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Effect of MLN0128 on the QTc Interval in Participants With Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT02197572
Recruitment Status : Completed
First Posted : July 22, 2014
Last Update Posted : March 22, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Brief Summary:
The purpose of this study is to characterize the effect of a single dose of 40 mg MLN0128 on the electrocardiographic QT/QTc interval in participants with advanced solid tumors.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Drug: MLN0128 Phase 1

Detailed Description:

The drug being tested in this study is called MLN0128. MLN0128 is being tested to determine the effect of a single 40 mg dose on the electrocardiographic measure of the time between the start of the Q wave and the end of the T wave in the electrical cycle of the heart (QT)/rate corrected QT (QTc) interval in patients with advanced solid tumors. This study will look at electrocardiogram (ECG) results before and after a single dose of MLN0128.

The study will enroll approximately 30 patients. All participants will receive a single 40 mg dose of MLN0128 capsules on Day 1. To avoid nausea and vomiting, participants will also be administered 0.25 mg palonosetron on Day 1 as an antiemetic agent. Participants may continue to receive MLN0128 for up to 1 year at a dose of up to 30 mg once weekly if a clinical benefit is being derived.

This multi-centre trial will be conducted in the United States. The overall time to participate in this study is up to 14 months. Participants will make 6 visits to the clinic including and end of study visit 30 to 40 days after last dose of study drug for a follow-up assessment. Participants that continue treatment with MLN0128 will continue to make additional visits to the clinic once or twice every 4 weeks and the end of study visit 30 to 40 days after last dose of study drug for a follow-up assessment.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 44 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study to Evaluate the Effect of MLN0128 on the QTc Interval in Patients With Advanced Solid Tumors
Actual Study Start Date : September 15, 2014
Actual Primary Completion Date : June 10, 2016
Actual Study Completion Date : February 28, 2019

Arm Intervention/treatment
Experimental: MLN0128
MLN0128 40 mg, capsules, orally, once, on Day 1, Cycle 1. MLN0128 may be continued at the discretion of the investigator at a dose of up to 30 mg, capsules, orally, once weekly (QW) until disease progression, unacceptable MLN0128-related toxicity, withdrawal of consent, or for up to 12 months (whichever occurs first).
Drug: MLN0128
MLN0128 capsules




Primary Outcome Measures :
  1. Change from Time-Matched Baseline in Individual Baseline Corrected Rate-Corrected QT Interval (QTcI) at Cycle 1 Day 1 [ Time Frame: From time-matched baseline to Day 1, Cycle 1 of a 28-day cycle predose and up to 48hours postdose ]
    Holter monitors will be used to collect triplicate electrocardiogram (ECG) measurements.


Secondary Outcome Measures :
  1. Number of Participants With Adverse Events (AEs) [ Time Frame: From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 13 months) ]

    An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment.

    Serious adverse event (SAE) means any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug will be determined by the Investigator.


  2. Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings [ Time Frame: From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 13 months) ]
  3. Number of Participants With Potentially Clinically Significant Vital Signs Findings [ Time Frame: From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 13 months) ]
  4. Change from Time-Matched Baseline in QTc with Rate-Corrected QT Interval (millisec) with Bazett Correction (QTcB) at Cycle 1 Day 1 [ Time Frame: From time-matched baseline to Day 1, Cycle 1 of a 28-day cycle predose and up to 48 hours postdose ]
    Holter monitors will be used to collect triplicate electrocardiogram (ECG) measurements.

  5. Change from Time-Matched Baseline in QTc with Rate-Corrected QT interval (millisec) Fridericia Correction (QTcF) at Cycle 1 Day 1 [ Time Frame: From time-matched baseline to Day 1, Cycle 1 of a 28-day cycle predose and up to 48 hours postdose ]
    Holter monitors will be used to collect triplicate electrocardiogram (ECG) measurements.

  6. Change from Time-Matched Baseline in QRS Interval at Cycle 1 Day 1 [ Time Frame: From time-matched baseline to Day 1, Cycle 1 of a 28-day cycle predose and up to 48 hours postdose ]
    Holter monitors will be used to collect triplicate electrocardiogram (ECG) measurements.

  7. Change from Time-Matched Baseline in PR Interval at Cycle 1 Day 1 [ Time Frame: From time-matched baseline to Day 1, Cycle 1 of a 28-day cycle predose and up to 48 hours postdose ]
    Holter monitors will be used to collect triplicate electrocardiogram (ECG) measurements.

  8. Change from Time-Matched Baseline in Heart Rate at Cycle 1 Day 1 [ Time Frame: From time-matched baseline to Day 1, Cycle 1 of a 28-day cycle ]
  9. Cmax: Maximum Observed Plasma Concentration for MLN0128 [ Time Frame: Cycle 1, Day 1 predose and up to 48 hours postdose ]
    Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.

  10. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 [ Time Frame: Cycle 1, Day 1 predose and and up to 48 hours postdose ]
    Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.

  11. AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128 [ Time Frame: Cycle 1, Day 1 predose and up to 48 hours postdose ]
    (AUC(0-tlqc) is a measure of total plasma exposure to the drug from time 0 to time of the last quantifiable concentration (AUC[0-tlqc]).

  12. AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 [ Time Frame: Cycle 1, Day 1 predose and up to 48 hours postdose ]
    AUC(0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity.

  13. Terminal Elimination Half-life (T1/2) Pharmacokinetic Parameter for MLN0128 [ Time Frame: Cycle 1, Day 1 predose and up to 48 hours postdose ]
    Terminal Phase Elimination Half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.



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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. Men or women participants 18 years or older.
  2. Must have a radiographically or clinically evaluable solid tumor Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  3. Female participants who:

    • Are postmenopausal for at least 1 year before the screening visit, OR
    • Are surgically sterile, OR
    • If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 3 months after the last dose of study drug, OR
    • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)
  4. Male participants, even if surgically sterilized (ie, status postvasectomy), who:

    • Agree to practice effective barrier contraception during the entire study treatment period and through 3 months after the last dose of study drug, or
    • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.)
  5. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
  6. Ability to swallow oral medications, willingness to perform mucositis prophylaxis, and suitable venous access for the study-required blood sampling.

Exclusion Criteria

  1. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the screening period.
  2. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
  3. Treatment with any investigational products within 14 days before the first dose of study drug and systemic anticancer therapy within 28 days before the first dose of study drug.
  4. Untreated brain metastasis or history of leptomeningeal disease or spinal cord compression.
  5. Tumors with involvement of the mediastinum.
  6. Failure to recover from the reversible effects of prior anticancer therapies with the exception of alopecia, and after-effects associated with prior tyrosine kinase inhibitor therapy such as hair depigmentation, hypothyroidism, and/or splinter hemorrhage.
  7. Systemic corticosteroid (inhalers are allowed) within 7 days before the first dose of study drug.
  8. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown or other reason that may alter the absorption of MLN0128.
  9. Diagnosis of diabetes mellitus; participants with a history of transient glucose intolerance due to corticosteroid administration may be enrolled if all other inclusion/exclusion criteria are met.
  10. Significant active cardiovascular or pulmonary disease at study entry

    ◦ History of arrhythmia requiring an implantable cardiac defibrillator

  11. Clinically significant comorbidities such as uncontrolled pulmonary disease, active central nervous system disease, active infection, serious infection within 14 days before the first dose of study drug, or any other condition that could compromise study participation by the participant.

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): NCT02197572


Locations
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United States, Florida
Sarasota, Florida, United States
United States, Missouri
Saint Louis, Missouri, United States
United States, New York
Bronx, New York, United States
United States, Oklahoma
Oklahoma City, Oklahoma, United States
United States, Texas
Dallas, Texas, United States
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
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Study Director: Medical Director Clinical Science Millennium Pharmaceuticals, Inc.

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Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02197572     History of Changes
Other Study ID Numbers: C31002
U1111-1156-4099 ( Other Identifier: World Health Organization )
First Posted: July 22, 2014    Key Record Dates
Last Update Posted: March 22, 2019
Last Verified: March 2019

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