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| Name | Class |
|---|---|
| British Columbia Cancer Agency | OTHER |
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The goal of this clinical trial is to learn if the timing of treatments plays a role in how effective the standard-of-care drugs nivolumab/ipilimumab (ICI/ICI) works to treat adults with advanced kidney cancer. The trial will also learn if time-of-day reduces ICI/ICI side-effects. Researchers will compare ICI/ICI given in the morning (before 11:30am) vs in the afternoon (after 1:30pm), to see if circadian rhythm effects how ICI/ICI works to treat advanced kidney cancer. Participants will be randomized in Arm A or Arm B to receive drugs ICI/ICI either in the morning (Arm A) or afternoon (Arm B) as part of their standard-of-care treatment for advanced kidney cancer. Participants will:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm A: Morning ICI/ICI Treatment | Active Comparator | Participants will receive standard-of-care therapy (ICI/ICI) administered in the morning (before 11:30am). |
|
| Arm B: Afternoon ICI/ICI Treatment | Active Comparator | Participants will receive standard-of-care therapy (ICI/ICI) administered in the afternoon (after 1:30pm). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Nivolumab & Ipilimumab | Drug | Participants will receive ICI/ICI as part of their standard-of-care therapy administered in the morning before 11:30am (Arm A) , as determined by randomization. |
| Measure | Description | Time Frame |
|---|---|---|
| Assess Overall-Survival in time-of-day administration of ICI/ICI treatment | To assess overall survival (OS) in patients treated with time-of day dependent administration of nivolumab-ipilimumab (ICI/ICI) standard-of-care therapy in advanced kidney cancer. OS is defined as the time from randomization to death from any cause. The primary analysis will compare OS curves between study arms and estimate 2-year OS rates for each group. | From enrollment to the end of follow-up at 24 months. |
| Measure | Description | Time Frame |
|---|---|---|
| Determine Objective Response Rate in time-of-day administration of ICI/ICI treatment | Objective response rate (ORR) will be determined by Proportion of patients achieving a complete or partial response as assessed by RECIST v1.1 criteria, confirmed by central or investigator review. Tumor assessments will be performed as standard of care (typically every 12 weeks), and best overall response prior to disease progression will be used for ORR determination. |
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Inclusion Criteria:
Participants must meet all of the following criteria to be eligible for participation in this trial. Waivers to the inclusion criteria will NOT be allowed.
Exclusion Criteria:
Participants are excluded from the trial if any of the following criteria apply. Waivers to the exclusion criteria will NOT be allowed.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Dr. Guliz Ozgun, MD | Contact | 604-877-6000 | 676213 | guliz.ozgun@bccancer.bc.ca |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| BC Cancer - Vancouver Cancer Centre | Vancouver | British Columbia | V5Z 4E6 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38723627 | Background | Wang C, Zeng Q, Gul ZM, Wang S, Pick R, Cheng P, Bill R, Wu Y, Naulaerts S, Barnoud C, Hsueh PC, Moller SH, Cenerenti M, Sun M, Su Z, Jemelin S, Petrenko V, Dibner C, Hugues S, Jandus C, Li Z, Michielin O, Ho PC, Garg AD, Simonetta F, Pittet MJ, Scheiermann C. Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy. Cell. 2024 May 23;187(11):2690-2702.e17. doi: 10.1016/j.cell.2024.04.015. Epub 2024 May 8. | |
| 38806707 |
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This study is a randomized, controlled trial designed to evaluate the effects of timing of standard-of-care (SOC) treatment administration on patient outcomes. Participants will be randomly assigned to receive SOC nivolumab/ipilimumab either in the morning or in the afternoon, with no additional interventions planned. Patients will be scheduled for treatments at the same time for the first four cycles, with a ±1 hour flexibility, to minimize the impact of timing as a confounding factor in the analyses. The trial is open-label and not blinded due to the nature of the intervention (timing of treatment).
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|
| Nivolumab + Ipilimumab | Drug | Participants will receive ICI/ICI as part of their standard-of-care therapy administered in the afternoon after 1:30pm (Arm B) , as determined by randomization. |
|
| From enrollment to the end of follow-up at 24-months. |
| Evaluate Progression-Free Survival in time-of-day administration of ICI/ICI treatment | Progression-free Survival (PFS) will be determined by time of randomization to disease progression or death from any cause. | From enrollment to the end of follow-up at 24-months. |
| Determine the Time-to-Treatment Failure in time-of-day administration of ICI/ICI treatment | Time to treatment failure (TTF) is determined by assessing time from treatment initiation to treatment discontinuation for any reason, including disease progression, unacceptable toxicity, patient withdrawal, or death, capturing both treatment efficacy and tolerability. | From enrollment to the end of follow-up at 24-months. |
| Assess treatment-related tolerability and toxicity differences | Differences in steroid use (yes/no) for the management of treatment-related toxicity, treatment interruptions (yes/no) due to treatment-related toxicity, and treatment discontinuations (yes/no) due to treatment-related toxicity will be used as surrogate safety outcomes, as comprehensive adverse event documentation is beyond the scope of this pragmatic clinical trial. The study seeks to determine whether treatment administration at a predefined time of day is associated with differences in the need for toxicity-related clinical interventions. Given that the relevant adverse events are well characterized in the existing literature, the focus of this study is on comparative safety between groups using these surrogate measures rather than on detailed characterization of individual adverse events. | From enrollment to the end of follow-up at 24-months. |
| Immune Profiling | Immune cell populations will be characterized from the blood samples at baseline (prior to treatment initiation) and at three predefined time points during therapy: 1 day after treatment initiation, 3 weeks into treatment, and 12 weeks into treatment. Cytometry by time-of-flight (CyTOF) will be used to comprehensively profile immune cell populations allowing for high-dimensional assessment of immune cell composition and activation states across treatment timing groups. | At 4 time points: Baseline, 1-day post first cycle of treatment, 3 weeks into treatment and 12 weeks into treatment |
| Bulk RNA sequencing (RNA-seq) | Bulk RNA sequencing (RNA-seq) will be performed to comprehensively characterize global gene expression profiles and to evaluate time-of-day-associated differences in immune-related transcriptional signatures. This approach will enable the identification of circadian variation in gene expression and provide insight into temporal regulation of immune pathways in response to treatment. | At 4 time points: Baseline, 1-day post first cycle of treatment, 3 weeks into treatment and 12 weeks into treatment |
| Cytokine and chemokine analyses | Plasma will be isolated for cytokine and chemokine analyses to assess systemic immune signaling and inflammatory profiles. Quantitative evaluation of circulating cytokines and chemokines will provide insight into treatment- and time-dependent changes in immune activation, inflammation, and immune regulation, complementing cellular and transcriptional immune profiling. | At 4 time points: Baseline, 1-day post first cycle of treatment, 3 weeks into treatment and 12 weeks into treatment |
| Background |
| Fortin BM, Pfeiffer SM, Insua-Rodriguez J, Alshetaiwi H, Moshensky A, Song WA, Mahieu AL, Chun SK, Lewis AN, Hsu A, Adam I, Eng OS, Pannunzio NR, Seldin MM, Marazzi I, Marangoni F, Lawson DA, Kessenbrock K, Masri S. Circadian control of tumor immunosuppression affects efficacy of immune checkpoint blockade. Nat Immunol. 2024 Jul;25(7):1257-1269. doi: 10.1038/s41590-024-01859-0. Epub 2024 May 28. |
| 34615982 | Background | Lee Y. Roles of circadian clocks in cancer pathogenesis and treatment. Exp Mol Med. 2021 Oct;53(10):1529-1538. doi: 10.1038/s12276-021-00681-0. Epub 2021 Oct 7. |
| 38834742 | Background | Karaboue A, Innominato PF, Wreglesworth NI, Duchemann B, Adam R, Levi FA. Why does circadian timing of administration matter for immune checkpoint inhibitors' efficacy? Br J Cancer. 2024 Sep;131(5):783-796. doi: 10.1038/s41416-024-02704-9. Epub 2024 Jun 4. |
| 37495481 | Background | Dizman N, Govindarajan A, Zengin ZB, Meza L, Tripathi N, Sayegh N, Castro DV, Chan EH, Lee KO, Prajapati S, Feng M, Loo V, Pace M, O'Brien S, Bailey E, Barragan-Carrillo R, Chehrazi-Raffle A, Hsu J, Li X, Agarwal N, Pal SK. Association Between Time-of-Day of Immune Checkpoint Blockade Administration and Outcomes in Metastatic Renal Cell Carcinoma. Clin Genitourin Cancer. 2023 Oct;21(5):530-536. doi: 10.1016/j.clgc.2023.06.004. Epub 2023 Jun 25. |
| 38531662 | Background | Patel JS, Woo Y, Draper A, Jansen CS, Carlisle JW, Innominato PF, Levi FA, Dhabaan L, Master VA, Bilen MA, Khan MK, Lowe MC, Kissick H, Buchwald ZS, Qian DC. Impact of immunotherapy time-of-day infusion on survival and immunologic correlates in patients with metastatic renal cell carcinoma: a multicenter cohort analysis. J Immunother Cancer. 2024 Mar 26;12(3):e008011. doi: 10.1136/jitc-2023-008011. |
| 16877722 | Background | Giacchetti S, Bjarnason G, Garufi C, Genet D, Iacobelli S, Tampellini M, Smaaland R, Focan C, Coudert B, Humblet Y, Canon JL, Adenis A, Lo Re G, Carvalho C, Schueller J, Anciaux N, Lentz MA, Baron B, Gorlia T, Levi F; European Organisation for Research and Treatment of Cancer Chronotherapy Group. Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group. J Clin Oncol. 2006 Aug 1;24(22):3562-9. doi: 10.1200/JCO.2006.06.1440. |
| 20055686 | Background | Levi F, Okyar A, Dulong S, Innominato PF, Clairambault J. Circadian timing in cancer treatments. Annu Rev Pharmacol Toxicol. 2010;50:377-421. doi: 10.1146/annurev.pharmtox.48.113006.094626. |
| 29562145 | Background | Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthelemy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. doi: 10.1056/NEJMoa1712126. Epub 2018 Mar 21. |
| ID | Term |
|---|---|
| D000077594 | Nivolumab |
| D000074324 | Ipilimumab |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
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