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A Study of Sapanisertib, Combination of Sapanisertib With MLN1117, Paclitaxel and Combination of Sapanisertib With Paclitaxel in Women With Endometrial Cancer

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ClinicalTrials.gov Identifier: NCT02725268
Recruitment Status : Completed
First Posted : March 31, 2016
Results First Posted : June 9, 2020
Last Update Posted : November 27, 2020
Sponsor:
Collaborators:
European Network of Translational Research in Ovarian Cancer - EUTROC
European Network of Individualized Treatment in Endometrial Cancer - ENITEC
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Tracking Information
First Submitted Date  ICMJE March 28, 2016
First Posted Date  ICMJE March 31, 2016
Results First Submitted Date  ICMJE May 22, 2020
Results First Posted Date  ICMJE June 9, 2020
Last Update Posted Date November 27, 2020
Actual Study Start Date  ICMJE April 1, 2016
Actual Primary Completion Date July 2, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 22, 2020)
Progression Free Survival (PFS) [ Time Frame: Up to 30 months ]
PFS is defined as the time in months from the date of randomization to the date of first documentation of progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST v1.1, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Original Primary Outcome Measures  ICMJE
 (submitted: March 28, 2016)
Progression Free Survival (PFS) [ Time Frame: Up to 30 months ]
PFS is defined as the time from the date of randomization to the date of first documentation of progressive disease or death due to any cause, whichever occurs first. For a participant who has not progressed and is last known to be alive, PFS will be censored at the last response assessment that is stable disease (SD) or better.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 22, 2020)
  • Number of Participants Who Experienced at Least One Treatment-emergent Adverse Event (TEAE) [ Time Frame: From the first dose of study drug through 30 days after the last dose of study drug (Up to 31 months) ]
    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.
  • Overall Survival (OS) [ Time Frame: Up to 36 months ]
    OS is defined as the time in months from the date of randomization to the date of death.
  • Time to Tumor Progression (TTP) [ Time Frame: Up to 30 months ]
    TTP is defined as the time in months from the date of randomization to the date of first documentation of progression. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
  • Overall Response Rate (ORR) [ Time Frame: Up to 30 months ]
    ORR is defined as the percentage of participants who achieved a best response of a complete response (CR) or partial response (PR). Per RECIST v1.1, CR was defined as disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.
  • Clinical Benefit Rate (CBR) [ Time Frame: Up to 30 months ]
    CBR is defined as the percentage of participants with CR or PR or SD (SD of any duration). Per RECIST v1.1, CR was defined as disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
  • Clinical Benefit Rate (CBR) at Week 16 (CBR-16) [ Time Frame: Week 16 ]
    CBR-16 is defined as the percentage of participants who achieved CR or PR of any duration or have SD with a duration of at least 16 weeks. Per RECIST v1.1, CR was defined as disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 28, 2016)
  • Percentage of Participants who Experience at Least One Treatment-emergent Adverse Event (TEAE) [ Time Frame: From the first dose of study drug through 30 days after the last dose of study drug (Up to 30 Months) ]
  • Overall Survival (OS) [ Time Frame: Up to 30 months ]
    OS is defined as the time from the date of randomization to the date of death. Participants without documentation of death at the time of analysis will be censored at the date last known to be alive.
  • Time to Progression (TTP) [ Time Frame: Up to 30 months ]
    TTP is defined as the time from the date of randomization to the date of first documentation of progression. For a participant who has not progressed, TTP will be censored at the last response assessment that is stable disease (SD) or better.
  • Overall Response Rate (ORR) [ Time Frame: Up to 30 months ]
    ORR is defined as the percentage of participants who achieve a best response of a complete response (CR) or partial response (PR) using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.
  • Clinical Benefit Rate (CBR) [ Time Frame: Up to 30 months ]
    CBR is defined as the percentage of participants with complete response (CR) or partial response (PR) or stable disease (SD).
  • Clinical Benefit Rate (CBR) at Week 16 (CBR-16) [ Time Frame: Up to 30 months ]
    CBR-16 is defined as the percentage of participants who achieve CR or PR of any duration or have SD with a duration of at least 16 weeks.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Sapanisertib, Combination of Sapanisertib With MLN1117, Paclitaxel and Combination of Sapanisertib With Paclitaxel in Women With Endometrial Cancer
Official Title  ICMJE A Phase 2, Randomized Study of MLN0128 (a Dual TORC1/2 Inhibitor), MLN0128+MLN1117 (a PI3Kα Inhibitor), Weekly Paclitaxel, or the Combination of Weekly Paclitaxel and MLN0128 in Women With Advanced, Recurrent, or Persistent Endometrial Cancer
Brief Summary The primary purpose of this study is to determine if sapanisertib in combination with weekly paclitaxel improves progression-free survival (PFS) compared to weekly paclitaxel alone.
Detailed Description

The drugs being evaluated in this study are sapanisertib and MLN1117. Sapanisertib is being evaluated as a single agent and in combination with paclitaxel or MLN1117 to treat women with advanced, recurrent, or persistent endometrial cancer. This study will evaluate the efficacy and safety of each drug or drug combination.

The study will enroll approximately 241 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of 4 treatment groups:

  • Paclitaxel 80 mg/m^2
  • Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg
  • Sapanisertib 30 mg
  • Sapanisertib 4 mg + MLN1117 200 mg

Participants will receive either paclitaxel intravenous (IV) weekly, Paclitaxel IV along with sapanisertib orally, sapanisertib orally, or sapanisertib and MLN1117 orally.

This is a multicenter, multinational trial. Participants will make multiple visits to the clinic, with an end of treatment visit (EOT) which will occur 30 to 40 days after receiving their last dose of study drug or before the start of any subsequent anticancer therapy. After EOT, participants will be followed for PFS and overall survival (OS).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Endometrial Neoplasms
Intervention  ICMJE
  • Drug: Paclitaxel
    Paclitaxel intravenous solution.
  • Drug: Sapanisertib
    Sapanisertib capsules.
    Other Names:
    • MLN0128
    • INK128
    • TAK-228
  • Drug: MLN1117
    MLN1117 capsules.
    Other Names:
    • TAK-117
    • INK1117
Study Arms  ICMJE
  • Experimental: Paclitaxel 80 mg/m^2
    Paclitaxel 80 milligrams per square meter (mg/m^2), IV, weekly on Days 1, 8, and 15 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was up to approximately 13 weeks).
    Intervention: Drug: Paclitaxel
  • Experimental: Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg
    Paclitaxel 80 mg/m^2, IV, weekly on Days 1, 8, and 15 of a 28-day cycle along with sapanisertib 4 milligrams (mg), capsule, orally on Days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was up to approximately 20 weeks).
    Interventions:
    • Drug: Paclitaxel
    • Drug: Sapanisertib
  • Experimental: Sapanisertib 30 mg
    Sapanisertib 30 mg, capsule, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was up to approximately 6 weeks).
    Intervention: Drug: Sapanisertib
  • Experimental: Sapanisertib 4 mg + MLN1117 200 mg
    Sapanisertib 4 mg, capsule, orally and MLN1117 200 mg, capsule, orally on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was up to approximately 8 weeks).
    Interventions:
    • Drug: Sapanisertib
    • Drug: MLN1117
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 13, 2020)
241
Original Estimated Enrollment  ICMJE
 (submitted: March 28, 2016)
260
Actual Study Completion Date  ICMJE October 30, 2020
Actual Primary Completion Date July 2, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Histologic or cytologic diagnosis of endometrial carcinoma (including endometrioid, serous, mixed adenocarcinoma, clear-cell carcinoma, or carcinosarcoma).
  2. Evidence that the endometrial cancer is advanced, recurrent, or persistent and has relapsed or is refractory to curative therapy or established treatments.
  3. At least 1 prior platinum-based chemotherapeutic regimen, but not more than 2 prior chemotherapeutic regimens, for management of endometrial carcinoma. Prior treatment may include chemotherapy, chemotherapy/radiation therapy, and/or consolidation/maintenance therapy. Chemotherapy administered in conjunction with primary radiation as a radio-sensitized therapy will be considered a systemic chemotherapy regimen.
  4. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least 1 lesion that can be accurately measured in at least 1 dimension (longest diameter to be recorded). Each lesion must be greater than or equal to (>=) 10 millimeter (mm) in long axis when measured by computed tomography (CT), magnetic resonance imaging (MRI), or caliper measurement by clinical exam. Lymph nodes must be >= 15 mm in short axis when measured by CT or MRI.
  5. Tumor accessible and participant consents to undergo fresh tumor biopsies.
  6. Female participants 18 years or older.
  7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
  8. 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 1 highly effective method of contraception and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through 90 days (or longer, as mandated by local labeling [example, United States Prescribing Information (USPI), Summary of Product Characteristics (SmPC), etc.]) 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 [example, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
  9. Clinical laboratory values as specified below within 4 weeks before the first dose of study drug:

    • Bone marrow reserve consistent with absolute neutrophil count (ANC) >= 1500 per micro liter (/mcL); platelet count >= 100,000/mcL; hemoglobin A1c (HbA1c) less than (<) 6.5 percent (%).
    • Total bilirubin must be less than or equal to (<=) 1.5 * the upper limit of normal (ULN).
    • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) must be <= 2.5 * the upper limit of the normal range. AST and ALT may be elevated up to 5 times the ULN if their elevation can be reasonably ascribed to the presence of metastatic disease in liver.
    • Creatinine clearance >= 50 milliliter per minute per 1.73 square meter (mL/min/1.73 m^2) based either on Cockcroft-Gault estimate or based on a 12- or 24-hour urine collection.
    • Fasting serum glucose < 130 milligram per deciliter (mg/dL) and fasting triglycerides <= 300 mg/dL.
  10. Ability to swallow oral medications, willingness to perform mucositis prophylaxis, and suitable venous access for the study-required blood sampling.
  11. 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.

Exclusion Criteria:

  1. Positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug. Women who are lactating and breastfeeding are not eligible.
  2. Previous treatment with any weekly taxane regimen.
  3. History of severe hypersensitivity reactions to paclitaxel or any of its excipients.
  4. Previous treatment with phosphoinositide 3-kinase (PI3K), serine/threonine-specific protein kinase (AKT), dual PI3K/ mammalian (or mechanistic) target of rapamycin (mTOR) inhibitors, target of rapamycin complex 1/2 (TORC1/2) inhibitors or TORC1 inhibitors.
  5. Initiation of treatment with hematopoietic growth factors, transfusions of blood and blood products, or systemic corticosteroids (either intravenous [IV] or oral steroids, excluding inhalers) within 1 week before administration of the first dose of study drug (participants already receiving erythropoietin on a chronic basis for >=4 weeks are eligible).
  6. Participants who are taking proton pump inhibitors (PPIs) within 7 days of the first dose of study drug or who require treatment with PPIs throughout the trial or those who are taking H2 receptor antagonists within 24 hours of the first dose of study drug.
  7. A prothrombin time (PT) or activated partial thromboplastin time (aPTT) above the ULN or a history of a coagulopathy or bleeding disorder.
  8. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.
  9. Sensory or motor neuropathy >= Grade 2.
  10. Central nervous system (CNS) metastasis, endometrial leiomyosarcoma, or endometrial stromal sarcoma.
  11. Manifestations of malabsorption due to prior gastrointestinal surgery, gastrointestinal disease, or for some other reason that may alter the absorption of sapanisertib or MLN1117. In addition, participants with enteric stomata are also excluded.
  12. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active CNS disease, active infection, or any other condition that could compromise participation of the participant in the study.
  13. Known human immunodeficiency virus infection.
  14. History of any of the following within the last 6 months before administration of the first dose of study drug:

    • Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures.
    • Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures.
    • Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation, or ventricular tachycardia).
    • Placement of a pacemaker for control of rhythm.
    • New York Heart Association Class III or IV heart failure.
    • Pulmonary embolism.
  15. Significant active cardiovascular or pulmonary disease before administration of the first dose of study drug, including:

    • Uncontrolled hypertension (that is, either systolic blood pressure > 180 millimeter of mercury [mm Hg] or diastolic blood pressure > 95 mm Hg).
    • Pulmonary hypertension.
    • Uncontrolled asthma or oxygen saturation < 90% by arterial blood gas analysis or pulse oximetry on room air.
    • Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention; or history of valve replacement.
    • Medically significant (symptomatic) bradycardia.
    • History of arrhythmia requiring an implantable cardiac defibrillator.
    • Baseline prolongation of the rate-corrected QT interval (QTc; example, repeated demonstration of QTc interval > 480 millisecond [ms], or history of congenital long QT syndrome, or torsades de pointes).
  16. Diagnosed or treated for another malignancy within 2 years before administration of the first dose of study drug or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
  17. Participants with endometrioid histology and histologically confirmed expression of estrogen receptors (ER) and/or progesterone receptors (PgR) who have not received prior endocrine therapy and for whom endocrine therapy is currently indicated.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Belgium,   Canada,   Germany,   Italy,   Netherlands,   Norway,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02725268
Other Study ID Numbers  ICMJE C31004
U1111-1168-1824 ( Other Identifier: WHO )
2014-005394-37 ( EudraCT Number )
02725268 ( Registry Identifier: ClinicalTrials.gov )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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.
Responsible Party Takeda ( Millennium Pharmaceuticals, Inc. )
Study Sponsor  ICMJE Millennium Pharmaceuticals, Inc.
Collaborators  ICMJE
  • European Network of Translational Research in Ovarian Cancer - EUTROC
  • European Network of Individualized Treatment in Endometrial Cancer - ENITEC
Investigators  ICMJE
Study Director: Medical Director Clinical Science Millennium Pharmaceuticals, Inc.
PRS Account Takeda
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP