Atezolizumab in Combination With Entinostat and Bevacizumab in Patients With Advanced Renal Cell Carcinoma

Inclusion Criteria: Patients must meet the following criteria for study entry: * Signed Informed Consent Form (ICF) * Ability and willingness to comply with the requirements of the study protocol * Age ≥ 18 years * Measurable disease per RECIST v1.1 (see Appendix 4) for patients with solid malignancies or patients with bone disease must have disease evaluable by bone scan and/or PET scan * Metastatic renal cell carcinoma o During Phase I - All prior treatments or none are allowed * During Phase II/Cohort A - No prior treatments with PD1 or PDL1 inhibitors allowed * During Phase II/Cohort B - Must have at least one prior treatment with a PD1 or PDL1 inhibitor for metastatic disease for at least 3 months and have progressed by either clinical or radiographic assessment * Life expectancy of at least 6 months * Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment (Cycle 1, Day 1): * Absolute neutrophil count (ANC) ≥ 1500 cells/microL * White blood cell (WBC) counts \> 2500/microL * Lymphocyte count ≥ 300/microL * Platelet count ≥ 100,000/microL; for patients with hematologic malignancies, platelet count ≥ 75,000/microL * Hemoglobin ≥ 9.0 g/dL * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) with the following exception: Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be enrolled. Direct bilirubin ≤ ULN for patients with total bilirubin levels \> 1.5 x ULN \- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN with the following exception: Patients with liver involvement: AST and/or ALT ≤ 5 x ULN \- Alkaline phosphatase (ALP) ≤ 2.0 x ULN with the following exception: Patients with documented liver involvement or bone metastases: ALP ≤ 5 x ULN * Serum creatinine ≤ 1.25 x ULN or creatinine clearance ≥ 60 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation: (140 - age) x (weight in kg) x (0.85 if female) / 72 x (serum creatinine in mg/dL) * Urine dipstick for proteinuria \< 2+ or 24-hour urine protein \< 1 g of protein is demonstrated * International Normalized Ratio (INR) and activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation (such as low-molecular-weight heparin or warfarin) should be on a stable dose. • If a female of childbearing potential, negative serum blood pregnancy test during screening and a negative urine pregnancy test ≤ 3 days prior to receiving the first dose of study drug. If the screening serum test is done ≤ 3 days prior to receiving the first dose of study drug, a urine test is not required. * Non-childbearing potential is defined as (by other than medical reasons): * ≥ 45 years of age and has not had menses for \> 2 years * Amenorrheic for \< 2 years without a hysterectomy and/or oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation * Post hysterectomy or oophorectomy. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. * For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use two forms of highly effective contraception (i.e., one that results in a low failure rate \[\< 1% per year\] when used consistently and correctly) and to continue its use for 150 days after the last dose of all study drugs (atezolizumab, entinostat, and bevacizumab). * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Exclusion Criteria Patients who meet any of the following criteria will be excluded from study entry. General Exclusion Criteria: * Any approved anti-cancer therapy, including chemotherapy, hormonal therapy, or radiotherapy, ≤ 3 weeks prior to first dose of study drug; however, the following are allowed: * Hormone-replacement therapy or oral contraceptives * Herbal therapy \> 1 week prior to Cycle 1, Day 1 (herbal therapy intended as anti-cancer therapy must be discontinued at least 1 week prior to Cycle 1, Day 1) * Palliative radiotherapy for bone metastases \> 2 weeks prior to Cycle 1, Day 1 * Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device ≤ 4 weeks of the first dose of study drug. * AEs from prior anti-cancer therapy that have not resolved to Grade ≤ 1 except for alopecia and neuropathy * Any contraindication to oral agents or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the investigator, would preclude adequate absorption. * Bisphosphonate therapy for symptomatic hypercalcemia * Use of bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is allowed. * Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease * Patients with acute leukemias, accelerated/blast phase chronic myelogenous leukemia, chronic lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, or non-secretory myeloma * Known primary central nervous system (CNS) malignancy or symptomatic CNS metastases - Patients with asymptomatic untreated CNS disease may be enrolled, provided all of the following criteria are met: Evaluable or measurable disease outside the CNS No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm) No history of intracranial hemorrhage or spinal cord hemorrhage No ongoing requirement for dexamethasone for CNS disease; patients on a stable dose of anticonvulsants are permitted. No neurosurgical resection or brain biopsy ≤ 28 days prior to Cycle 1, Day 1 \- Patients with asymptomatic treated CNS metastases may be enrolled, provided all the criteria listed above are met as well as the following: Radiographic demonstration of improvement upon the completion of CNS directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study No stereotactic radiation or whole-brain radiation ≤ 28 days prior to Cycle 1, Day 1 Screening CNS radiographic study ≥ 4 weeks from completion of radiotherapy and ≥ 2 weeks from discontinuation of corticosteroids * Pregnancy, lactation, or breastfeeding * Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies * Known hypersensitivity to any component of bevacizumab * Allergy to benzamide or inactive components of entinostat * Inability to comply with study and follow-up procedures * Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study. * Uncontrolled hypertension (defined as systolic blood pressure \>150 mmHg and/or diastolic blood pressure \> 100 mmHg) that persists over 3 weeks and 3 consecutive measurements (each one week apart) despite medication * Prior history of hypertensive crisis or hypertensive encephalopathy * Uncontrolled diabetes mellitus * History or risk of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis * Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible. * Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions: Rash must cover less than 10% of body surface area (BSA) Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%) No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation \[PUVA\], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids) * History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan \- History of radiation pneumonitis in the radiation field (fibrosis) is permitted. * Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications * History of HIV infection (HIV 1/2 antibodies) or active hepatitis B (chronic or acute) or hepatitis C infection * Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen \[HBsAg\] test and a positive anti-HBc \[antibody to hepatitis B core antigen\] antibody test) are eligible. HBV DNA test must be performed in these patients prior to study treatment. * Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. * Active tuberculosis * Clinically significant (i.e. active) cardiovascular disease (e.g., myocardial infarction or arterial thromboembolic events ≤ 6 months prior to screening or severe or unstable angina, New York Heart Association (NYHA) Class III or IV disease, Grade II or greater congestive heart failure, or serious cardiac arrhythmia (see Appendix 5), or a QTc interval \> 470 msec.) * Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis ≤ 6 months of study enrollment * Any previous venous thromboembolism \> NCI CTCAE Grade 3 * History of hemoptysis (≥ ½ teaspoon of bright red blood per episode) ≤ 28 days of study enrollment * Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation) * Current or recent (≤ 10 days of study enrollment) use of aspirin (\> 325 mg/day), clopidogrel (\>75 mg/day), or therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to medical standard of the institution) and the patient has been on a stable dose of anticoagulants for at least 2 week at the time of study enrollment. Prophylactic use of anticoagulants is allowed. * Severe infections ≤ 4 weeks prior to Cycle 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia * Signs or symptoms of infection ≤ 2 weeks prior to Cycle 1, Day 1 * Received oral or IV antibiotics ≤ 2 weeks prior to Cycle 1, Day 1 \- Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible. * Major surgical procedure ≤ 28 days prior to Cycle 1, Day 1 or anticipation of need for a major pre-planned surgical procedure during the course of the study * Administration of a live, attenuated vaccine ≤ 4 weeks before Cycle 1, Day 1 or anticipation that such a live, attenuated vaccine will be required during the study \- Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine (e.g., FluMist ®) ≤ 4 weeks prior to Cycle 1, Day 1 or at any time during the study. * History of abdominal fistula or gastrointestinal perforation ≤ 6 months before Cycle 1, Day 1. Serious non-healing wound, active ulcer, or untreated bone fracture (adjuvant trials: bone fractures must be healed) * Proteinuria as demonstrated by a UPC ratio ≥ 1.0 at screening * Malignancies other than the disease under study ≤ 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent) or undergoing active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason score ≤ 6, and prostate-specific antigen \[PSA\] ≤ 10 mg/mL, etc.) Medication-Related Exclusion Criteria: * Treatment with systemic immunostimulatory agents (including but not limited to interferon \[IFN\]- α or interleukin \[IL\]-2) ≤ 6 weeks or five half-lives of the drug (whichever is shorter) prior to Cycle 1, Day 1 * Treatment with investigational agent ≤ 4 weeks prior to Cycle 1, Day 1 (or within five half lives of the investigational product, whichever is longer) * Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor \[anti-TNF\] agents) ≤ 2 weeks prior to Cycle 1, Day 1 * Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled. * The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed. * History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins * Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation