The Impact of Time-of-day-Dependent Administration of Nivolumab-Ipilimumab (ICI/ICI) Combination on Overall Survival in Adults With Advanced Kidney Cancer: A Pragmatic Multicenter, Randomized Controlled Trial.

Phase 3Not Yet RecruitingNCT07338981

Guliz Ozgun142 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 nivolumab/ipilimumab (ICI/ICI) works to treat adults with advanced kidney cancer. The trial will also learn if time-of-day reduces ICI/ICI side-effects. Researchers will compare ICI/ICI given in the morning (before 11:30am) vs in the afternoon (after 1:30pm), to see if circadian rhythm effects how ICI/ICI works to treat advanced kidney cancer. Participants will be randomized in Arm A or Arm B to receive drugs ICI/ICI either in the morning (Arm A) or afternoon (Arm B) as part of their standard-of-care treatment for advanced kidney cancer. Participants will: * Visit the clinic either in the morning (Arm A) or afternoon (Arm B) to receive ICI/ICI treatment as part of their regular medical care for advanced kidney cancer * Frequency of visits will follow standard-of-care guidelines

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

142

Conditions

Advanced Kidney Cancer

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: Participants must meet all of the following criteria to be eligible for participation in this trial. Waivers to the inclusion criteria will NOT be allowed. 1. Age 18 or older 2. Able to provide informed consent 3. Histologically confirmed advanced clear cell kidney cancer 4. Eligible for standard-of-care nivolumab/ipilimumab 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) Exclusion Criteria: Participants are excluded from the trial if any of the following criteria apply. Waivers to the exclusion criteria will NOT be allowed. 1. Non-clear cell RCC histology 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 the first 4 cycles 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.

Outcomes

Primary Outcomes

Assess Overall-Survival in time-of-day administration of ICI/ICI treatment

To assess overall survival (OS) in patients treated with time-of day dependent administration of nivolumab-ipilimumab (ICI/ICI) standard-of-care therapy in advanced kidney cancer. OS is defined as the time from randomization to death from any cause. The primary 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.

Secondary Outcomes

Determine Objective Response Rate in time-of-day administration of ICI/ICI 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 or investigator review. 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 the end of follow-up at 24-months.

Evaluate Progression-Free Survival in time-of-day administration of ICI/ICI treatment

Progression-free Survival (PFS) will be determined by time of randomization to disease progression or death from any cause.

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

Determine the Time-to-Treatment Failure in time-of-day administration of ICI/ICI treatment

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 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

The Impact of Time-of-day-Dependent Administration of Nivolumab-Ipilimumab (ICI/ICI) Combination on Overall Survival in Adults With Advanced Kidney Cancer: A Pragmatic Multicenter, Randomized Controlled Trial.

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts