| Eligibility |
Inclusion Criteria:
- Patients must have:
- A diagnosis of HLRCC with a histologic or cytologic confirmation of RCC
consistent with this diagnosis (Cohort 1) OR
- Cytologically or histologically confirmed sporadic/non-HLRCC papillary renal cell
carcinoma (presence of papillary component) (Cohort 2)
- Patients must have advanced RCC with measurable disease, defined as at least one
lesion that can be accurately measured in at least one dimension (longest diameter to
be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2
cm) by chest x-ray or as >= 10 mm (>= 1 cm) with CT scan, MRI, or calipers by clinical
exam. To be considered pathologically enlarged and measurable, a lymph node must be >=
15 mm (>= 1.5 cm) in short axis
- Patients must have received no more than two prior regimens targeting the VEGF pathway
and no prior bevacizumab therapy in the metastatic/advanced setting. No prior
treatment with PD-1 or PD-L1 inhibitors in the metastatic/advanced setting. No prior
therapy is required for eligibility
- Age >= 12 years
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Absolute neutrophil count >= 1,000/mcL
- Platelets >= 100,000/mcL
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (< 3 x upper limit
of reference range in patients with known/suspected Gilbert's disease)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN (or =< 5 x upper limit of reference range if considered to
be related to liver or bone metastases by the principal investigator [PI])
- Alkaline phosphatase =< 2.5 x institutional ULN (or =< 5 x upper limit of reference
range if considered to be related to liver or bone metastases by the PI)
- Note: For pediatric patients (< 18 years of age), ULN for alkaline phosphatase
will be defined as 390 IU/L for males and 320 IU/L for females
- Glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2
- Note: For pediatric patients (< 18 years of age) the following creatinine
thresholds will be utilized. Patients with a creatinine that exceeds this
threshold will require further testing with a confirmation of GFR >= 40 as
determined by either 24-hour urine collection or with radioisotope based nuclear
medicine evaluation
- Age: 12 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female)
- Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)
- Age: 16 to < 18 years; Maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)
- The threshold creatinine values in this table were derived from the Schwartz
formula for estimating GFR, utilizing child length and stature data
published by the Centers for Disease Control and Prevention (CDC)
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with an undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
- Patients with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of
progression/recurrence for >= 3 months and the patient no longer requires more than a
physiologic dose of steroids
- Patients with a prior or concurrent invasive malignancy whose natural history or
treatment does not have the potential to interfere with the safety or efficacy
assessment of the investigational regimen are eligible for this trial
- Patients with a known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class 2B or better
- The effects of study drugs on the developing human fetus are unknown. For this reason,
all women and men of childbearing potential must agree to use adequate contraception
(including but not limited to abstinence, barrier methods, hormonal contraceptives
[birth control pills, injections, or implants], intrauterine device [IUD], tubal
ligation, vasectomy) prior to study entry and for 6 months after completion of study
therapy. Should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, she should inform her treating physician
immediately. Men treated or enrolled on this protocol must also agree to use adequate
contraception prior to the study, and 6 months after completion of study drugs
administration
- Subjects must provide archival tissue block or unstained tumor tissue or be willing to
undergo biopsy to collect samples for retrospective central pathology review
- The ability of subject or parent/guardian to understand and the willingness to sign a
written informed consent document or subjects with impaired decision making capacity
(IDMC) if they are represented by a legally authorized representative (LAR)
Exclusion Criteria:
- Any prior systemic therapy to treat the patient's kidney cancer within 4 weeks or, if
known, 5 half-lives of the prior agent (whichever is shorter) prior to cycle 1 day 1
- Other prior therapies for kidney cancer: Radiotherapy < 2 weeks prior to cycle 1, day
1
- Major surgical procedure < 28 days before cycle 1, day 1. Surgical procedure change
(including open biopsy, surgical resection, wound revision, or any other major surgery
involving entry into a body cavity) or significant traumatic injury within 28 days
prior to initiation of study treatment, or anticipation of need for major surgical
procedure during the course of the study. Surgical wounds must be healed prior to
starting therapy. However, the following therapies are allowed:
- Hormone-replacement therapy or oral contraceptives
- Herbal therapy > 1 week prior to cycle 1, day 1. All herbal 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
- Patients who have not recovered from adverse events due to prior systemic anti-cancer
therapy (i.e., have residual toxicities > grade 1 of the Common Terminology Criteria
for Adverse Events [CTCAE] version [v]5, pre-treatment baseline or to a level
permitted under other sections of inclusion/exclusion criteria) with the exception of
alopecia or electrolyte abnormalities that can be corrected to =< grade 1 prior to
treatment initiation
- Treatment with any other investigational agent within 4 weeks prior to cycle 1, day 1
- Treatment with systemic immunostimulatory agents (including, but not limited to,
interferon [IFN]-alpha or interleukin [IL]-2) within 6 weeks prior to cycle 1, day 1
- Treatment with systemic immunosuppressive medications (including, but not limited to,
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor [anti-TNF] agents) within 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 or for purposes of
pre-medication prior to radiology studies) may be enrolled
- The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone)
for patients with orthostatic hypotension or adrenocortical insufficiency is
allowed
- Hypercalcemia > grade 1 of the CTCAE v5 that is not corrected prior to treatment
initiation
- Patients taking bisphosphonate therapy for symptomatic hypercalcemia. Use of
bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is
allowed
- History 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, Sjogren's
syndrome, Bell's palsy, Guillain-Barre 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 controlled type 1 diabetes mellitus on a stable insulin regimen 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:
- Patients with psoriasis must have a baseline ophthalmologic exam to rule out
ocular manifestations
- Rash must cover less than 10% of body surface area (BSA)
- The disease is well controlled at baseline and only requiring low potency
topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)
- No acute exacerbations of the 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. History of radiation pneumonitis
in the radiation field (fibrosis) is permitted
- Patients with active tuberculosis (TB) are excluded
- Severe infections within 4 weeks prior to cycle 1, day 1, including, but not limited
to, hospitalization for complications of infection, bacteremia, or severe pneumonia
- Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 or
anticipation that such a live, attenuated vaccine will be required during the study
and up to 5 months after the last dose of atezolizumab
- NOTE: Seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist)
are live attenuated vaccines and are not allowed. Influenza vaccination should be
given during influenza season only (approximately October to March)
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection requiring intravenous antibiotics, symptomatic congestive heart failure,
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations
that would limit compliance with study requirements
- Poorly controlled hypertension with at least 2 occasions of elevated blood pressure
within a week before treatment initiation (Adults: resting systolic blood pressure
greater than 140 mmHg or diastolic blood pressure greater than 90 mmHg. Pediatric [<
18 years old]: Blood pressure [BP] >= the 95th percentile for age, height, and gender
on at least two occasions separated by a 24-hour period despite optimal medical
management). History of hypertensive crisis or hypertensive encephalopathy
- Patients with prior allogeneic bone marrow transplantation or prior solid organ
transplantation
- History of anaphylactic or severe allergic reactions attributed to compounds of
similar chemical or biologic composition to the study agents
- Patients with myocardial infarction, gastrointestinal (GI) perforation/fistula,
intraabdominal abscess, or cerebrovascular accidents within 6 months before cycle 1,
day 1
- Documented baseline proteinuria > 1000 mg/day on 24-hour urine collection. Only
patients with 1+ or greater proteinuria on urinalysis (UA) and a spot urine
protein:creatinine ratio of > 0.5 will undergo a 24-hour urine collection for
quantitation of proteinuria
- Pregnant women are excluded from this study because study drugs may have the potential
for teratogenic or abortifacient effects. Because there is an unknown but potential
risk for adverse events in nursing infants secondary to treatment of the mother with
study drugs, breastfeeding should be discontinued if the mother is treated with study
drugs
- Serious, non-healing wound or ulcer; bone fracture within 3 months prior to treatment
initiation
- Concomitant therapy with potent inhibitors of CYP450 3A4 (e.g. ketoconazole,
verapamil, etc.) or potent CYP3A4 inducers or with potent CYP450 1A2 inhibitors
(fluoroquinolone antibiotics including ciprofloxacin, levofloxacin, and norfloxacin;
ticlopidine, cimetidine, amiodarone, etc.) who cannot discontinue or change these
medications prior to the start of study treatment
- Patients who use tobacco or nicotine products and cannot stop their use of these
products for the duration of study treatment
- Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
recent arterial thrombosis) within 6 months prior to cycle 1, day 1
- History of or active hemoptysis within 1 month prior to cycle 1 day 1
- History of grade >= 4 venous thromboembolism
- History or evidence of inherited bleeding diathesis or significant coagulopathy at
risk of bleeding (i.e., in the absence of therapeutic anticoagulation)
- Current or recent (< 10 days prior to initiation of study treatment) use of aspirin (>
325 mg/day), or clopidogrel (> 75 mg/day)
- Note: The use of full-dose oral or parenteral anticoagulants for therapeutic
purpose is permitted as long as the International Normalized Ratio (INR) and/or a
partial thromboplastin time (PTT) is within therapeutic limits (according to
institution standards) within 7 days prior to initiation of study treatment and
the patient has been on a stable dose of anticoagulants for >= 2 weeks prior to
initiation of study treatment. Prophylactic use of anticoagulants is allowed.
However, the use of direct oral anticoagulant therapies such as dabigatran
(Pradaxa [registered trademark]) and rivaroxaban (Xarelto [registered trademark])
may be used per PI discretion
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