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Dose Escalation, Multi-arm Study of MLN4924 Plus Docetaxel, Gemcitabine, or Combination of Carboplatin and Paclitaxel in Participants With Solid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01862328
Recruitment Status : Completed
First Posted : May 24, 2013
Results First Posted : June 22, 2020
Last Update Posted : June 22, 2020
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Brief Summary:
The purpose of this study is to establish the maximum tolerated dose (MTD) and assess the safety and tolerability of MLN4924 (pevonedistat) in combination with docetaxel, paclitaxel and carboplatin, and gemcitabine in participants with solid tumors.

Condition or disease Intervention/treatment Phase
Solid Tumors Drug: MLN4924 Drug: Paclitaxel Drug: Gemcitabine Drug: Docetaxel Drug: Carboplatin Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 64 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: A Phase 1b, Open-Label, Dose Escalation, Multi-arm Study of MLN4924 Plus Docetaxel, Gemcitabine, or Combination of Carboplatin and Paclitaxel in Patients With Solid Tumors
Actual Study Start Date : June 10, 2013
Actual Primary Completion Date : May 21, 2018
Actual Study Completion Date : May 21, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: MLN4924 and Docetaxel (Arm 1) Drug: MLN4924

MLN4924 (intravenously [IV]) in participants in a 21-day cycle:

  • MLN4924 on Days 1,3,5 of each cycle
Other Name: Pevonedistat

Drug: Docetaxel

Docetaxel (IV) in participants in a 21-day cycle:

- Docetaxel on Day 1 of each cycle


Experimental: MLN4924 + Paclitaxel + Carboplatin (Arm 2) Drug: MLN4924

MLN4924 (intravenously [IV]) in participants in a 21-day cycle:

  • MLN4924 on Days 1,3,5 of each cycle
Other Name: Pevonedistat

Drug: Paclitaxel

Paclitaxel (IV) in a 21-day cycle:

  • Paclitaxel on Day 1 of each cycle

Drug: Carboplatin

Carboplatin (IV) in participants in a 21-day cycle:

- Carboplatin on Day 1 of each cycle


Experimental: MLN4924 + Gemcitabine (Arm 3) Drug: MLN4924

MLN4924 (intravenously [IV]) in participants in a 21-day cycle:

  • MLN4924 on Days 1,3,5 of each cycle
Other Name: Pevonedistat

Drug: Gemcitabine

Gemcitabine (IV) in participants in a 28-day cycle:

-Gemcitabine on Days 1,8,15 of each cycle





Primary Outcome Measures :
  1. Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 30 days after the last dose of study drug (up to 5 years) ]
  2. Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings [ Time Frame: Baseline up to 30 days after the last dose of study drug (up to 5 years) ]
  3. Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings [ Time Frame: Baseline up to 30 days after the last dose of study drug (up to 5 years) ]

Secondary Outcome Measures :
  1. Percentage of Participants With Objective Response [ Time Frame: Screening, Cycle 2 Days 15 (Arm 1, 2a, and 2) and 22 (Arm 3) then every other Cycle thereafter up to 30 days after the last dose of study drug (up to 5 years) (Cycle Length = 21 days [Arm 1, 2a, and 2] and 28 days [Arm 3]) ]
    Percentage of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: complete disappearance of all target lesions and non-target disease, with exception of nodal disease; all nodes, both target and non-target, must decrease to normal (short axis less than [<] 10 millimeter [mm]); no new lesions. PR: greater than or equal to (>=) 30 percent (%) decrease under baseline of sum of diameters of all target lesions; short axis was used in sum for target nodes, while longest diameter was used in sum for all other target lesions; no unequivocal progression of non-target disease; no new lesions.

  2. Duration of Response [ Time Frame: From the date of first documented response (CR or PR) to the date of first documented PD or the date of last disease assessment if the participants discontinued the study before PD (up to 5 years) ]
    Duration of response: time from the date of first documented response per the investigator response assessment (CR or PR) to the date of PD or the date of last disease assessment if the participant discontinued the study before PD using RECIST 1.1 CR: complete disappearance of all target lesions and non-target disease, with exception of nodal disease; all nodes, both target and non-target, must decrease to normal (short axis <10 mm); no new lesions. PR: >=30% decrease under baseline of sum of diameters of all target lesions; short axis was used in sum for target nodes, while longest diameter was used in sum for all other target lesions; no unequivocal progression of non-target disease; no new lesions. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in sum of diameters of target lesions, taking as reference smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.

  3. Dose-escalation Phase: Plasma Concentrations-time Data of MLN4924 [ Time Frame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 20 hours) post-dose (Cycle Length=21 days [Arm 1 and 2] and 28 days [Arm 3]) ]
  4. MTD Expansion Phase: Plasma Concentrations-time Data of MLN4924 [ Time Frame: Cycle 1 Days 1 and 5 pre-dose and at multiple time points (up to 20 hours) post-dose (Cycle Length=21 days [Arm 1 and 2]) ]
    The number of participants analyzed includes only those participants who had data available for this measure.



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. 18 years of age or older
  2. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1
  3. Have a histologically or cytologically confirmed metastatic or locally advanced and incurable solid tumor that is felt to be appropriate for treatment with 1 of the 3 chemotherapy regimens in this study, or have progressed despite standard therapy, or for whom conventional therapy is not considered effective. The tumor must be radiographically or clinically evaluable and/or measurable
  4. Recovered (that is, <=Grade 1 toxicity) from the effects of prior antineoplastic therapy
  5. Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to practice true abstinence
  6. Male participants who agree to practice effective barrier contraception or agree to practice true abstinence
  7. Voluntary written consent must be given before performance of any study-related procedure
  8. Suitable venous access for the study-required blood sampling
  9. Adequate clinical laboratory values during the screening period as specified in the protocol
  10. Participants who are willing to refrain from donating blood for at least 90 days after their final dose of MLN4924 and (for male participants) willing to refrain from donating semen for at least 4 months after their final dose of MLN4924
  11. Availability of fixed tumor specimen (block or slides) for exploratory biomarker analysis. If no slides or block are available, fresh tumor biopsies should be obtained and used for these assessments

Exclusion Criteria:

  1. Major surgery within 14 days before the first dose of study drug
  2. Female participants who are lactating or pregnant
  3. Active uncontrolled infection or severe infectious disease
  4. Receiving antibiotic therapy within 14 days before the first dose of study treatment
  5. Life-threatening illness unrelated to cancer
  6. Known hypersensitivity to study-assigned chemotherapy
  7. Prior treatment with MLN4924; however, prior treatment with docetaxel, paclitaxel,carboplatin, and gemcitabine is allowed
  8. History of severe hypersensitivity reactions to docetaxel (polysorbate 80-based formulations) for participants to be enrolled in Arm 1 (MLN4924 + docetaxel), history of hypersensitivity to carboplatin for participants to be enrolled in Arm 2 (MLN4924 + paclitaxel + carboplatin), or history of severe hypersensitivity to paclitaxel (cremophor-based formulations) for participants to be enrolled in Arm 2
  9. Persistent diarrhea (greater than Grade 2) lasting >3 days within 2 weeks before the first dose of study treatment
  10. Systemic antineoplastic therapy within 21 days before the first dose of study drug
  11. Radiotherapy within 14 days preceding the first dose of study treatment
  12. Prior treatment with radiation therapy involving greater than or equal to (>=) 25% of the hematopoietically active bone marrow
  13. Treatment with cytochrome P450 3A (CYP3A) inducers within 14 days before the first dose of MLN4924.

Treatment with CYP3A inhibitors within 14 days before the first dose of MLN4924; however, voriconazole and fluconazole need only be stopped for 3 days before MLN4924. Participants must have no history of amiodarone use in the 6 months before the first dose of MLN4924 14. Clinically uncontrolled central nervous system (CNS) involvement 15. Any serious medical or psychiatric illness 16. Treatment with any investigational products 21 days prior to treatment 17. Unwilling or unable to refrain from using statins 24 hours before, the day of, and 24 hours after each MLN4924 administration 18. Known human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection 19. Known hepatic cirrhosis 20. Known cardiac/cardiopulmonary disease 21. Left ventricular ejection fraction 23. with a cardiac pacer whose heart rate is set at a fixed rate and participants on concomitant medication that may limit increase in heart rate in response to hypotension 24 History of severe intolerance to cytotoxic agent(s) given in the assigned arm


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): NCT01862328


Locations
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United States, Georgia
Atlanta, Georgia, United States, 30322
United States, Missouri
Saint Louis, Missouri, United States, 63110
United States, North Carolina
Chapel Hill, North Carolina, United States, 27599
United States, Ohio
Cleveland, Ohio, United States, 44106-4948
United States, Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
Nashville, Tennessee, United States, 37203
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
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Study Director: Medical Monitor Millennium Pharmaceuticals, Inc.
  Study Documents (Full-Text)

Documents provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Statistical Analysis Plan  [PDF] March 22, 2016
Study Protocol  [PDF] October 17, 2017

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT01862328    
Other Study ID Numbers: C15010
U1111-1220-1470 ( Other Identifier: WHO )
First Posted: May 24, 2013    Key Record Dates
Results First Posted: June 22, 2020
Last Update Posted: June 22, 2020
Last Verified: June 2020
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 for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com 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.
Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
MLN4924
Solid Tumors
Additional relevant MeSH terms:
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Neoplasms
Gemcitabine
Paclitaxel
Docetaxel
Carboplatin
Pevonedistat
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs