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.

NCT ID: NCT07338981

Last Updated: 2026-01-14

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

NOT_YET_RECRUITING

Clinical Phase

PHASE3

Total Enrollment

142 participants

Study Classification

INTERVENTIONAL

Study Start Date

2026-04-30

Study Completion Date

2032-12-31

Brief Summary

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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:

* 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

Detailed Description

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Conditions

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Advanced Kidney Cancer

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

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).
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Arm A: Morning ICI/ICI Treatment

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

Group Type ACTIVE_COMPARATOR

Nivolumab & Ipilimumab

Intervention Type 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.

Arm B: Afternoon ICI/ICI Treatment

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

Group Type ACTIVE_COMPARATOR

Nivolumab + Ipilimumab

Intervention Type 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.

Interventions

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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.

Intervention Type 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.

Intervention Type DRUG

Other Intervention Names

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ICI/ICI

Eligibility Criteria

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Inclusion Criteria

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

Exclusion Criteria

1. Non-clear cell RCC histology
2. Concurrent malignancy requiring active systemic therapy, unless disease-free for at least 2 years
3. Inability to comply with protocol-specified infusion timing for the first 4 cycles
4. Night shift workers
5. Clinical evidence of new or enlarging brain metastasis or carcinomatous meningitis
6. Known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial
7. 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.
8. 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.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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British Columbia Cancer Agency

OTHER

Sponsor Role collaborator

Guliz Ozgun

OTHER

Sponsor Role lead

Responsible Party

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Guliz Ozgun

Medical Oncologist, Principal Investigator

Responsibility Role SPONSOR_INVESTIGATOR

Locations

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BC Cancer - Vancouver Cancer Centre

Vancouver, British Columbia, Canada

Site Status

Countries

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Canada

Central Contacts

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Dr. Guliz Ozgun, MD

Role: CONTACT

604-877-6000 ext. 676213

References

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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.

Reference Type BACKGROUND
PMID: 38723627 (View on PubMed)

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.

Reference Type BACKGROUND
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Reference Type BACKGROUND
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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.

Reference Type BACKGROUND
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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.

Reference Type BACKGROUND
PMID: 37495481 (View on PubMed)

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.

Reference Type BACKGROUND
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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.

Reference Type BACKGROUND
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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.

Reference Type BACKGROUND
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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.

Reference Type BACKGROUND
PMID: 29562145 (View on PubMed)

Other Identifiers

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Chrono-RCC

Identifier Type: -

Identifier Source: org_study_id

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