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

Age Range:18 - Any
Start Date:April 2016
End Date:October 2023
Contact:Toni Choueiri, MD

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

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

This research study is a Phase II clinical trial. In this research the investigators are
studying the combination of Atezolizumab with Bevacizumab. Participants will receive both
vascular endothelial targeted therapy and immunotherapy.

The FDA (the U.S. Food and Drug Administration) has not approved Atezolizumab for Advanced
Non-Clear Cell Kidney Cancer, but it has been approved for other uses.

The FDA has approved Bevacizumab with Interferon (IFNα) as a treatment option for Advanced
Kidney Cancer.

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

- 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

- 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

- 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

- 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

- 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.
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