MLN0128 and MLN0128 + MLN1117 Compared With Everolimus in the Treatment of Adults With Advanced or Metastatic Clear-Cell Renal Cell Carcinoma
Condition: Clear-cell Metastatic Renal Cell Carcinoma
MeSH terms: Carcinoma; Carcinoma, Renal Cell
Intervention: Everolimus; MLN0128; MLN1117
Intervention description: Everolimus capsules.; MLN0128 capsules.; MLN1117 capsules.
Intervention MeSH terms: Everolimus; Serabelisib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 96.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Drug therapy

Summary:

      The purpose of this study is to evaluate the efficacy and safety of single-agent MLN0128 and
      the combination of MLN0128 + MLN1117 compared with everolimus in the treatment of
      participants with metastatic clear-cell renal cell carcinoma (mccRCC) that have progressed on
      vascular endothelial growth factor (VEGF)-targeted therapy.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male or female participants aged 18 years or older.

          2. Histologically confirmed renal cell carcinoma (RCC) with a clear-cell component.

          3. Evidence that the RCC is advanced or metastatic.

          4. Radiologic evidence of PD (according to RECIST Version 1.1) either during or within 6
             months after stopping their most recent systemic therapy for RCC before enrollment
             into this study.

          5. At least 1, prior line of VEGF-targeted therapy, but not more than 4 total prior lines
             of systemic therapy. Exposure to more than 1 line of VEGF-targeted therapy is
             acceptable. Participants may also have received prior therapies with interferon,
             interleukin 2 (IL-2), anti-PD1 antibodies, cabozantinib or other experimental agents,
             but not prior therapy with any agent that targets phosphoinositide 3-kinase (PI3K),
             serine/ threonine-specific protein kinase (AKT), or mechanistic (or mammalian) target
             of rapamycin (mTOR).

          6. Karnofsky Performance Status (KPS) greater than or equal to (>=) 70%.

          7. Life expectancy of >=3 months.

          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 labelling [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.).

             Male participants, even if surgically sterilized (that is, status postvasectomy), who:

               -  Agree to practice highly effective barrier contraception during the entire study
                  treatment period and through 120 days after the last dose of study drug (or
                  longer, as mandated by local labelling [example, USPI, SmPC, etc]), 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 for the female partner],
                  withdrawal, spermicides only, and lactational amenorrhea are not acceptable
                  methods of contraception. Female and male condoms should not be used together.).

               -  Agree not to donate sperm during the course of this study or within 120 days
                  after receiving their last dose of study drug.

          9. Suitable venous access for the study-required blood sampling.

         10. Screening clinical laboratory values:

               -  Absolute neutrophil count >=2000 per microliter (/mcL) and platelet count
                  >=100,000/mcL;

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or
                  equal to (<=) 2.5*the upper limit of normal (ULN);

               -  Total bilirubin <=1.5*ULN;

               -  Estimated creatinine clearance by Cockcroft-Gault >=40 milliliter per minute
                  (mL/min) / 1.73 square meter (m^2);

               -  Glycosylated hemoglobin (HbA1c) less than (<) 7.0%, fasting serum glucose <=130
                  milligram per deciliter (mg/dL), and fasting triglycerides <=300 mg/dL.

         11. At least 14 days since the end of prior systemic VEGF-targeted treatment (that is,
             sunitinib, pazopanib, axitinib, or sorafenib), radiotherapy, or surgical procedure
             with resolution of all treatment-related toxicity (except alopecia and hypothyroidism)
             either to Grade 0 or 1 (National Cancer Institute Common Terminology Criteria for
             Adverse Events [NCI CTCAE] Version 4.03) or to baseline.

         12. At least 21 days since the last dose of bevacizumab, other antibody, or interferon.

         13. Voluntary written consent 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. Central nervous system (CNS) metastasis.

          2. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease,
             active CNS disease, active infection, or any other condition that might compromise the
             participant's participation in the study.

          3. Known human immunodeficiency virus infection.

          4. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C
             infection.

          5. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI
             disease, or for an unknown reason that may alter the absorption of everolimus,
             MLN0128, or MLN1117. In addition, participants with enteric stomata are excluded.

          6. Women who are either breast feeding or pregnant.

          7. 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.

          8. Significant active cardiovascular or pulmonary disease including:

               -  Uncontrolled hypertension (that is, either systolic blood pressure greater than
                  [>] 160 millimeter of mercury [mm Hg]; diastolic blood pressure >95 mm Hg). Use
                  of anti-hypertensive agents to control hypertension before Cycle 1 Day 1 is
                  allowed;

               -  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).

          9. 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 nonmelanoma skin cancer,
             superficial bladder cancer, very low risk prostate on observation, or carcinoma in
             situ of any type are not excluded if they have undergone complete resection.

         10. Prior therapy with agents that target Phosphatidylinositide 3-kinases (PI3K), Protein
             kinase B (AKT), or mechanistic target of rapamycin (mTOR). Participants with known
             hypersensitivity to everolimus or rapamycin derivatives are also excluded.

         11. Any serious medical or psychiatric illness that could, in the investigator's opinion,
             potentially interfere with the completion of treatment according to this protocol.

         12. Participants who have taken a proton pump inhibitor (PPI) within 3 days before
             receiving the first dose of study drug.