Study of Atezolizumab + Bevacizumab in Patients With Advanced Non-Clear Cell Renal Cell Carcinoma
Condition: Advanced Non-Clear Cell Kidney Cancer
MeSH terms: Carcinoma, Renal Cell; Kidney Neoplasms
Intervention: Bevacizumab; Atezolizumab
Intervention MeSH terms: Bevacizumab; Atezolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 65.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Kidney Cancer

Summary:

      This research study is studying the combination of Atezolizumab and Bevacizumab as a possible
      treatment for Advanced Non-Clear Cell Kidney Cancer.
    

Eligibility criteria:

        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.