SBRT With Combination Ipilimumab/Nivolumab for Metastatic Kidney Cancer
SBRT With Combination Ipilimumab/Nivolumab for Metastatic Kidney Cancer
This trial will evaluate the addition of cytoreductive stereotactic body radiation therapy
 (SBRT) to standard of care combination ipilimumab and nivolumab (I/N) versus I/N alone for
 the treatment of metastatic kidney cancer.
This is a multi-centre, open label, phase II randomized clinical trial evaluating SBRT as
 upfront cytoreductive therapy to the primary renal mass along with combination I/N therapy in
 patients with intermediate/poor risk mRCC who are not candidates for cytoreductive
 nephrectomy. Eligible and consenting, newly diagnosed and histologically confirmed
 intermediate/poor risk mRCC patients based on IMDC criteria with primary disease in-situ will
 be randomized in a 2:1 fashion to either induction I/N followed by SBRT prior to the second
 cycle (experimental arm) versus I/N alone (standard arm). Patients will be stratified based
 on IMDC criteria (intermediate 1-2 versus poor 3-6).

 -  Standard Arm: induction ipilimumab 1 mg/kg combined with nivolumab 3 mg/kg (I/N) every 3
 weeks for cycles 1-4 followed by maintenance treatment with nivolumab 240mg every 2
 weeks or 480mg every 4 weeks until disease progression (as determined by RECIST 1.1),
 intolerance, or patient/physician decision to stop treatment.

 -  Experimental Arm: induction ipilimumab 1 mg/kg combined with nivolumab 3 mg/kg (I/N)
 every 3 weeks for one cycle, followed by SBRT to the primary disease in-situ, prior to
 cycle 2-4 of I/N. Patients randomized to SBRT will undergo radiation planning during the
 first cycle of I/N to their primary kidney mass, and then the radiation will be
 delivered between cycles 1 and 2 to a dose of 30-40 Gy in 5 fractions every other day
 over 1.5 weeks. Approximately one week following completion of SBRT, patients will start
 cycle 2 of I/N as per standard of care. The total time elapsed between the start of
 cycle 1 and 2 of I/N should be no more than 6 weeks. After completion of up to four
 cycles of I/N, patients will proceed to standard of care maintenance treatment with
 nivolumab 240mg every 2 weeks or 480mg every 4 weeks until disease progression (as
 determined by RECIST 1.1), intolerance, or patient/physician decision to stop treatment.

 During treatment (standard and experimental arm) participants will be assessed for radiation
 toxicity and the occurrence of adverse events. Following treatment, participants will be
 assessed at a clinic visit every 3 months, for a period of 1 year. Progression free survival
 will be assessed by CT scan (chest; abdomen and pelvis), which is performed after the final
 I/N treatment and every 3 months as per standard of care. Participants will be followed for
 one additional year, seen at 18 and 24 months to assess survival. The planned sample size is
 78 study participants.
Inclusion Criteria:

 1. Biopsy proven renal cell carcinoma of any histology.

 2. Imaging proven metastatic disease based on CT or MRI within 10 weeks of screening.

 3. Intermediate/poor risk disease based on IMDC criteria (see Appendix II).

 4. Primary kidney lesion amenable to SBRT.

 5. Eligible for standard of care delivery of ipilimumab and nivolumab (I/N) according to
 approved product monograph.

 Exclusion Criteria:

 1. A maximum primary renal lesion size of 20 cm or greater.

 2. Candidate for cytoreductive nephrectomy, unless a patient has refused cytoreductive
 nephrectomy (in this case, a discussion of cytoreductive nephrectomy and patient
 refusal must be documented).

 3. Treatment with prior systemic therapy in the adjuvant or metastatic setting for renal
 cell carcinoma.

 4. Previous abdominal radiation precluding SBRT.

 5. Kanofsky Performance (KPS) score below 60 (see Appendix III).

 6. History of auto-immune disorder precluding treatment with ipilimumab or nivolumab.

 7. History of ataxia telangiectasia or other radiation sensitivity disorders.

 8. Chronic corticosteroid use or other chronic immune suppressive therapy. (Participants
 are permitted the use of topical, ocular, intra-articular, intranasal, and
 inhalational corticosteroids (with minimal systemic absorption). Adrenal replacement
 steroid doses of prednisone ≤ 10 mg daily are permitted).

 9. Use of medicinal herbal preparations (not including medical cannabis) unless
 prescribed by a treating physician.

 10. Inability to lie flat for at least 30 minutes without moving.

 11. Pregnant or lactating women.

 12. Geographic inaccessibility for follow-up.

 13. Inability to provide informed consent.