Clinical trial NCT02725268: A Study of Sapanisertib, Combination of Sapanisertib With MLN1117, Paclitaxel and Combination of Sapanisertib With Paclitaxel in Women With Endometrial Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Endometrial Neoplasms
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: European Network of Translational Research in Ovarian Cancer - EUTROC
name: European Network of Individualized Treatment in Endometrial Cancer - ENITEC
First posted: 2016-03-31
Enrollment: 241
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Eligibility criteria: 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.

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Up to approximately 30 months
Secondary outcomes:
measure: Number of Participants Who Experienced at Least One Treatment-emergent Adverse Event (TEAE)
timeFrame: From the first dose of study drug through 30 days after the last dose of study drug (Up to approximately 54 months)
measure: Overall Survival (OS)
timeFrame: Up to approximately 54 months
measure: Time to Tumor Progression (TTP)
timeFrame: Up to 30 months
measure: Overall Response Rate (ORR)
timeFrame: Up to 30 months
measure: Clinical Benefit Rate (CBR)
timeFrame: Up to 30 months
measure: Clinical Benefit Rate (CBR) at Week 16 (CBR-16)
timeFrame: Week 16
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Comprehensive Cancer Center
state: Alabama
city: Phoenix
country: United States
facility: University of Arizona Cancer Center
state: Arizona
city: Greenbrae
country: United States
facility: Marin Cancer Care
state: California
city: La Jolla
country: United States
facility: University of California San Diego Medical Center
state: California
city: San Francisco
country: United States
facility: University of California at San Francisco (PARENT)
state: California
city: Stanford
country: United States
facility: Stanford School of Medicine
state: California
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute, Inc
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Augusta
country: United States
facility: Augusta University
state: Georgia
city: Indianapolis
country: United States
facility: Franciscan St. Francis Health
state: Indiana
city: Westwood
country: United States
facility: University of Kansas Medical Center Research Institute, Inc.
state: Kansas
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: NYU Langone Medical Center Clinic
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Oklahoma City
country: United States
facility: Oklahoma University Health Sciences Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center Cancer Center at Magee-Womens Hospital
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Kogarah
country: Australia
facility: St George Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Clayton
country: Australia
facility: Monash Medical Centre Clayton
state: Victoria
city: Footscray
country: Australia
facility: Sunshine Hospital
state: Victoria
city: Malvern
country: Australia
facility: Cabrini Hospital Malvern
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre-East Melbourne
state: Victoria
city: Edegem
country: Belgium
facility: UZ Antwerpen
state: Antwerpen
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Leuven
country: Belgium
facility: UZ Leuven
city: Liege
country: Belgium
facility: Centre Hospitalier Universitaire de Liege Site Sart Tilman
city: Wilrijk
country: Belgium
facility: GasthuisZusters Antwerpen Sint-Augustinus
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Hamilton
country: Canada
facility: Juravinski Cancer Clinic
state: Ontario
city: London
country: Canada
facility: LHSC - Victoria Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: University Health Network - Princess Margaret Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: CHUM Hopital Notre-Dame
state: Quebec
city: Greifswald
country: Germany
facility: Universitaetsmedizin Greifswald
state: Mecklenburg Vorpommern
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
state: Niedersachsen
city: Dresden
country: Germany
facility: Universitaetsklinikum Carl Gustav Carus TU Dresden
state: Sachsen
city: Luebeck
country: Germany
facility: Universitaetsklinikum Schleswig-Holstein - Campus Luebeck
state: Schleswig Holstein
city: Berlin
country: Germany
facility: Charite - Universitaetsmedizin Berlin - Campus Virchow-Klinikum
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori
state: Forli - Cesena
city: Brescia
country: Italy
facility: Spedali Civili di Brescia
city: Genova
country: Italy
facility: Ente Ospedaliero Ospedali Galliera
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
city: Milano
country: Italy
facility: IEO Istituto Europeo di Oncologia
city: Napoli
country: Italy
facility: Istituto Tumori Napoli Fondazione G. Pascale
city: Ravenna
country: Italy
facility: Azienda Unita Sanitaria Locale di Ravenna
city: Roma
country: Italy
facility: Istituto Nationale Tumori Regina Elena
city: Roma
country: Italy
facility: Universita degli Studi di Roma "La Sapienza" - Umberto I Policlinico di Roma
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli
city: Maastricht
country: Netherlands
facility: Maastricht Universitair Medisch Centrum
state: Limburg
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum
state: Noord-holland
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum Daniel den Hoed
state: Zuid-holland
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Bergen
country: Norway
facility: Haukeland universitetssykehus, Kvinneklinikken
city: Oslo
country: Norway
facility: Radiumhospitalet
city: Stavanger
country: Norway
facility: Stavanger University Hospital
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: MD Anderson Cancer Centre
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: Centro Integral Oncologico Clara Campal
city: Valencia
country: Spain
facility: Instituto Valenciano de Oncologia IVO
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
state: Avon
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital (Wonford)
state: Devon
city: London
country: United Kingdom
facility: University College London Hospitals
state: Greater London
city: London
country: United Kingdom
facility: Royal Marsden Hospital
state: Greater London
city: London
country: United Kingdom
facility: Hammersmith Hospital
state: Greater London
city: Manchester
country: United Kingdom
facility: The Christie
state: Greater Manchester
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital
state: Surrey
city: Coventry
country: United Kingdom
facility: University Hospital Coventry
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Director Clinical Science
role: STUDY_DIRECTOR
References: