Trial of SBRT in Combination With Nivolumab/Ipilimumab in RCC / Kidney Cancer Patients

The study is planned based on a two-stage design that allows early termination for lack of
efficacy. A safety run-in phase will be included comprising the first 6 patients at minimum
to ensure that the combination of nivolumab plus ipilimumab and SBRT is safe. Then, the
investigators will determine whether the combination of nivolumab plus ipilimumab and SBRT
yields a clinically compelling antitumor activity measured as ORR, and evaluate other
endpoints including TTP, DOR, PFS, OS and local control of irradiated sites.

There is no previous experience with SBRT used concurrently with nivolumab and ipilimumab in
this study population. Therefore, to ensure that the combination is safe, the first six
patients will be treated and observed for toxicity for 6 weeks after radiation before
continuing with further accrual. Therefore, six patients will be enrolled at the proposed
dose of nivolumab and ipilimumab in combination with SBRT. If 4 out of the first 6 patients
experience Grade 3/4 toxicity or a lower grade toxicity requiring immune suppressive therapy
during the safety run-in observation period (defined as the first 4-cycles, 12 weeks),
enrollment will cease and the study will be halted until further safety analysis of the
combination regimen can be performed. If less than 4 out of the first 6 patients experience
Grade 3/4 toxicities or require steroids, the investigators will proceed with additional
accrual with this regimen.

Inclusion Criteria:

- Histological confirmation of RCC with a clear-cell component

- Metastatic (AJCC Stage IV) RCC

- Prior adjuvant or neoadjuvant therapy for localized or locally advanced RCC is allowed
provided recurrence occurred = or > 6 months after the last dose of the adjuvant or
neoadjuvant therapy

- Any number of prior systemic treatment regimen in the advanced/metastatic setting is
allowed (cytokine, anti-angiogenic, mTOR inhibitor or clinical trial) including
previously untreated patients

- Karnofsky Performance Status (KPS) of at least 70%

- Life expectancy of at least 3 months

- At least 2 metastatic sites of which at least 1 must be measurable as per RECIST 1.1

- Archival Formalin-fixed paraffin-embedded (FFPE) tumor tissue must be available for
correlative studies (Note: Fine Needle Aspiration [FNA] and bone metastases samples
are not acceptable for submission)

- Patients with favorable, intermediate and poor risk categories will be eligible for
the study. Patients must be categorized according to favorable versus
intermediate/poor risk status at registration. International Metastatic RCC Database
Consortium (IMDC) must be used to determine prognostic factors

Exclusion Criteria:

- Subjects with previously treated brain or CNS metastases are eligible provided that
the subject has recovered from any acute effects of radiotherapy and is not requiring
steroids, and any whole brain radiation therapy was completed at least 4 weeks prior
to study drug administration, or any stereotactic radiosurgery was completed at least
2 weeks prior to study drug administration. Liver metastases will not be included as
part of the radiated lesions to be treated.

Medical History and Concurrent Diseases:

- Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4
antibody, or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways. Prior treatment with HD IL-2 is allowed.

- Any active or recent history of a known or suspected autoimmune disease or recent
history of a syndrome that required systemic corticosteroids (> 10 mg daily prednisone
equivalent) or immunosuppressive medications except for syndromes which would not be
expected to recur in the absence of an external trigger. Subjects with vitiligo or
type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only
requiring hormone replacement are permitted to enroll. Patients with psoriasis not
requiring active, systemic treatment are allowed.

- Any condition requiring systemic treatment with corticosteroids (> 10 mg daily
prednisone equivalents) or other immunosuppressive medications within 14 days prior to
first dose of study drug. Inhaled steroids and adrenal replacement steroid doses up to
10 mg daily prednisone equivalents are permitted in the absence of active autoimmune
disease

- Uncontrolled adrenal insufficiency

- Requirement for anti-coagulation with Coumadin, low molecular weight heparin and
anti-thrombin inhibitors will be accepted if anticoagulation has been stable for at
least 4 weeks and no recent history of prior bleeding complications.

- Prior malignancy active within the previous 3 years except for locally curable cancers
that have been apparently cured such as basal or squamous cell skin cancer,
superficial bladder cancer, or carcinoma in situ of the cervix, breast or low risk
Gleason 6 prostate cancer

- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS)

- Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic
infection

- Known medical condition (eg, a condition associated with diarrhea or acute
diverticulitis) that, in the investigator's opinion, would increase the risk
associated with study participation or study drug administration or interfere with the
interpretation of safety results

- Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study
drug

- Anti-cancer therapy less than 14 days prior to the first dose of study drug or
palliative, focal radiation therapy less than 14 days prior to the first dose of study
drug

- Presence of any toxicities attributed to prior anti-cancer therapy, other than
alopecia, that have not resolved to Grade 1 (NCI CTCAE v4) or baseline before
administration of study drug

Physical and Laboratory Test Findings:

- Any of the following laboratory test findings:

- WBC < 2,000/mm3

- Neutrophils < 1,500/mm3

- Platelets < 100,000/mm3

- AST or ALT > 3 x ULN (> 5 x ULN if liver metastases are present)

- Total Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome, who can have
total bilirubin < 3.0 mg/dL)

- Serum creatinine > 1.5 x upper limit of normal (ULN) or creatinine clearance < 40
mL/min (measured or calculated by Cockroft-Gault formula)

Allergies and Adverse Drug Reaction:

- History of severe hypersensitivity reaction to any monoclonal antibody or study drug
components

Other Exclusion Criteria:

- Prisoners or subject who are involuntarily incarcerated

- Not suitable for SBRT treatment

- Subjects who are compulsorily detained for treatment of either a psychiatric or
physical illness