Study of Atezolizumab + Bevacizumab in Patients With Advanced Non-Clear Cell Renal Cell Carcinoma

Inclusion Criteria:

* Age ≥ 18 years.
* Unresectable advanced or metastatic non-clear cell RCC to include but not limited to:

  * Papillary RCC, any type
  * Unclassified RCC
  * Translocation RCC
  * Chromophobe RCC
  * Collecting duct RCC
  * Medulary RCC
  * Clear cell RCC or any histology with \> 20% sarcomatoid features will be eligible.
  * Other non-clear cell histologies that are not included above need to be discussed with the PI.
* Request for formalin-fixed, paraffin-embedded (FFPE) archival tumor specimens if available and willingness of the participant to undergo mandatory fresh tumor biopsy unless determined medically unsafe or not feasible. A note from the study team should be provided documenting availability of tissue. If a target lesion is biopsied at screening, this lesion must be followed as non-target lesion after the biopsy unless it is the patient's only target lesion. If there is only one target lesion, it should be followed as a target lesion regardless.

  * The archival specimen should contain adequate viable tumor tissue.
  * The specimen may consist of a tissue block (preferred and should contain the highest grade of tumor) or at least 30 unstained serial sections. Fine-needle aspiration, brushings, cell pellet from pleural effusion, bone marrow aspirate/biopsy are not acceptable.
  * Fresh tumor biopsy at progression will be required in cases where patients experience relapse after an initial response if medically safe.
* Measurable disease as defined by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1.
* ECOG performance status ≤ 2 (See Appendix A).
* Adequate hematologic and end-organ function as defined by the following laboratory results obtained within 28 days prior to the first study treatment:

  * Absolute neutrophil count (ANC) ≥ 1500 cells/uL.
  * Lymphocyte count ≥ 500/uL.
  * Platelet count ≥ 100,000/uL.
  * Hemoglobin ≥ 9 g/dL (patients may be transfused to meet this criterion).
  * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN) with the following exceptions: Patients with documented liver metastases should have AST and ALT ≤ 5 x ULN.
  * Serum bilirubin ≤ 2.0 x ULN with the following exception: Patients with known Gilbert's disease should have a serum bilirubin ≤ 3 x ULN.
  * Creatinine clearance ≥ 30 mL/min as calculated by Cockcroft-Gault equation.
* For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use highly effective forms of contraception and to continue its use 6 months after the last dose of atezolizumab or bevacizumab.
* Signed informed consent form.
* Ability and capacity to comply with study and follow-up procedures.

Exclusion Criteria

•Prior treatment with CD137 agonists, anti- cytotoxic T-lymphocyte-associated protein 4, anti-PD-1, or anti-PDL1 therapeutic antibody or pathway targeting agents.

Prior IFNα or IL-2 is allowed following 4 week washout from treatment end date.

* Receipt of any type of small molecule 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 4 weeks of enrollment.
* Prior therapy with bevacizuamab.
* Thrombologic event within 3 weeks of treatment start date, unless stable on anticoagulation with LMWH or Factor Xa inhibitor for at least 2 weeks.
* Treatment with systemic immunosuppressive medications including but not limited to: prednisone, dexamethasone, cyclosporin, azathioprine, methotrexate, thalidomide, anti- tumor necrosis factor (TNF) agents, hydroxychloroquine within 2 weeks of first study dose.

  * Patients who have received acute, low-dose systemic immunosuppressant medications may be enrolled.
  * Patients with adrenal insufficiency on physiologic replacement doses of steroids may be enrolled.
  * The use of inhaled, topical intraocular, or intra articular corticosteroids or, mineralocorticoids are allowed.
* Radiotherapy for RCC within 14 days of first study treatment with the exception of a single fraction of radiation administered for palliation of symptoms.
* Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks prior to the initiation of study treatment. Stability must be confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) imaging and/or treating investigator determination.
* Malignancies other than RCC within 2 years of first study treatment with the exception of those with negligible risk of metastases or death (included but not limited to 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, or other malignancy not deemed to impact that patients 5-year life expectancy).
* History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein.
* Known hypersensitivity to any component of the atezolizumab product.
* History of autoimmune disease including: myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, Wegner's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, type I diabetes mellitus, vasculitis, or glomerulonephritis. Patients with a history of autoimmune-related hypothyroidism on thyroid replacement hormone or those with autoimmune dermatologic conditions not requiring the use of prednisone \> 10 mg or equivalent are eligible.
* History of idiopathic pulmonary fibrosis, organized pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening imaging CT of the chest. History of radiation pneumonitis in the radiation field is permitted.
* Positive test for HIV (test to be performed within 28 days of first treatment start).
* Patients with active or chronic hepatitis B (defined as having a positive hepatitis B surface antigen \[HBsAg\] test at screening). Patients with past/resolved HBV infection (defined as having negative HBsAg test and a positive antibody to hepatitis B core antigen \[anti-HBc\] antibody test) are eligible. A negative HBA DNA test must be obtained in patients with positive hepatitis B core antibody prior to Cycle 1 Day 1.
* Active hepatitis C infection. Patients positive hepatitis C antibody test are eligible if PCR is negative for hepatitis C viral DNA.
* Infection requiring receipt of therapeutic oral or IV anti-microbials within 2 weeks of first study treatment. Patients receiving routine anti-microbial prophylaxis (for dental extractions/procedures) are eligible.
* Significant cardiovascular disease such as New York Heart Association (NYHA) class II or greater, myocardial infarction within the previous 3 months of first study treatment, unstable arrhythmias, unstable angina. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction \< 50% must be on a stable regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist when appropriate.
* Inadequately controlled hypertension (defined as systolic blood pressure \> 150 mmHg and/or diastolic blood pressure \> 100 mmHg). Anti-hypertensive therapy to achieve these parameters is allowed.
* Prior history of hypertensive crisis or hypertensive encephalopathy within the previous 3 months of first study treatment.
* History of stroke or transient ischemic attack within 3 months of first study dose.
* Significant vascular disease (such as aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months of first study dose. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
* Current or recent use of dipyramidole, ticlopidine, clopidogrel, cilostazol is excluded. Aspirin (≤ 325 mg per day) is allowed. Prophylactic anticoagulation with oral or parenteral anticoagulants for the patency of venous access devices or other indications is allowed. Therapeutic use of low-molecular weight heparin (such as enoxaparin), and factor Xa inhibitors are allowed. Use of warfarin is prohibited.
* Use of plaquenil must be discontinued two weeks prior to first study treatment.
* History of abdominal or tracheoesophageal fistula or GI perforation within 6 months of first study treatment.
* Clinical signs or symptoms of active GI obstruction or requirement of routine parenteral nutrition or tube feedings.
* Evidence of abdominal free air not explained by paracentesis or recent surgical procedure.
* Serious, non-healing or dehiscing wound or active ulcer.
* Proteinuria, as demonstrated by \> 1.5 gram of protein in a 24-hour urine collection. All patients with ≥ 2+ protein on dipstick urinalysis at baseline must undergo 24-hour urine collection for protein.
* Major surgical procedure within 21 days of first study treatment.
* Prior allogenic stem cell or solid organ transplant.
* Administration of a live, attenuated vaccine within 4 weeks for first study treatment.
* Pregnant or lactating women.