The Impact of Time-of-day Administration of EV/P on Objective Response Rate in Adults With Advanced Bladder Cancer

Official title

CHRONO-EVP: Time-of-day Dependent Administration of Enfortumab Vedotin and Pembrolizumab (EV/P) in Advanced Bladder 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 enfortumab vedotin and pembrolizumab (EV/P) works to treat adults with advanced bladder cancer. The trial will also learn if time-of-day reduces EV/P side-effects. Researchers will compare EV/P given in the morning (before 11:30am) vs in the afternoon (after 1:30pm), to see if circadian rhythm effects how EV/P works to treat advanced bladder cancer. Participants will be randomized in Arm A or Arm B to receive drugs EV/P either in the morning (Arm A) or afternoon (Arm B) as part of their standard-of-care treatment for advanced bladder cancer. Participants will: * Visit the clinic either in the morning (Arm A) or afternoon (Arm B) to receive EV/P treatment as part of their regular medical care for advanced bladder cancer * Frequency of visits will follow standard-of-care guidelines * Participants will be followed-up by the study team for up to 24 months.

Interventions

• Drug enfortumab vedotin and pembrolizumab (EV/P)
  Participants will receive EV/P as part of their standard-of-care therapy administered either in the morning (Arm A) or afternoon (Arm B), as determined by randomization.

Primary outcome measures

• Objective response rate in in time-of-day administration of EV/P treatment [Time frame: From enrollment to end of follow-up at 24-months.]

Secondary outcome measures (9)

• Evaluate Progression-Free Survival in time-of-day administration of EV/P [Time frame: From enrollment to end of follow-up at 24-months.]
• Assess Overall-Survival in time-of-day administration of EV/P [Time frame: From enrollment to the end of follow-up at 24-months.]
• Evaluate the Time-to-Treatment Failure in time-of-day administration of EV/P [Time frame: From enrollment to the end of follow-up at 24-months.]
• Assess quantitative changes in ctDNA Kinetics of time-of-day administration of EV/P [Time frame: Baseline, 3 weeks, and 12-weeks.]
• 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]
• Circulating Tumor DNA (ctDNA) Analyses [Time frame: At 3 time points: Baseline, 3 weeks into treatment and 12 weeks into treatment]

Eligibility criteria

Inclusion criteria

• Participants must meet all of the following inclusion criteria to be eligible for participation in this trial:

• Age 18 or older
• Able to provide informed consent
• Histologically confirmed advanced urothelial cancer
• Eligible for standard-of-care EV/P 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) Waivers to the inclusion criteria will NOT be allowed.

Exclusion criteria

• Participants who meet any of following exclusion criteria will not be eligible for participation in this trial:

• Non-urothelial histology or mixed histology with predominant non-urothelial components
• Concurrent malignancy requiring active systemic therapy, unless disease-free for at least 2 years
• Inability to comply with protocol-specified infusion timing for at least the first 3 months
• 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.

Waivers to the exclusion criteria will NOT be allowed.

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 · 5 centers

• BC Cancer - Abbotsford — Abbotsford British Columbia
• BC Cancer - Kelowna (Sindi Ahluwalia Hawkins Centre) — Kelowna
• BC Cancer - Surrey — Surrey
• BC Cancer - Vancouver Cancer Centre — Vancouver
• BC Cancer - Victoria — Victoria

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
• Goncalves L, Guedes H, Fortuna AR, Lemos T, Gramaca J, Mourao N, Cunha G, Pichel R, Simoes P, Luis JA, Freitas R, Dunoes I, Spencer AS, Marinho J, Costa L. Avelumab Maintenance Therapy in Advanced Urothelial Carcinoma: Implications of Timing and Treatment Sequencing. Cancers (Basel). 2025 Mar 6;17(5):898. doi: 10.3390/cancers17050898. PMID 40075745
• 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
• Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gumus M, Mar N, Loriot Y, Flechon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390 PMID 38446675

Identifiers

NCT: NCT07346053 · Chrono-EVP

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗