SBRT With Combination Ipilimumab/Nivolumab for Metastatic Kidney Cancer (CYTOSHRINK)

• ClinicalTrials.gov Identifier: NCT04090710
• Recruitment Status: Recruiting
• First Posted: September 16, 2019
• Last Update Posted: March 23, 2023
• Sponsor: Ontario Clinical Oncology Group (OCOG)
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): Ontario Clinical Oncology Group (OCOG)

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Metastatic Renal Cell Carcinoma	Drug: Ipilimumab/ Nivolumab; Radiation: SBRT + Ipilimumab/Nivolumab	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 78 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• 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).
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Cytoreductive Stereotactic Hypofractionated Radiotherapy With Combination Ipilimumab/Nivolumab for Metastatic Kidney Cancer
• Actual Study Start Date: January 29, 2020
• Estimated Primary Completion Date: March 31, 2024
• Estimated Study Completion Date: March 31, 2024

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Standard of Care I/N alone; 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.	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; Other Name: Yervoy/Opdivo
Experimental: Standard of Care I/N plus primary disease SBRT; 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 immunotherapy 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.	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.

Outcome Measures

Primary Outcome Measures :

1. Progression free survival (PFS) [ Time Frame: 2 years ]
   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.

Secondary Outcome Measures :

1. Subject safety [ Time Frame: Date of randomization until 1year post treatment ]
   Incidence and attribution of deaths
2. Overall Survival [ Time Frame: 2 years ]
   • 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.
3. Objective response rate [ Time Frame: 1 year ]
   • 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.
4. Quality of Life: EORTC QLQ-C30 questionnaire [ Time Frame: 1 year ]
   • Quality of life, which will be evaluated using the EORTC QLQ-C30 questionnaire.
5. Subject safety [ Time Frame: 1 Year ]
   Number of Adverse Events and Serious Adverse Events using NCI CTCAE v5.0
6. Ipilimumab/ Nivolumab drug tolerability [ Time Frame: From the date of randomization until date of first documented disease progression up to 1 year. ]
   Ipilimumab/Nivolumab treatment discontinuation rates
7. Ipilimumab/ Nivolumab drug tolerability [ Time Frame: From the date of randomization until date of first documented disease progression, up to 1 year. ]
   Number of doses of Ipilimumab/Nivolumab combination treatment
8. Ipilimumab/ Nivolumab drug tolerability [ Time Frame: From the date of randomization until date of first documented disease progression, up to 1 year. ]
   Number of Nivolumab maintenance doses
9. Ipilimumab/ Nivolumab drug tolerability [ Time Frame: From the date of randomization until date of first documented disease progression, up to 1 year. ]
   Time to treatment discontinuation from the date of randomization

Other Outcome Measures:

1. Exploratory Outcomes: Evaluation of baseline and changes during treatment in blood immune signatures [ Time Frame: 1 year ]
   Changes in blood immune signatures through interrogation of circulating blood biomarkers.
2. Exploratory Outcomes: Evaluation of baseline and changes during treatment in stool microbiome [ Time Frame: 1 year ]
   Changes in stool microbiome using 16S RNA.
3. Correlation with blood or stool immune signatures [ Time Frame: 1 year ]
   Tumor tissue analysis using immunohistochemistry

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Contacts

Contact: Lisa Rudd-Scott, RN BScN MN; 905-527-2299 ext 43793; ruddl@mcmaster.ca

Contact: Erin McGean; 905-527-2299 ext 42656; mcgeane@mcmaster.ca

Locations

Australia

Peter MacCallum Cancer Centre; Recruiting

Melbourne, Australia, 3000

Contact: Erin Cassidy PCCTU.MonCA@petermac.org

Sub-Investigator: Shanker Siva, MD

Principal Investigator: Arun Azad, MD

Canada, Alberta

Cross Cancer Institute; Recruiting

Edmonton, Alberta, Canada, T6G 1Z2

Contact: Romeo Felix, RN romeo.felix@albertahealthservices.ca

Principal Investigator: Naveen Bassappa, MD

Canada, Ontario

Juravinski Cancer Centre; Recruiting

Hamilton, Ontario, Canada

Contact 905-521-2100

Principal Investigator: Aly-Khan Lalani, MD

Grand River Regional Cancer Centre; Recruiting

Kitchener, Ontario, Canada, N2G1G3

Contact: Darin Gopaul, MD darin.gopaul@grhosp.on.ca

Principal Investigator: Darin Gopaul, MD

London Regional Cancer Centre; Withdrawn

London, Ontario, Canada, N2G1G3

The Ottawa Regional Cancer Centre; Recruiting

Ottawa, Ontario, Canada, K1H8L6

Contact: Amy Hutt amcarkner@ohri.ca

Principal Investigator: Scott Morgan, MD

Sunnybrook Health Sciences Centre- Odette Cancer Centre; Recruiting

Toronto, Ontario, Canada, M4N3M5

Contact: Nesan Bandali, RN 416-480-5000 ext 82139 nesan.bandali@sunnybrook.ca

Principal Investigator: William Chu, MD

Canada, Quebec

McGill University Health Centre - Glen site; Recruiting

Montréal, Quebec, Canada

Contact: Fabio Cury, MD 514-934-1934 ext 64222 fabio.cury.med@ssss.gouv.qc.ca

Sponsors and Collaborators

Ontario Clinical Oncology Group (OCOG)

Bristol-Myers Squibb

Investigators

• Principal Investigator: Aly-Khan Lalani, MD; Juravinski Cancer Centre

More Information

• Responsible Party: Ontario Clinical Oncology Group (OCOG)
• ClinicalTrials.gov Identifier: NCT04090710
• Other Study ID Numbers: OCOG-2019-CYTOSHRINK; CA209-7DR ( Other Grant/Funding Number: BMS )
• First Posted: September 16, 2019
• Last Update Posted: March 23, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ontario Clinical Oncology Group (OCOG):

SBRT; Ipilimumab; Nivolumab

Additional relevant MeSH terms:

Carcinoma, Renal Cell; Kidney Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Nivolumab; Ipilimumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action