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.

NCT07338981 | Not Yet Recruiting Phase 3

• 1 other identifier: Chrono-RCC
• Study Type: interventional
• Target: 142
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Advanced Kidney Cancer

Keywords

Chronoimmunotherapy; Time-of-day administration; Chronotherapy; Circadian rhythm; Advanced kidney cancer; Nivolumab/Ipilimumab

Outcome Measures

Primary Outcomes (1)

• 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.

Secondary Outcomes (7)

• Determine Objective Response Rate in time-of-day administration of ICI/ICI treatment

  From enrollment to the end of follow-up at 24-months.

• Evaluate Progression-Free Survival in time-of-day administration of ICI/ICI treatment

  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

  From enrollment to the end of follow-up at 24-months.

• Assess treatment-related tolerability and toxicity differences

  From enrollment to the end of follow-up at 24-months.

• Immune Profiling

  At 4 time points: Baseline, 1-day post first cycle of treatment, 3 weeks into treatment and 12 weeks into treatment

Study Arms (2)

Arm A: Morning ICI/ICI Treatment

ACTIVE COMPARATOR

Participants will receive standard-of-care therapy (ICI/ICI) administered in the morning (before 11:30am).

Drug: Nivolumab & Ipilimumab

Arm B: Afternoon ICI/ICI Treatment

ACTIVE COMPARATOR

Participants will receive standard-of-care therapy (ICI/ICI) administered in the afternoon (after 1:30pm).

Drug: Nivolumab + Ipilimumab

Interventions

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.

Arm B: Afternoon ICI/ICI Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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.

Sponsors & Collaborators

• Guliz Ozgun: lead
• British Columbia Cancer Agency: collaborator

Study Sites (1)

BC Cancer - Vancouver Cancer Centre

Vancouver, British Columbia, V5Z 4E6, Canada

Location

Related Publications (9)

• 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.

  PMID: 38723627 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.

  PMID: 38806707 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.

  PMID: 34615982 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.

  PMID: 38834742 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.

  PMID: 37495481 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.

  PMID: 38531662 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.

  PMID: 16877722 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.

  PMID: 20055686 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.

  PMID: 29562145 BACKGROUND

MeSH Terms

Interventions

Nivolumab; Ipilimumab

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Central Study Contacts

Dr. Guliz Ozgun, MD

CONTACT

604-877-6000; guliz.ozgun@bccancer.bc.ca

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Medical Oncologist, Principal Investigator

Model Details: 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).

Study Record Dates

• First Submitted: December 5, 2025
• First Posted: January 14, 2026
• Study Start: April 1, 2026
• Primary Completion (Estimated): December 1, 2030
• Study Completion (Estimated): December 1, 2032
• Last Updated: January 14, 2026

Record last verified: 2026-01

Locations

CA (1)