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Advanced Solid NeoplasmPhase 1NCT03330106

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

A Phase 1 study testing Pevonedistat, Docetaxel and Carboplatin in people with Advanced Solid Neoplasm, run by Millennium Pharmaceuticals, Inc. at 8 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Advanced Solid Neoplasm
What is being tested?
Pevonedistat, Docetaxel and Carboplatin
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
68 participants
Where
8 sitesUnited States
Study dates
15 Nov 2017to 21 Jun 2021
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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).

Who cannot join

  • 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).
Show all 16Show fewer
  • 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).
  • Computed tomography (CT) scan or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis within 28 days of Cycle 1 Day 1.

Trial locations and contacts

8 sites in 1 country.

8 sites in 1 country

United States8 sites

  • Case Western Reserve University

    Cleveland, Ohio, 44106

  • Mary Crowley Medical Research

    Dallas, Texas, 75231

  • Henry Ford Hospital

    Detroit, Michigan, 48202

  • Virginia Cancer Specialists

    Fairfax, Virginia, 22031

  • University of Oklahoma Health Sciences Center

    Oklahoma City, Oklahoma, 23801

  • Sarcoma Oncology Center

    Santa Monica, California, 90403

  • Moffitt Cancer Center

    Tampa, Florida, 33612

  • Montefiore Medical Center

    The Bronx, New York, 10467

Other trials in United States

About this study

Official title: A Randomized, Crossover Phase 1 Study to Evaluate the Effects of Pevonedistat on the QTc Interval in Patients With Advanced Solid Tumors

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).

Read the detailed description

The drug being tested in this study is called pevonedistat. Pevonedistat in combination with standard of care will be used to treat participants who have advanced solid tumors. This study will assess the effects of pevonedistat on the QTc interval in participants with advanced solid tumors.

The study will enroll approximately 45 participants. The study will be conducted in two Parts: Part A and Part B. Part A will have a 2-way crossover design and will involve the collection of triplicate ECGs. In Part A, participants will be randomly assigned to one of the two treatment groups as follow:

  • Pevonedistat 25 mg/m^2 + Pevonedistat 50 mg/m^2
  • Pevonedistat 50 mg/m^2 + Pevonedistat 25 mg/m^2

Eligible participants from Part A will continue treatment in optional Part B with pevonedistat in combination with SoC, docetaxel or carboplatin plus paclitaxel. The investigator will decide which pevonedistat combination a participant will receive.

  • Pevonedistat 25 mg/m^2 + Docetaxel
  • Pevonedistat 20 mg/m^2 + Carboplatin + Paclitaxel

This multi-center trial will be conducted in the United States. The overall time to participate in this study is 9.6 months. Participants will make a final visit to the clinic 30 days after receiving their last dose of study drug for a follow-up assessment.

Being tested
Pevonedistat, Docetaxel, Carboplatin, Paclitaxel
Keywords
Drug therapy

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PevonedistatDrug

    Also called MLN4924, TAK-924

    Pevonedistat intravenous infusion.

  • DocetaxelDrug

    Docetaxel intravenous infusion.

  • CarboplatinDrug

    Carboplatin intravenous infusion.

  • PaclitaxelDrug

    Paclitaxel intravenous infusion.

Study groups in NCT03330106
Study groupRoleWhat they receive
Part A: Pevonedistat 25 mg/m^2 + Pevonedistat 50 mg/m^2ExperimentalPevonedistat 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.
Receives: Drug: Pevonedistat
Part A: Pevonedistat 50 mg/m^2 + Pevonedistat 25 mg/m^2ExperimentalPevonedistat 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.
Receives: Drug: Pevonedistat
Part B: PevonedistatExperimentalPevonedistat 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.
Receives: Drug: Pevonedistat; Drug: Docetaxel; Drug: Carboplatin; Drug: Paclitaxel

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Baseline up to Day 8

Secondary outcomes (8)

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

    Change from time-matched baseline in QTcI 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. ANOVA was used for the analysis.

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

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

    Change from time-matched baseline in QRS 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. ANOVA was used for the analysis.

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

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

    Change from time-matched baseline in PR 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. ANOVA was used for the analysis.

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

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

    Change from time-matched baseline in HR 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. ANOVA was used for the analysis.

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

  5. Part A: Cmax: Maximum Observed Plasma Concentration for Pevonedistat

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

  6. Part A: AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Postdose for Pevonedistat

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

  7. Part A: Terminal Phase Elimination Half-life (t1/2) for Pevonedistat

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

  8. Part B: Overall Response Rate (ORR)

    Percentage of participants who achieve an overall response per investigator's assessment at end of treatment,according to Response Evaluation Criteria in Solid Tumor(RECIST),version 1.1 guideline. Complete response(CR):Disappearance of all target lesions.Any pathological lymph nodes(whether target and non target)must have reduction in short axis to <10 millimeter(mm).Partial Response(PR):atleast 30% decrease in sum of diameter of target lesions,taking as reference baseline sum of diameter.Stable Disease(SD):Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression(PD),taking as reference smallest sum of diameter; PD:atleast 20% increase in sum of diameter of target lesions,taking as reference,smallest sum on study(this includes baseline sum if that is smallest on study).In addition to relative increase of 20%,sum must also demonstrate an absolute increase of atleast 5 mm.Appearance of 1 or more new lesions is also considered progression.

    Measured: Up to Cycle 45 (end of treatment) (Cycle length=21 days)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Nov 2017
  2. Study start15 Nov 2017
  3. Primary completion7 Jan 2019
  4. Study completion21 Jun 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Other
Allocation
Randomised
Intervention model
Crossover
Masking
None (open label)
Enrolment
68 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03330106
Sponsor's protocol ID
Pevonedistat-1014
Other IDs
2017-002610-31, U1111-1201-10111, 2017
Status last verified
Jun 2022
First submitted
31 Oct 2017
Last updated
28 Mar 2023
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: 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.

Publications

  • 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.

    PubMed 36382849

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Pevonedistat, Docetaxel and Carboplatin in people with Advanced Solid Neoplasm, run by Millennium Pharmaceuticals, Inc. at 8 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 8 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 Mar 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration (time frame: Baseline up to Day 8). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03330106, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Mar 2023.

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