A Study to Evaluate the Effects of Pevonedistat on the Corrected QT (QTc) Interval in Participants With Advanced Solid Tumors

NCT03330106 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: Pevonedistat-10142017-002610-31U1111-1201-10111
• Study Type: interventional
• Target: 68
• Locations: 1 country
• Sites: 8

Brief Summary

The purpose of this study is to characterize the effects of 25 and 50 milligram per square meter (mg/m\^2) pevonedistat on the Fridericia corrected QT interval (QTcF) of the electrocardiogram (ECG).

Conditions

Advanced Solid Neoplasm

Keywords

Drug therapy

Outcome Measures

Primary Outcomes (1)

• Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration

  Change from time-matched baseline in QTcF was assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m\^2 and was analysed by dose. Some participants were treated with pevonedistat 25 mg/m\^2 or 50 mg/m\^2 on Day 1 while others received treatment on Day 8. Data is reported at pre-dose and at multiple timepoints (1, 2, 3, 4, 6, 9, 11 and 24 hours) postdose up to Day 8 in Part A. Analysis of variance (ANOVA) was used for the analysis.

  Baseline up to Day 8

Secondary Outcomes (8)

• Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration

  Predose, and at multiple time points up to 24 hours post dose on Day 1 or Day 8 in Part A

• Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration

  Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A

• Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration

  Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A

• Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration

  Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A

• Part A: Cmax: Maximum Observed Plasma Concentration for Pevonedistat

  Days 1 or 8 predose and at multiple time points (up to 24 hours) post dose in Part A

Study Arms (3)

Part A: Pevonedistat 25 mg/m^2 + Pevonedistat 50 mg/m^2

EXPERIMENTAL

Pevonedistat 25 mg/m\^2, infusion, intravenously, once on Day 1 of Cycle 1, followed by pevonedistat 50 mg/m\^2, infusion, intravenously, once on Day 8 of Cycle 1.

Drug: Pevonedistat

Part A: Pevonedistat 50 mg/m^2 + Pevonedistat 25 mg/m^2

EXPERIMENTAL

Pevonedistat 50 mg/m\^2, infusion, intravenously, once on Day 1 of Cycle 1, followed by pevonedistat 25 mg/m\^2, infusion, intravenously, once on Day 8 of Cycle 1.

Drug: Pevonedistat

Part B: Pevonedistat

EXPERIMENTAL

Pevonedistat 25 mg/m\^2 in combination with docetaxel 75 mg/m\^2 or pevonedistat 20 mg/m\^2 in combination with carboplatin plus paclitaxel 175 mg/m\^2, infusion, intravenously, once on Day 1 in each 21-day treatment cycle followed by pevonedistat 25 mg/m\^2 or 20 mg/m\^2 infusion, intravenously, once on Days 3 and 5 in each 21-day treatment cycle for up to 12 cycles or symptomatic deterioration or PD, treatment is discontinued for another reason, or until the study is stopped. The combination and dose of pevonedistat will be based on investigator discretion.

Drug: Pevonedistat; Drug: Docetaxel; Drug: Carboplatin; Drug: Paclitaxel

Interventions

Pevonedistat DRUG

Pevonedistat intravenous infusion.

Also known as: MLN4924, TAK-924

Part A: Pevonedistat 25 mg/m^2 + Pevonedistat 50 mg/m^2; Part A: Pevonedistat 50 mg/m^2 + Pevonedistat 25 mg/m^2; Part B: Pevonedistat

Docetaxel DRUG

Docetaxel intravenous infusion.

Part B: Pevonedistat

Carboplatin DRUG

Carboplatin intravenous infusion.

Part B: Pevonedistat

Paclitaxel DRUG

Paclitaxel intravenous infusion.

Part B: Pevonedistat

Eligibility Criteria

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

You may qualify if:

• Participants must have a histologically or cytologically confirmed metastatic or locally advanced solid tumor(s) appropriate for treatment with one of the 2 combination therapies in Part B of this study, have progressed despite standard therapy, or for whom conventional therapy is not considered effective.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Expected survival longer than 3 months from enrollment in the study.
• Recovered (that is, grade less than or equal to \[\<=\] 1 toxicity) from the reversible effects of prior anticancer therapy.
• Suitable venous access for the study-required blood sampling (including pharmacokinetic \[PK\] sampling).

You may not qualify if:

• Treatment with strong cytochrome P3A (CYP3A) inducers within 14 days before the first dose of pevonedistat. Participants must have no history of amiodarone use within 6 months before the first dose of pevonedistat nor require the use of these medications during the study.
• Treatment with QT-prolonging drugs with a risk of causing torsades de pointes (TdP. Participants taking drugs with a possible or conditional risk of QT prolongation or drugs that are to be avoided by participants with congenital long QT syndrome may be considered if on a stable dose, pending discussion and agreement between the investigator and the sponsor.
• History of Brugada syndrome, risk factors for TdP, or family history of long QT syndrome.
• Implantable cardioverter defibrillator.
• Cardiac pacemaker with heart rate (HR) set at a fixed rate and treatment with concomitant medication that may limit increase in HR in response to hypotension (example, high-dose beta blocker).
• Known moderate to severe aortic stenosis, moderate to severe mitral stenosis, or other valvulopathy (ongoing).
• Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
• Entry Criteria for Continuation to Optional Part B:
• After completing Part A of the study, participants may choose to enter the optional Part B of the study. To be eligible for the optional Part B, participants must have completed Part A and be reassessed to determine if they meet the entry criteria for optional Part B. Only participants who meet the following criteria may enter into Part B:
• ECOG performance status of 0 to 1.
• Absolute neutrophil count (ANC) greater than or equal to (\>=) 1500 per cubic millimeter (/mm\^3).
• Platelet count \>=100,000/mm\^3.
• Laboratory values for hemoglobin, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and serum creatinine or calculated/measured creatinine clearance.
• Diarrhea symptoms resolved to Grade 1 or better.
• QTc interval \<480 millisecond (msec).

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (8)

Sarcoma Oncology Center

Santa Monica, California, 90403, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

Montefiore Medical Center

The Bronx, New York, 10467, United States

Location

Case Western Reserve University

Cleveland, Ohio, 44106, United States

Location

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 23801, United States

Location

Mary Crowley Medical Research

Dallas, Texas, 75231, United States

Location

Virginia Cancer Specialists

Fairfax, Virginia, 22031, United States

Location

Related Publications (1)

• Zhou X, Richardson DL, Dowlati A, Goel S, Sahebjam S, Strauss J, Chawla S, Wang D, Mould DR, Samnotra V, Faller DV, Venkatakrishnan K, Gupta N. Effect of Pevonedistat, an Investigational NEDD8-Activating Enzyme Inhibitor, on the QTc Interval in Patients With Advanced Solid Tumors. Clin Pharmacol Drug Dev. 2023 Mar;12(3):257-266. doi: 10.1002/cpdd.1194. Epub 2022 Nov 16.

  PMID: 36382849 DERIVED

MeSH Terms

Interventions

pevonedistat; Docetaxel; Carboplatin; Paclitaxel

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Coordination Complexes

Results Point of Contact

• Title: Study Director
• Organization: Takeda

TrialDisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Director

  Millennium Pharmaceuticals, Inc.

  STUDY DIRECTOR

Publication Agreements

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

Study Design

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

Study Record Dates

• First Submitted: October 31, 2017
• First Posted: November 6, 2017
• Study Start: November 15, 2017
• Primary Completion: January 7, 2019
• Study Completion: June 21, 2021
• Last Updated: March 28, 2023
• Results First Posted: March 28, 2023

Record last verified: 2022-06

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 (8)