Study of TAK-228 In Patients With Previously Treated Metastatic Renal Cell Carcinoma

Inclusion Criteria: * Age ≥ 18 years. * Measurable disease according to RECIST 1.1 within 28 days prior to registration. * Documented pathologic diagnosis of RCC. All subtypes eligible including but not limited to clear cell, papillary, chromophobe, collecting duct carcinoma, medullary carcinoma, and unclassified categories. Sarcomatoid and rhabdoid differentiation are allowed. * Patients with clear cell histology must have demonstrated: 1) Progression on at least one prior anti -angiogenic agent unless intolerable; AND 2) progression on at least one agent that blocks the PD-1 pathway unless felt by the treating physician to be contraindicated (examples include but are not limited to: patients with autoimmune disease or patients requiring systemic steroids greater than 10 mg/day prednisone or its equivalent) or if they have been discontinued due to toxicity. Prior rapalogues are allowed. * Patients with non-clear cell histology must have received at least one prior anti-cancer therapy. Prior rapalogues are allowed. * Left ventricular ejection fraction (LVEF) ³ lower limit of normal (LLN) as assessed by either multigated acquisition (MUGA) scan or echocardiogram (ECHO). * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. * Must have adequate organ and bone marrow function. * Hematological * Absolute Neutrophil Count (ANC) ≥ 1500 K/mm\^3 (without use of G-CSF 4 weeks prior to enrollment) * Hemoglobin (Hgb) ≥ 9 g/dL (transfusions allowed) * Platelets (Plts) ≥ 100 k/mm\^3 * Renal * Calculated creatinine clearance (Cockcroft-Gault formula will be used to calculate creatinine clearance) ≥ 30 mL/min * Urinalysis: For patients with 2+ proteinuria on urinalysis, 24 hour urine collection should be obtained, 24 hour urine protein should be \<2 grams. * Hepatic * Bilirubin ≤ 1.5 × upper limit of normal (ULN). For subjects with Gilbert's disease ≤ 3.0 mg/dL * Aspartate aminotransferase (AST) ≤ 2.5 × ULN; ≤ 5 x ULN if liver metastases are present * Alanine aminotransferase (ALT) ≤ 2.5 × ULN; ≤ 5 x ULN if liver metastases are present * Metabolic * Glycosylated hemoglobin (HbA1c) \< 7.0%, * Fasting serum glucose ≤ 130 mg/dL * Fasting triglycerides ≤ 300 mg/dL * Recovery to baseline or ≤ grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 from toxicities related to any prior treatment, unless adverse events are clinically non-significant and/or stable on supportive therapy. * Capable of understanding and complying with the protocol requirements and has signed the informed consent document. 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 subject at any time without prejudice to future medical care. * Submission of formalin-fixed, paraffin-embedded (FFPE) archival tumor specimens from the previous 18 months, if available. If not available, a fresh tumor biopsy prior to treatment initiation is MANDATORY unless determined medically unsafe or not feasible by the site investigator. * The archival specimen must contain adequate viable tumor tissue. * Specimens may consist of a tissue block (preferred and should contain the highest grade of tumor) or a recommended minimum of 20 unstained serial sections. Fine-needle aspiration, brushings, cell pellet from pleural effusion, bone marrow aspirate/biopsy are not acceptable. * Distant metastases specimens are preferred but if not available primary nephrectomy specimens are acceptable. * Subjects who experience a disease response per RECIST 1.1 criteria followed by subsequent progression will be required to have a post-treatment biopsy if feasible and safe. * Sexually active subjects and their partners must agree to use medically accepted methods of contraception. * For women: * Postmenopausal for at least 1 year before the screening visit, OR * Surgically sterile, OR * Agree to practice 1 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 \[eg. USPI, SmPC, etc.\] 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 subject (Periodic abstinence \[e.g, calendar, ovulation, symptothermal, postovulation methods\] and withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) * For men: * Even if surgically sterilized (ie, status post-vasectomy), they must 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 * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject (Periodic abstinence \[e.g, calendar, ovulation, symptothermal, postovulation methods for the female partner\] and 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 120 days after receiving their last dose of study drug Exclusion Criteria: * Subjects with a history of deep vein thrombosis (DVT) or pulmonary embolism (PE) within 6 months of study treatment initiation. * Receipt of any type of small molecular kinase inhibitor (including investigational kinase inhibitors) within 2 weeks of enrollment or receipt of any anti-cancer therapy (including investigational therapy, monoclonal antibodies, cytokine therapy) within 3 weeks of enrollment. * Treatment with any investigational products within 3 weeks before the first dose of study drug. * Radiation therapy for bone metastases within 2 weeks, other external radiation therapy within 4 weeks of enrollment. * Received prior hemibody external radiotherapy. * Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks prior to enrollment as documented by magnetic resonance imaging (MRI) or computed tomography (CT) imaging. Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 4 weeks prior to enrollment as documented by MRI or CT imaging. * Imminent or established spinal cord compression based on clinical and/or imaging. In subjects with untreated imminent or established spinal cord compression, treatment with standard of care as clinically indicated should be completed at least 4 weeks before enrollment. * The subject has a history of any of the following within the last 6 months before administration of the first dose of the 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 (NYHA) Class III or IV heart failure * Significant active cardiovascular or pulmonary disease including: * Uncontrolled hypertension defined as sustained BP \>160 mm Hg systolic or \> 95 mm Hg diastolic despite optimal antihypertensive treatment. * Pulmonary hypertension * Uncontrolled asthma or O2 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 * History of arrhythmia requiring an implantable cardiac defibrillator * Medically significant (symptomatic) bradycardia * Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) \> 7%; subjects with a history of transient glucose intolerance due to corticosteroid administration may be enrolled in this study if all other inclusion/exclusion criteria are met * Active gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation. Subjects with enteric stomata (such as ileostomy, colostomy) are also excluded: * Tumors invading the GI-tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction. --Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intraabdominal abscess within 12 weeks before enrollment. NOTE: Complete healing of an intra-abdominal abscess must be confirmed before enrollment. * Clinically significant hematemesis or hemoptysis of \> 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (such as pulmonary hemorrhage) within 4 weeks of enrollment. * Other clinically significant disorders such as: * Known active infection requiring systemic treatment, infection with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, chronic hepatitis B or known or suspected active hepatitis C infection. * Serious non-healing wound or ulcer. * Malabsorption syndrome. * Symptomatic hypothyroidism. * Moderate to severe hepatic impairment (Child-Pugh B or C). * Requirement for hemodialysis or peritoneal dialysis. * History of solid organ transplantation. * Major surgery (such as GI surgery) within 6 weeks of enrollment. However, subjects who have had a nephrectomy may be enrolled 4 weeks after surgery, providing there are no wound-healing complications. Subjects with clinically relevant ongoing complications from prior surgery are not eligible. The following are not considered to be major procedures: Thoracentesis, paracentesis, port placement, laparoscopy, thoracoscopy, bronchoscopy, endoscopic ultrasonographic procedures, mediastinoscopy, skin biopsies, incisional biopsies, imaging-guided biopsy for diagnostic purposes, and routine dental procedures. * QTcF (Fridericia formula for the QT interval correction for the heart rate) \> 480 msec within 4 weeks of enrollment. If the initial QTcF is found to be \> 480 msec, two additional electrocardiograms (EKGs) separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is ≤ 480 msec, the subject meets eligibility in this regard. Subjects with history of congenital long QT syndrome, or torsades de pointes, are not allowed. * Pregnant or lactating females. * Inability to swallow tablets or capsules. * Previously identified allergy or hypersensitivity to components of the study treatment formulations. * Malignancies other than RCC within 5 years of first study treatment with the exception of those with negligible risk of metastases or death (carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, ductal carcinoma in situ of the breast, non-muscle invasive urothelial carcinoma). * Any serious medical or psychiatric illness that could, in the site investigator's opinion, potentially interfere with the completion of treatment according to this protocol. * Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI within 7 days before receiving the first dose of study drug.