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

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ClinicalTrials.gov Identifier: NCT03330106
Recruitment Status : Active, not recruiting
First Posted : November 6, 2017
Last Update Posted : July 12, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

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).

Condition or disease Intervention/treatment Phase
Advanced Solid Neoplasm Drug: Pevonedistat Drug: Docetaxel Drug: Carboplatin Drug: Paclitaxel Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 44 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: A Randomized, Crossover Phase 1 Study to Evaluate the Effects of Pevonedistat on the QTc Interval in Patients With Advanced Solid Tumors
Actual Study Start Date : November 15, 2017
Actual Primary Completion Date : January 7, 2019
Estimated Study Completion Date : December 31, 2019

Arm Intervention/treatment
Experimental: Part A: Pevonedistat 25 mg/m^2 + Pevonedistat 50 mg/m^2
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
Pevonedistat intravenous infusion.
Other Name: MLN4924, TAK-924

Experimental: Part A: Pevonedistat 50 mg/m^2 + Pevonedistat 25 mg/m^2
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
Pevonedistat intravenous infusion.
Other Name: MLN4924, TAK-924

Experimental: Part B: Pevonedistat
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
Pevonedistat intravenous infusion.
Other Name: MLN4924, TAK-924

Drug: Docetaxel
Docetaxel intravenous infusion.

Drug: Carboplatin
Carboplatin intravenous infusion.

Drug: Paclitaxel
Paclitaxel intravenous infusion.




Primary Outcome Measures :
  1. Part A: Change From Time-matched Baseline in QTcF Post-dose Pevonedistat on Day 1 [ Time Frame: Baseline and Day 1 ]
    Change from time-matched baseline in QTcF will be assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m^2.

  2. Part A: Change From Time-matched Baseline in QTcF Post-dose Pevonedistat on Day 8 [ Time Frame: Baseline and Day 8 ]
    Change from time-matched baseline in QTcF will be assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m^2.


Secondary Outcome Measures :
  1. Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI), QRS, PR, and HR Post-dose Pevonedistat on Days 1 and 8 [ Time Frame: Baseline, Day 1 and 8 ]
    Change from time-matched baseline in QTcI, QRS, PR, and HR will be assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m^2.

  2. Part A: Cmax: Maximum Observed Plasma Concentration for Pevonedistat [ Time Frame: Days 1 and 8 pre-dose and at multiple time points (up to 24 hours) post-dose ]
  3. Part A: AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Postdose for Pevonedistat [ Time Frame: Days 1 and 8 pre-dose and at multiple time points (up to 24 hours) post-dose ]
  4. Part A: Terminal Phase Elimination Half-life (T1/2) for Pevonedistat [ Time Frame: Days 1 and 8 pre-dose and at multiple time points (up to 24 hours) post-dose ]
  5. Part B: Objective Response Rate [ Time Frame: Baseline up to 12 months ]
    Percentage of participants who achieve an objective response per investigator's assessment at end of treatment, according to the 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 less than(<) 10 millimeter(mm).Partial Response (PR):at least 30 percent(%)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: at least 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 at least 5 mm. Appearance of 1 or more new lesions is also considered progression.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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.
  2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
  3. Expected survival longer than 3 months from enrollment in the study.
  4. Recovered (that is, grade less than or equal to [<=] 1 toxicity) from the reversible effects of prior anticancer therapy.
  5. Suitable venous access for the study-required blood sampling (including pharmacokinetic [PK] sampling).

Exclusion Criteria:

  1. 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.
  2. 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.
  3. History of Brugada syndrome, risk factors for TdP, or family history of long QT syndrome.
  4. Implantable cardioverter defibrillator.
  5. 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).
  6. Known moderate to severe aortic stenosis, moderate to severe mitral stenosis, or other valvulopathy (ongoing).
  7. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03330106


Locations
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United States, California
Sarcoma Oncology Center
Santa Monica, California, United States, 90403
United States, Florida
Moffitt Cancer Center
Tampa, Florida, United States, 33612
United States, Michigan
Henry Ford Hospital
Detroit, Michigan, United States, 48202
United States, New York
Montefiore Medical Center
Bronx, New York, United States, 10467
United States, Ohio
Case Western Reserve University
Cleveland, Ohio, United States, 44106
United States, Oklahoma
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States, 23801
United States, Texas
Mary Crowley Medical Research
Dallas, Texas, United States, 75231
United States, Virginia
Virginia Cancer Specialists
Fairfax, Virginia, United States, 22031
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
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Study Director: Medical Director Millennium Pharmaceuticals, Inc.

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Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03330106     History of Changes
Other Study ID Numbers: Pevonedistat-1014
2017-002610-31 ( EudraCT Number )
U1111-1201-10111 ( Registry Identifier: WHO )
First Posted: November 6, 2017    Key Record Dates
Last Update Posted: July 12, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available after applicable marketing approvals and commercial availability have been received, an opportunity for the primary publication of the research has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com/Approach for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Drug therapy

Additional relevant MeSH terms:
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Paclitaxel
Docetaxel
Albumin-Bound Paclitaxel
Carboplatin
Pevonedistat
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors