfarin, direct thrombin inhibitors, direct factor Xa inhibitors, or heparin are excluded from enrollment.
• For advanced solid tumors:

Sponsors & Collaborators

• Takeda: lead

Study Sites (8)

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27514, United States

Location

ICO lHospitalet Hospital Duran i Reynals

LHospitalet de Llobregat, Barcelona, 8908, Spain

Location

Hospital Universitario Vall d'Hebron - PPDS

Barcelona, 8035, Spain

Location

Hospital de San Pedro de Alcantara

Cáceres, 10003, Spain

Location

C.H. Regional Reina Sofia

Córdoba, 14004, Spain

Location

Complejo Asistencial Universitario de Salamanca H. Clinico

Salamanca, 37007, Spain

Location

Hospital Universitario Virgen del Rocio - PPDS

Seville, 41013, Spain

Location

Related Links

• To obtain more information on the study, click here/on this link

MeSH Terms

Conditions

Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic; Leukemia, Myeloid, Acute; Renal Insufficiency; Liver Diseases; Neoplasms

Interventions

Azacitidine; pevonedistat

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Study Director
• Organization: Takeda

TrialDisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 21, 2019
• First Posted: January 23, 2019
• Study Start: July 10, 2019
• Primary Completion: March 19, 2021
• Study Completion: April 19, 2022
• Last Updated: September 5, 2024
• Results First Posted: September 5, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• 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.

Locations

US (2); ES (6)