CYTOSHRINK: SBRT With Combination Ipilimumab/Nivolumab for Metastatic Kidney Cancer

Sponsor
Ontario Clinical Oncology Group (OCOG) (Other)
Overall Status
Recruiting
CT.gov ID
NCT04090710
Collaborator
Bristol-Myers Squibb (Industry)
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Study Details

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
  • 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
Anticipated 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).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 :
Jan 29, 2020
Anticipated Primary Completion Date :
Dec 31, 2022
Anticipated Study Completion Date :
Dec 31, 2023

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 Names:
  • 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) [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 [Date of randomization until 1year post treatment]

      Incidence and attribution of deaths

    2. Overall Survival [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 [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 [1 year]

      • Quality of life, which will be evaluated using the EORTC QLQ-C30 questionnaire.

    5. Subject safety [1 Year]

      Number of Adverse Events and Serious Adverse Events using NCI CTCAE v5.0

    6. Ipilimumab/ Nivolumab drug tolerability [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 [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 [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 [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 [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 [1 year]

      Changes in stool microbiome using 16S RNA.

    3. Correlation with blood or stool immune signatures [1 year]

      Tumor tissue analysis using immunohistochemistry

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Locations

    Site City State Country Postal Code
    1 Peter MacCallum Cancer Centre Melbourne Australia 3000
    2 Cross Cancer Institute Edmonton Alberta Canada T6G 1Z2
    3 Juravinski Cancer Centre Hamilton Ontario Canada
    4 Grand River Regional Cancer Centre Kitchener Ontario Canada N2G1G3
    5 London Regional Cancer Centre London Ontario Canada N2G1G3
    6 The Ottawa Regional Cancer Centre Ottawa Ontario Canada K1H8L6
    7 Sunnybrook Health Sciences Centre- Odette Cancer Centre Toronto Ontario Canada M4N3M5
    8 McGill University Health Centre - Glen site Montréal Quebec Canada

    Sponsors and Collaborators

    • Ontario Clinical Oncology Group (OCOG)
    • Bristol-Myers Squibb

    Investigators

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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Ontario Clinical Oncology Group (OCOG)
    ClinicalTrials.gov Identifier:
    NCT04090710
    Other Study ID Numbers:
    • OCOG-2019-CYTOSHRINK
    • CA209-7DR
    First Posted:
    Sep 16, 2019
    Last Update Posted:
    Mar 31, 2022
    Last Verified:
    Mar 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    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)
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Mar 31, 2022