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

NCT07346053 | Not Yet Recruiting Phase 3

• 1 other identifier: Chrono-EVP
• Study Type: interventional
• Target: 224
• Locations: 1 country
• Sites: 5

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 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.

Conditions

Advanced Bladder Cancer

Keywords

time-of-day administration; chronotherapy; advanced bladder cancer; circadian rhythm; enfortumab vedotin and pembrolizumab (EV/P); urothelial cancer; chronoimmunotherapy

Outcome Measures

Primary Outcomes (1)

• Objective response rate in in time-of-day administration of EV/P 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 review or investigator assessment. 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.

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

Secondary Outcomes (9)

• Evaluate Progression-Free Survival in time-of-day administration of EV/P

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

• Assess Overall-Survival in time-of-day administration of EV/P

  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

  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

  Baseline, 3 weeks, and 12-weeks.

• Assess treatment-related tolerability and toxicity differences

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

Study Arms (2)

Arm A: Morning EV/P Treatment

ACTIVE COMPARATOR

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

Drug: enfortumab vedotin and pembrolizumab (EV/P)

Arm B: Afternoon EV/P Treatment

ACTIVE COMPARATOR

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

Drug: enfortumab vedotin and pembrolizumab (EV/P)

Interventions

enfortumab vedotin and pembrolizumab (EV/P) DRUG

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.

Arm A: Morning EV/P Treatment; Arm B: Afternoon EV/P 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 urothelial cancer
• Eligible for standard-of-care EV/P regimen
• Measurable disease per RECIST 1.1
• ECOG performance status 0-2

You may not qualify if:

• 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.

Sponsors & Collaborators

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

Study Sites (5)

BC Cancer - Abbotsford

Abbotsford British Columbia, British Columbia, V2S 0C2, Canada

Location

BC Cancer - Kelowna (Sindi Ahluwalia Hawkins Centre)

Kelowna, British Columbia, V1Y 5L3, Canada

Location

BC Cancer - Surrey

Surrey, British Columbia, V3V 1Z2, Canada

Location

BC Cancer - Vancouver Cancer Centre

Vancouver, British Columbia, V5Z 4E6, Canada

Location

BC Cancer - Victoria

Victoria, British Columbia, V8R 6V5, Canada

Location

Related Publications (7)

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  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

• 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 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

• 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(10):875-888. doi: 10.1056/NEJMoa2312117.

  PMID: 38446675 BACKGROUND

MeSH Terms

Interventions

enfortumab vedotin; pembrolizumab

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 enfortumab vedotin and pembrolizumab (EV/P) 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. To preserve the immune priming effect, which is most pronounced during the initial treatment period, infusion timing will be strictly enforced during the first four cycles. After this period, patients will be allowed to have a flexible schedule. Treatment will be initiated in accordance with the standard of care, with no additional interventions planned. The trial is open-label and not blinded due to the nature of the intervention (timing of treatment).

Study Record Dates

• First Submitted: December 8, 2025
• First Posted: January 16, 2026
• Study Start: May 1, 2026
• Primary Completion (Estimated): December 1, 2030
• Study Completion (Estimated): December 1, 2032
• Last Updated: January 16, 2026

Record last verified: 2026-01

Locations

CA (5)