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 160 mm Hg systolic or > 95 mm Hg diastolic despite optimal antihypertensive treatment.
• Pulmonary hypertension
• Uncontrolled asthma or O2 saturation 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 ultrasonographi