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| Name | Class |
|---|---|
| British Columbia Cancer Agency | OTHER |
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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 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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm A: Morning EV/P Treatment | Active Comparator | Participants will receive standard-of-care therapy (Ev/P) administered in the morning (before 11:30am). |
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| Arm B: Afternoon EV/P Treatment | Active Comparator | Participants will receive standard-of-care therapy (EV/P) administered in the afternoon (after 1:30pm). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | From enrollment to end of follow-up at 24-months. |
| Assess Overall-Survival in time-of-day administration of EV/P |
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Inclusion Criteria:
Participants must meet all of the following inclusion criteria to be eligible for participation in this trial:
Exclusion Criteria:
Participants who meet any of following exclusion criteria will not be eligible for participation in this trial:
Waivers to the exclusion criteria will NOT be allowed.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Dr. Guliz Ozgun, MD | Contact | 604-877-6000 | 676225 | guliz.ozgun@bccancer.bc.ca |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| BC Cancer - Abbotsford | Abbotsford British Columbia | British Columbia | V2S 0C2 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38723627 | Background | 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. | |
| 38806707 |
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| ID | Term |
|---|---|
| C000632577 | enfortumab vedotin |
| C582435 | pembrolizumab |
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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).
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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 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 | 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. |
| 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. | 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. | 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. | 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. | 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. | At 3 time points: Baseline, 3 weeks into treatment and 12 weeks into treatment |
| BC Cancer - Kelowna (Sindi Ahluwalia Hawkins Centre) | Kelowna | British Columbia | V1Y 5L3 | Canada |
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| BC Cancer - Surrey | Surrey | British Columbia | V3V 1Z2 | Canada |
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| BC Cancer - Vancouver Cancer Centre | Vancouver | British Columbia | V5Z 4E6 | Canada |
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| BC Cancer - Victoria | Victoria | British Columbia | V8R 6V5 | Canada |
|
| 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. |
| 34615982 | 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. |
| 40075745 | 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. |
| 16877722 | 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. |
| 20055686 | 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. |
| 38446675 | 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. |