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A Study of [14 C]-Pevonedistat in Participants With Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT03057366
Recruitment Status : Completed
First Posted : February 20, 2017
Last Update Posted : November 14, 2018
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Brief Summary:
The purpose of this study is to assess the mass balance (that is, cumulative excretion of total radioactivity [TRA] in urine and feces) of pevonedistat following a single 1-hour infusion of 25 milligram per square meter (mg/m^2) [14C]-pevonedistat intravenous (IV) solution containing approximately 60 to 85 microcurie (mCi) (approximately 2.22-3.145 megabecquerel [MBq]) of TRA in participants with advanced solid tumors in Part A.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors, Neoplasms, Advanced Solid Drug: Pevonedistat Drug: [14C]-Pevonedistat Drug: Docetaxel Drug: Carboplatin Drug: Paclitaxel Phase 1

Detailed Description:

The drug being tested in this study is called Pevonedistat. Pevonedistat is being tested to treat people with advanced solid tumors.

The study will enroll approximately 4 to 6 pharmacokinetics (PK)-evaluable participants in part A. After completion of the mass balance and absorption, distribution, metabolism, excretion (ADME) assessment in Part A of the study, eligible participants will have the opportunity to continue into Part B at a secondary study site, which would begin in approximately 2 weeks of completion of Part A.

  • Part A: Pevonedistat 25 mg/m^2
  • Part B (optional): Pevonedistat in combination with chemotherapy regimens (Pevonedistat 25 mg/m^2 + docetaxel 75 mg/m^2 or pevonedistat 20 mg/m^2 + carboplatin 20 mg/m^2 + paclitaxel 175 mg/m^2)

All participants will receive study drug via intravenous route. This multi-center trial will be conducted in Hungary. Participants will remain confined to the study site for 9 to 14 days in Part A. Participation in Part B is optional, participants will be re-evaluated for inclusion/exclusion criteria before administrating treatment. Participants will undergo treatment in Part B for a maximum of 12 cycles (21 days cycle each) and will include approximately 36 weeks for Part A and B combined. Participants will attend an end of study visit 30 days after the last dose of study drug in both Part A and B.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: A Phase 1 Study to Assess Mass Balance, Pharmacokinetics, and Metabolism of [14C]-Pevonedistat in Patients With Advanced Solid Tumors
Actual Study Start Date : May 11, 2017
Actual Primary Completion Date : February 8, 2018
Actual Study Completion Date : November 5, 2018

Arm Intervention/treatment
Experimental: [14C]-Pevonedistat 25 mg/m^2
[14C]-pevonedistat (containing approximately 60-98 mCi [approximately 2.22-3.626 MBq] of radioactive tracer), infusion, intravenously, single dose on Day 1 of Week 1 in Part A. After completion of Part A, participants will have opportunity to continue into Part B. Participant will receive Pevonedistat 25 mg/m^2, infusion, intravenously, single dose on Days 1, 3 and 5 of each 21 day cycle, for up to 12 cycles along with docetaxel 75 mg/m^2, infusion, intravenously, over 1 hour on Day 1 of each 21 day cycle; or pevonedistat 20 mg/m^2, infusion, intravenously, single dose on Days 1, 3 and 5 of each 21 day cycle, for up to 12 cycles, followed by paclitaxel 175 mg/m^2, infusion, intravenously, over 3 hours along with carboplatin 20 mg/m^2, infusion, intravenously, over 30 minutes on Day 1 of 21 each cycle up to 12 cycles.
Drug: Pevonedistat
Pevonedistat intravenous infusion
Other Name: MLN4924; TAK-924

Drug: [14C]-Pevonedistat
[14C]-Pevonedistat intravenous infusion

Drug: Docetaxel
Docetaxel intravenous infusion

Drug: Carboplatin
Carboplatin intravenous infusion

Drug: Paclitaxel
Paclitaxel intravenous infusion




Primary Outcome Measures :
  1. Part A: Cmax: Maximum Observed Plasma Concentration for Pevonedistat [ Time Frame: Up to 168 hours post-dose ]
    Cmax is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.

  2. Part A: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Pevonedistat [ Time Frame: Up to 168 hours post-dose ]
    Tmax is the time to reach the Cmax, equal to time (hours) to Cmax.

  3. Part A: AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Pevonedistat [ Time Frame: Up to 168 hours post-dose ]
    AUClast is the area under the plasma concentration-time curve from time zero to time of the last quantifiable concentration.

  4. Part A: Cmax: Maximum Observed Plasma and Whole Blood TRA Concentration for [14C]-Pevonedistat [ Time Frame: Up to 168 hours post-dose ]
    Cmax is the peak concentration of a drug after administration, obtained directly from the concentration-time curve.

  5. Part A: Tmax: Time to Reach the Maximum Plasma and Whole Blood TRA Concentration (Cmax) for [14C]-Pevonedistat [ Time Frame: Up to 168 hours post-dose ]
    Tmax is the time to reach the Cmax, equal to time (hours) to Cmax.

  6. Part A: AUClast: Area Under the Plasma and Whole Blood TRA Concentration Curve From Time 0 to Time of the Last Quantifiable Concentration for [14C]-Pevonedistat [ Time Frame: Up to 168 hours post-dose ]
    Area under the concentration curve from time zero to time of the last quantifiable concentration.

  7. Part A: Cumulative Amount of [14C]-Pevonedistat Excreted in Urine up to the Last Sampling Interval (Aeurine,14C) [ Time Frame: Up to 168 hours post-dose ]
    Aeurine,14C is a measure of the cumulative amount of drug excreted in the urine up to the last sampling interval for 168 hours post-dose.

  8. Part A: Aefeces,14C: Cumulative Amount of [14C]-Pevonedistat Excreted in Feces up to the Last Sampling Interval [ Time Frame: Up to 168 hours post-dose ]
    Aefeces,14C is a measure of the cumulative amount of drug excreted in the feces up to the last sampling interval for 168 hours post-dose.

  9. Part A: Aetotal,14C: Total Cumulative Excretion of [14C]-Pevonedistat From the Body [ Time Frame: Up to 168 hours post-dose ]
    Total cumulative excretion of drug from the body is calculated as Aetotal,14C=Aeurine,14C+Aefeces,14C.

  10. Part A: Aeurine,t: Cumulative Amount of Pevonedistat Excreted in Urine [ Time Frame: Up to 168 hours post-dose ]
    Aeurine,t is a cumulative amount of drug excreted in urine for 168 hours post-dose.

  11. Part A: Percentage of Dose Excreted in Urine [ Time Frame: Up to 168 hours post-dose ]
    The percentage of drug dose excreted into the urine is calculated as (amount of pevonedistat excreted in urine divided by dose)∗100.

  12. Part A: Renal Clearance (CLR) for Pevonedistat [ Time Frame: Up to 168 hours post-dose ]
    CLR is a measure of apparent clearance of the drug from the urine.


Secondary Outcome Measures :
  1. Number of Participants Reporting one or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Part A: Baseline up to Day 31; Part B: Cycle 1 Day 1 up to Cycle 12 Day 35 ]
    An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. A SAE is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is a medically important event.

  2. Number of Participants With Markedly Abnormal Laboratory Values [ Time Frame: Part A: Baseline up to Day 31; Part B: Cycle 1 Day 1 up to Cycle 12 Day 35 ]
    The number of participants with any markedly abnormal standard safety laboratory values collected throughout study.

  3. Part A: Relative Percentage of Circulatory and Excretory Metabolites [ Time Frame: Up to 168 hours post-dose ]
    Determination of relative percentage of circulatory and excretory metabolites.

  4. Part B: Best Overall Response [ Time Frame: Within 28 days of Cycle 1 Day 1 of Part B (Baseline), end of Cycle 2, and every 3 cycles thereafter (up to 36 weeks) ]
    Overall response is the percentage of participants with complete response (CR) and partial response (PR) based on modified Response Evaluation Criteria in Solid Tumors (RECIST). Evaluation of target lesions includes CR: disappearance of all target lesions, PR: at least a 30 percent (%) decrease in the sum of the diameters of target lesions. Evaluation of non-target lesions includes CR: disappearance of all non-target lesions and normalization of tumor marker level, non-CR/non-PD (progressive disease): persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits and PD: appearance of one or more new lesions and/or unequivocal progression of existing non target lesions.



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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. Have a histologically or cytologically confirmed metastatic or locally advanced and incurable solid tumor that is felt to be appropriate for treatment with one of the 2 chemotherapy regimens in Part B of this study (carboplatin+paclitaxel or docetaxel), or have progressed despite prior standard therapy, or for whom conventional therapy is not considered effective. The tumor must be radiographically or clinically evaluable and/or measurable.
  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, less than or equal to [<=] Grade 1 toxicity) from the effects of prior antineoplastic therapy.

Exclusion Criteria:

  1. Has irregular defecation patterns (less than 1 defecation per 2 days or excessive diarrhea) and/or has a history of changes in bowel habits with daily routine or environment changes.
  2. Prior treatment with radiation therapy involving greater than or equal to (>=) 25% of the hematopoietically active bone marrow.

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): NCT03057366


Locations
Hungary
Magyar Honvédség Egészségügyi Központ Onkológiai osztály
Budapest, Hungary, 1062
PRA Magyarország Kft. Fázis I-es Klinikai Farmakológiai Vizsgálóhely
Budapest, Hungary, 1076
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
Study Director: Medical Director Millennium Pharmaceuticals, Inc.

Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03057366     History of Changes
Other Study ID Numbers: Pevonedistat-1013
U1111-1169-6648 ( Registry Identifier: WHO )
2016-004132-37 ( EudraCT Number )
First Posted: February 20, 2017    Key Record Dates
Last Update Posted: November 14, 2018
Last Verified: November 2018

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

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

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