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

• 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