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

January 7, 2026 updated by: Guliz Ozgun

CHRONO-EVP: Time-of-day Dependent Administration of Enfortumab Vedotin and Pembrolizumab (EV/P) in Advanced Bladder Cancer

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

224

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Canada
    • British Columbia
      • Abbotsford, British Columbia, Canada, V2S 0C2
        • Bc Cancer - Abbotsford
        • Contact:
      • Kelowna, British Columbia, Canada, V1Y 5L3
        • BC Cancer - Kelowna (Sindi Ahluwalia Hawkins Centre)
        • Contact:
      • Surrey, British Columbia, Canada, V3V 1Z2
      • Vancouver, British Columbia, Canada, V5Z 4E6
        • BC Cancer - Vancouver Cancer Centre
        • Contact:
      • Victoria, British Columbia, Canada, V8R 6V5

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

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

    1. Age 18 or older
    2. Able to provide informed consent
    3. Histologically confirmed advanced urothelial cancer
    4. Eligible for standard-of-care EV/P 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) 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:

    1. Non-urothelial histology or mixed histology with predominant non-urothelial components
    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 at least the first 3 months
    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.

Waivers to the exclusion criteria will NOT be allowed.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Arm A: Morning EV/P Treatment
Participants will receive standard-of-care therapy (Ev/P) administered in the morning (before 11:30am).
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.
Active Comparator: Arm B: Afternoon EV/P Treatment
Participants will receive standard-of-care therapy (EV/P) administered in the afternoon (after 1:30pm).
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Assess treatment-related tolerability and toxicity differences
Time Frame: From enrollment to the end of follow-up at 24-months.
Differences in steroid use (yes/no) for the management of treatment-related toxicity, treatment interruptions (yes/no) due to treatment-related toxicity, and treatment discontinuations (yes/no) due to treatment-related toxicity will be used as surrogate safety outcomes, as comprehensive adverse event documentation is beyond the scope of this pragmatic clinical trial. The study seeks to determine whether treatment administration at a predefined time of day is associated with differences in the need for toxicity-related clinical interventions. Given that the relevant adverse events are well characterized in the existing literature, the focus of this study is on comparative safety between groups using these surrogate measures rather than on detailed characterization of individual adverse events.
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
Immune cell populations will be characterized from the blood samples at baseline (prior to treatment initiation) and at three predefined time points during therapy: 1 day after treatment initiation, 3 weeks into treatment, and 12 weeks into treatment. Cytometry by time-of-flight (CyTOF) will be used to comprehensively profile immune cell populations allowing for high-dimensional assessment of immune cell composition and activation states across treatment timing groups.
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
Bulk RNA sequencing (RNA-seq) will be performed to comprehensively characterize global gene expression profiles and to evaluate time-of-day-associated differences in immune-related transcriptional signatures. This approach will enable the identification of circadian variation in gene expression and provide insight into temporal regulation of immune pathways in response to treatment.
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
Plasma will be isolated for cytokine and chemokine analyses to assess systemic immune signaling and inflammatory profiles. Quantitative evaluation of circulating cytokines and chemokines will provide insight into treatment- and time-dependent changes in immune activation, inflammation, and immune regulation, complementing cellular and transcriptional immune profiling.
At 4 time points: Baseline, 1-day post first cycle of treatment, 3 weeks into treatment and 12 weeks into treatment
Evaluate Progression-Free Survival in time-of-day administration of EV/P
Time Frame: From enrollment to end of follow-up at 24-months.
Progression-free Survival (PFS) will be determined by time of randomization to radiographic progression or death from any cause, whichever occurs first.
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.
Overall-survival (OS) is defined as the time from randomization to death from any cause. The 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.
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.
Time to treatment failure (TTF) is determined by assessing time from treatment initiation to treatment discontinuation for any reason, including disease progression, unacceptable toxicity, patient withdrawal, or death, capturing both treatment efficacy and tolerability.
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.
Quantitative changes in circulating tumour DNA (ctDNA) levels will be collected and measured at baseline, post-cycle 1 (~3 weeks), and at post-cycle 4 (~12 weeks) at first radiographic assessment, with correlation to response and survival outcomes.
Baseline, 3 weeks, and 12-weeks.
Circulating Tumor DNA (ctDNA) Analyses
Time Frame: At 3 time points: Baseline, 3 weeks into treatment and 12 weeks into treatment
Circulating tumor DNA (ctDNA) analyses will be performed on plasma samples collected at baseline (prior to treatment initiation), 3 weeks into treatment, and 12 weeks into treatment. ctDNA dynamics will be evaluated to assess molecular response to therapy, including changes in ctDNA levels and ctDNA clearance rates over time. Comparisons will be made between treatment administration at different times of day to determine whether timing of therapy is associated with differences in ctDNA kinetics, clearance rates, and early molecular response.
At 3 time points: Baseline, 3 weeks into treatment and 12 weeks into treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Guliz Ozgun

Collaborators

British Columbia Cancer Agency

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

May 1, 2026

Primary Completion (Estimated)

December 1, 2030

Study Completion (Estimated)

December 1, 2032

Study Registration Dates

First Submitted

December 8, 2025

First Submitted That Met QC Criteria

January 7, 2026

First Posted (Estimated)

January 16, 2026

Study Record Updates

Last Update Posted (Estimated)

January 16, 2026

Last Update Submitted That Met QC Criteria

January 7, 2026

Last Verified

January 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Chrono-EVP

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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