SBRT With Combination Ipilimumab/Nivolumab for Metastatic Kidney Cancer

Metastatic Renal Cell Carcinoma Clinical Trial

— CYTOSHRINK  

Official title:

Cytoreductive Stereotactic Hypofractionated Radiotherapy With Combination Ipilimumab/Nivolumab for Metastatic Kidney Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04090710
• Other study ID #: OCOG-2019-CYTOSHRINK
• Secondary ID: CA209-7DR
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: January 29, 2020
• Est. completion date: March 31, 2025

Study information

• Verified date: April 2024
• Source: Ontario Clinical Oncology Group (OCOG)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 66
• Est. completion date: March 31, 2025
• Est. primary completion date: March 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma, Renal Cell
• Kidney Neoplasms
• Metastatic Renal Cell Carcinoma

Intervention

Drug:
• Ipilimumab/ Nivolumab
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

Radiation:
• SBRT + Ipilimumab/Nivolumab
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.

Locations

Country	Name	City	State
Australia	Peter MacCallum Cancer Centre	Melbourne
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	Juravinski Cancer Centre	Hamilton	Ontario
Canada	Grand River Regional Cancer Centre	Kitchener	Ontario
Canada	London Regional Cancer Centre	London	Ontario
Canada	The Ottawa Regional Cancer Centre	Ottawa	Ontario
Canada	Sunnybrook Health Sciences Centre- Odette Cancer Centre	Toronto	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
Ontario Clinical Oncology Group (OCOG)	Bristol-Myers Squibb

Countries where clinical trial is conducted

Australia,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Exploratory Outcomes: Evaluation of baseline and changes during treatment in blood immune signatures	Changes in blood immune signatures through interrogation of circulating blood biomarkers.	1 year
Other	Exploratory Outcomes: Evaluation of baseline and changes during treatment in stool microbiome	Changes in stool microbiome using 16S RNA.	1 year
Other	Correlation with blood or stool immune signatures	Tumor tissue analysis using immunohistochemistry	1 year
Primary	Progression free survival (PFS)	The primary outcome of this study is the hazard ratio for progression-free survival (PFS), defined from the date of randomization until the date of progression (PFS truncated at subsequent systemic therapy) as determined by RECIST 1.1, or death due to any cause, whichever comes first. All attempts will be made to follow-up patients for the primary outcome measure for at least one year, even if a patient stops treatment. Patients who do not have a primary outcome event at the time of analysis will be censored on the last date the patient can be confirmed as alive and progression-free.	2 years
Secondary	Subject safety	Incidence and attribution of deaths	Date of randomization until 1year post treatment
Secondary	Overall Survival	• Overall survival, defined from the date of randomization to the date of death due to any cause. Patients with no known death date at the time of analysis will be censored on the last date they are confirmed alive.	2 years
Secondary	Objective response rate	• Objective response rate, which is defined as the proportion of randomized subjects who achieve a best response of complete response (CR) or partial response (PR) using the RECIST 1.1 criteria.	1 year
Secondary	Quality of Life: EORTC QLQ-C30 questionnaire	• Quality of life, which will be evaluated using the EORTC QLQ-C30 questionnaire.	1 year
Secondary	Subject safety	Number of Adverse Events and Serious Adverse Events using NCI CTCAE v5.0	1 Year
Secondary	Ipilimumab/ Nivolumab drug tolerability	Ipilimumab/Nivolumab treatment discontinuation rates	From the date of randomization until date of first documented disease progression up to 1 year.
Secondary	Ipilimumab/ Nivolumab drug tolerability	Number of doses of Ipilimumab/Nivolumab combination treatment	From the date of randomization until date of first documented disease progression, up to 1 year.
Secondary	Ipilimumab/ Nivolumab drug tolerability	Number of Nivolumab maintenance doses	From the date of randomization until date of first documented disease progression, up to 1 year.
Secondary	Ipilimumab/ Nivolumab drug tolerability	Time to treatment discontinuation from the date of randomization	From the date of randomization until date of first documented disease progression, up to 1 year.