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

Phase 3Not Yet RecruitingNCT07346053

Guliz Ozgun224 enrolled

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

224

Conditions

Advanced Bladder Cancer

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (5)

BC Cancer - Abbotsford

Abbotsford British Columbia, British Columbia, Canada

BC Cancer - Kelowna (Sindi Ahluwalia Hawkins Centre)

Kelowna, British Columbia, Canada

BC Cancer - Surrey

Surrey, British Columbia, Canada

BC Cancer - Vancouver Cancer Centre

Vancouver, British Columbia, Canada

BC Cancer - Victoria

Victoria, British Columbia, Canada

Outcomes

Primary Outcomes

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.

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

Secondary Outcomes

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

Progression-free Survival (PFS) will be determined by time of randomization to radiographic progression or death from any cause, whichever occurs first.

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

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

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.

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 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.

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

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.

Time frame: Baseline, 3 weeks, and 12-weeks.

Assess treatment-related tolerability and toxicity differences

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.

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

Immune Profiling

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.

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)

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.

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

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.

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

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.

Time frame: At 3 time points: Baseline, 3 weeks into treatment and 12 weeks into treatment

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

Overview

Conditions

Interventions

Eligibility

Locations (5)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts