Clinical trial NCT04090710: SBRT With Combination Ipilimumab/Nivolumab for Metastatic Kidney Cancer
Official title: Cytoreductive Stereotactic Hypofractionated Radiotherapy With Combination Ipilimumab/Nivolumab for Metastatic Kidney Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Metastatic Renal Cell Carcinoma
Keywords: SBRT
Ipilimumab
Nivolumab
Lead sponsor: Ontario Clinical Oncology Group (OCOG)
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2019-09-16
Enrollment: 66
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Eligible and consenting, newly diagnosed and histologically confirmed intermediate/poor risk metastatic renal cell carcinoma patients 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).
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Progression free survival (PFS)
timeFrame: 2 years
Secondary outcomes:
measure: Subject safety
timeFrame: Date of randomization until 1year post treatment
measure: Overall Survival
timeFrame: 2 years
measure: Objective response rate
timeFrame: 1 year
measure: Quality of Life: EORTC QLQ-C30 questionnaire
timeFrame: 1 year
measure: Subject safety
timeFrame: 1 Year
measure: Ipilimumab/ Nivolumab drug tolerability
timeFrame: From the date of randomization until date of first documented disease progression up to 1 year.
measure: Ipilimumab/ Nivolumab drug tolerability
timeFrame: From the date of randomization until date of first documented disease progression, up to 1 year.
measure: Ipilimumab/ Nivolumab drug tolerability
timeFrame: From the date of randomization until date of first documented disease progression, up to 1 year.
measure: Ipilimumab/ Nivolumab drug tolerability
timeFrame: From the date of randomization until date of first documented disease progression, up to 1 year.
Other outcomes:
measure: Exploratory Outcomes: Evaluation of baseline and changes during treatment in blood immune signatures
timeFrame: 1 year
measure: Exploratory Outcomes: Evaluation of baseline and changes during treatment in stool microbiome
timeFrame: 1 year
measure: Correlation with blood or stool immune signatures
timeFrame: 1 year
Locations:
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre
state: Ontario
city: Kitchener
country: Canada
facility: Grand River Regional Cancer Centre
state: Ontario
city: London
country: Canada
facility: London Regional Cancer Centre
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Regional Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre- Odette Cancer Centre
state: Ontario
Study officials:
affiliation: Juravinski Cancer Centre
name: Aly-Khan Lalani, MD
role: PRINCIPAL_INVESTIGATOR
References: