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Effect of Sapanisertib (MLN0128) on the QTc Interval in Participants With Advanced 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: NCT02197572
Recruitment Status : Completed
First Posted : July 22, 2014
Results First Posted : March 3, 2020
Last Update Posted : March 3, 2020
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 sapanisertib (MLN0128) on the electrocardiographic QT/QTc interval in participants with advanced solid tumors.

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

Detailed Description:

The drug being tested in this study is called sapanisertib (MLN0128). Sapanisertib 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 sapanisertib.

The study will enroll approximately 30 patients. All participants will receive a single 40 mg dose of sapanisertib capsules on Day 1. Participants may continue to receive sapanisertib 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 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 sapanisertib 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
Allocation: N/A
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: Sapanisertib
Sapanisertib starting dose of 40 mg, capsules, orally, once, on Day 1, Cycle 1 (28 days cycle) followed by sapanisertib 30 mg, capsules, orally, once weekly (QW) starting on Cycle 1, Day 8 based on safety and tolerability and as per investigator's discretion up to disease progression, unacceptable sapanisertib-related toxicity, withdrawal of consent, or for up to 12 months (whichever occurred first).
Drug: Sapanisertib
Sapanisertib capsules.
Other Names:
  • MLN0128
  • INK128
  • TAK-228




Primary Outcome Measures :
  1. Mean Change From Time-Matched Baseline in QTcI, Individual Baseline Corrected Rate-Corrected QT Interval [ Time Frame: Baseline; Cycle 1 (28 days cycle): 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24 and 48 hours postdose ]
    The mean changes of QTcI from time-matched baseline was measured by electrocardiogram (ECG) to evaluate the potential effect of drug on QTc interval duration. Holter monitors were used to collect triplicate ECG measurements and were based on a repeated measures mixed effects linear model. A negative change from baseline indicates shortening and a positive change from baseline indicates prolongation of QTcI interval.


Secondary Outcome Measures :
  1. Number of Participants With Atleast One Adverse Event (AE) and Serious Adverse Event (SAE) [ Time Frame: From first dose of study drug 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 clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent.

  2. Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values Reported as AE [ Time Frame: From first dose of study drug through 30 days after the last dose of study drug (Up to 13 months) ]
    The laboratory parameters included clinical chemistry, hematology, and urinalysis. Any abnormal change in the laboratory values were assessed by Investigator and reported as AE. An 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. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug.

  3. Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Reported as AE [ Time Frame: From first dose of study drug through 30 days after the last dose of study drug (Up to 13 months) ]
    Vital sign measurements included blood pressure (diastolic and systolic), heart rate, and temperature. Any abnormal change in the vital sign values were assessed by Investigator and reported as AE. An 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. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug.

  4. Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval With Bazett Correction (QTcB) [ Time Frame: Baseline; Cycle 1 (28 days cycle): 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24 and 48 hours postdose ]
    The mean changes of QTcB from time-matched baseline was measured by ECG to evaluate the potential effect of drug on QTc interval duration. Holter monitors were used to collect triplicate ECG measurements and were based on a repeated measures mixed effects linear model. A negative change from baseline indicates shortening and a positive change from baseline indicates prolongation of QTcB interval.

  5. Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval Fridericia Correction (QTcF) [ Time Frame: Baseline; Cycle 1 (28 days cycle): 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24 and 48 hours postdose ]
    The mean changes of QTcF from time-matched baseline was measured by ECG to evaluate the potential effect of drug on QTc interval duration. Holter monitors were used to collect triplicate ECG measurements and were based on a repeated measures mixed effects linear model. A negative change from baseline indicates shortening and a positive change from baseline indicates prolongation of QTcF interval.

  6. Change From Time-Matched Baseline in QRS Interval [ Time Frame: Baseline; Cycle 1 (28 days cycle): 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24 and 48 hours postdose ]
    QRS interval is defined as the time between the start of the Q wave and end of the S wave on ECG. Holter monitors were used to collect triplicate ECG measurements and were based on a repeated measures mixed effects linear model. A negative change from baseline indicates shortening and a positive change from baseline indicates prolongation of QRS interval.

  7. Change From Time-Matched Baseline in PR Interval [ Time Frame: Baseline; Cycle 1 (28 days cycle): 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24 and 48 hours postdose ]
    PR interval is defined as the time between the start of the P wave and the beginning of the QRS complex on ECG. Holter monitors were used to collect triplicate ECG measurements and were based on a repeated measures mixed effects linear model. A negative change from baseline indicates shortening and a positive change from baseline indicates prolongation of PR interval.

  8. Change From Time-Matched Baseline in Heart Rate [ Time Frame: Baseline; Cycle 1 (28 days cycle): 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24 and 48 hours postdose ]
    Heart rate was assessed using the ECG. Holter monitors were used to collect triplicate ECG measurements and were based on a repeated measure mixed effects linear model. A negative change from baseline indicates decrease in heart rate.

  9. Cmax: Maximum Observed Plasma Concentration for Sapanisertib [ Time Frame: Cycle 1 (28 days cycle), Day 1, predose and at multiple timepoints (Up to 48 hours) postdose ]
  10. Tmax: Time to Reach Cmax for Sapanisertib [ Time Frame: Cycle 1 (28 days cycle), Day 1, predose and at multiple timepoints (Up to 48 hours) postdose ]
  11. AUCt: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Measurable Concentration for Sapanisertib [ Time Frame: Cycle 1 (28 days cycle), Day 1, predose and at multiple timepoints (Up to 48 hours) postdose ]
  12. AUCinf: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Sapanisertib [ Time Frame: Cycle 1 (28 days cycle), Day 1, predose and at multiple timepoints (Up to 48 hours) postdose ]
  13. T1/2: Terminal Elimination Half-life for Sapanisertib [ Time Frame: Cycle 1 (28 days cycle), Day 1, predose and at multiple timepoints (Up to 48 hours) postdose ]


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

  • Men or women participants 18 years or older.
  • Must have a radiographically or clinically evaluable solid tumor Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • 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 [e.g., calendar, ovulation, symptothermal, post ovulation methods] and withdrawal are not acceptable methods of contraception.)
  • Male participants, even if surgically sterilized (i.e., status post vasectomy), 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 [e.g., calendar, ovulation, symptothermal, post ovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.)
  • 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.
  • Ability to swallow oral medications, willingness to perform mucositis prophylaxis, and suitable venous access for the study-required blood sampling.

Exclusion Criteria

  • Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the screening period.
  • Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
  • 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.
  • Untreated brain metastasis or history of leptomeningeal disease or spinal cord compression.
  • Tumors with involvement of the mediastinum.
  • 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.
  • Systemic corticosteroid (inhalers are allowed) within 7 days before the first dose of study drug.
  • Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown or other reason that may alter the absorption of Sapanisertib.
  • 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.
  • Significant active cardiovascular or pulmonary disease at study entry
  • History of arrhythmia requiring an implantable cardiac defibrillator
  • 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.
  Study Documents (Full-Text)

Documents provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Study Protocol  [PDF] November 28, 2017
Statistical Analysis Plan  [PDF] February 18, 2015

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02197572    
Other Study ID Numbers: C31002
U1111-1156-4099 ( Other Identifier: World Health Organization )
First Posted: July 22, 2014    Key Record Dates
Results First Posted: March 3, 2020
Last Update Posted: March 3, 2020
Last Verified: February 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.

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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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Neoplasms