The Impact of Time-of-day-Dependent Administration of Nivolumab-Ipilimumab (ICI/ICI) Combination on Overall Survival in Adults With Advanced Kidney Cancer: A Pragmatic Multicenter, Randomized Controlled Trial.

Official title

(CHRONO-RCC) Time-of-day-Dependent Administration of Dual Immune Check Point Inhibitors (ICI) in Advanced Kidney Cancer

Overview

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: * Visit the clinic either in the morning (Arm A) or afternoon (Arm B) to receive ICI/ICI treatment as part of their regular medical care for advanced kidney cancer * Frequency of visits will follow standard-of-care guidelines

Interventions

• Drug Nivolumab & Ipilimumab
  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.
• Drug Nivolumab + Ipilimumab
  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.

Primary outcome measures

• Assess Overall-Survival in time-of-day administration of ICI/ICI treatment [Time frame: From enrollment to the end of follow-up at 24 months.]

Secondary outcome measures (7)

• Determine Objective Response Rate in time-of-day administration of ICI/ICI treatment [Time frame: From enrollment to the end of follow-up at 24-months.]
• Evaluate Progression-Free Survival in time-of-day administration of ICI/ICI treatment [Time frame: 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 frame: From enrollment to the end of follow-up at 24-months.]
• Assess treatment-related tolerability and toxicity differences [Time frame: From enrollment to the end of follow-up at 24-months.]
• Immune Profiling [Time frame: 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) [Time frame: 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 [Time frame: At 4 time points: Baseline, 1-day post first cycle of treatment, 3 weeks into treatment and 12 weeks into treatment]

Eligibility criteria

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.

• Age 18 or older
• Able to provide informed consent
• Histologically confirmed advanced clear cell kidney cancer
• Eligible for standard-of-care nivolumab/ipilimumab regimen
• Measurable disease per RECIST 1.1
• ECOG performance status 0-2
• Ability to adhere to scheduled infusion times (Before 11:30 a.m. or after 1:30 pm)

Exclusion criteria

Participants are excluded from the trial if any of the following criteria apply. Waivers to the exclusion criteria will NOT be allowed.

• Non-clear cell RCC histology
• Concurrent malignancy requiring active systemic therapy, unless disease-free for at least 2 years
• Inability to comply with protocol-specified infusion timing for the first 4 cycles
• Night shift workers
• Clinical evidence of new or enlarging brain metastasis or carcinomatous meningitis
• Known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial
• Patients who have traveled across ≥2 time zones within the past 14 days prior to randomization will be excluded, due to potential disruption of circadian rhythms (jet lag), which may affect chronotherapy-related endpoints.
• Patients with a clinically diagnosed sleep disorder, including but not limited to insomnia, obstructive sleep apnea, restless leg syndrome, or circadian rhythm sleep-wake disorders, that is moderate to severe, untreated, or poorly controlled, will be excluded.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Canada · 1 center

• BC Cancer - Vancouver Cancer Centre — Vancouver

Publications

• 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. PMID 38723627
• 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. PMID 38806707
• 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. PMID 34615982
• 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. PMID 38834742
• 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. do PMID 37495481
• 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 PMID 38531662
• 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 fluorour PMID 16877722
• 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. PMID 20055686

Identifiers

NCT: NCT07338981 · Chrono-RCC

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗