A Study of Sapanisertib, Combination of Sapanisertib With MLN1117, Paclitaxel and Combination of Sapanisertib With Paclitaxel in Women With Endometrial Cancer
Condition: Endometrial Neoplasms
MeSH terms: Endometrial Neoplasms
Intervention: Paclitaxel; Sapanisertib; MLN1117
Intervention description: Paclitaxel intravenous solution.; Sapanisertib capsules.; MLN1117 capsules.
Intervention MeSH terms: Paclitaxel; Serabelisib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 241.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Drug Therapy

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.
    

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.