Advanced Melanoma, Melanoma
Conditions
Keywords
Advanced melanoma, chrono-immunotherapy, phase IV, Nivolumab, Ipilimumab, relatlimab, Pembrplizumab, Opdivo, Keytruda, Opdualag, Yervoy, immune checkpoint inhibitor
Brief summary
Melanoma remains a common cancer with rising incidence, and despite significant improvements with immune checkpoint inhibitors (ICIs), clinical outcomes remain heterogeneous. Retrospective analyses across multiple tumor types, including melanoma, suggest that earlier daytime administration of ICIs may enhance therapeutic effectiveness, potentially due to circadian modulation of immune function. A pronounced survival benefit has been observed particularly among female patients receiving earlier infusions. This trial prospectively evaluates whether aligning ICI administration with circadian immune activity can improve outcomes in melanoma and support the development of sex-specific optimization of immunotherapy.
Detailed description
The introduction of ICIs a decade ago revolutionized the treatment of various malignancies, particularly melanoma. Yet treatment responses are heterogenous and depend on patient characteristics such as sex and age, and tumor characteristics. The relationship between sex and ICI response in melanoma is complex and may be influenced by various factors, including the type of ICI, tumor mutation burden, presence of infiltrating immune cells, microbiome, and concomitant medications affect the immune system's ability to mount antitumor responses. While some retrospective data indicate poorer outcomes for female patients, in other real-world reports female sex is associated with better outcomes. Prospective, sex-stratified clinical studies are necessary to provide a definitive answer and to integrate sex as a critical variable in personalizing melanoma treatment strategies. Temporal variations in antibody responses and anticancer immunity after vaccination have been reported in both humans and mice. Circadian rhythms also remain an important regulator of immune cell activities. The optimal time for inducing adaptive immune responses consistently appears to be situated around or just before behavioral activity; for nocturnal mice this optimal window appears to be the afternoon, while in diurnal humans this may be the early morning. However, the optimal time of day for ICI administration is currently unknown. A retrospective single-center analysis of advanced melanoma patients showed that receiving less than 20% of the ICI infusions after 16h30 was associated with enhanced overall survival. In subgroup analyses, female patients had a significantly longer OS when less than 20% of the treatment was administered after 16h30. Optimizing the timing of ICI therapy to target the immune system at the time of its highest sensitivity could significantly improve patient outcomes, particularly for female patients, without exposing patients to additional drugs and generating additional toxicity and costs. Given the limitations of retrospective analyses, a prospective randomized trial is essential to obtain results that could potentially change clinical practice.
Interventions
DRUGImmune Checkpoint Inhibitors
Morning administration of ICI per physician's choice, according to local practice: Nivolumab (Opdivo®) Monotherapy - 240 mg administered intravenously every 2 weeks (Q2W) Pembrolizumab (Keytruda®) Monotherapy \- 200 mg administered intravenously every 3 weeks (Q3W) Ipilimumab (Yervoy®) + Nivolumab (Opdivo®) Combination Therapy * Induction Phase: * Ipilimumab 3 mg/kg intravenously every 3 weeks (Q3W) * Nivolumab 1 mg/kg intravenously every 3 weeks (Q3W) * Administered for 4 cycles * Maintenance Phase: * Nivolumab 240 mg administered intravenously every 2 weeks (Q2W) Nivolumab + Relatlimab Fixed-Dose Combination (Opdualag®) Nivolumab 480 mg and relatlimab 160 mg administered intravenously every 4 weeks (Q4W)
Sponsors
Swiss Cancer Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Prospective, randomized, multicenter, open-label phase IV trial. Participants will be randomized 1:1 to receive standard-of-care ICI therapy in either an early (08:00 - 12:00) or late (15:00 - 18:00) infusion time window. Participants will be randomized in a 1:1 ratio for a total of 54 per time window using the minimization method 31 with 80% allocation probability according to the stratification factors: * Treatment: Ipilimumab and Nivolumab versus Nivolumab and Relatlimab versus anti-PD1 mono (assumed ratio 50 :30 :20) * Sex: female versus male
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent according to Swiss law and ICH GCP E6 regulations before registration and prior to any trial specific procedures. * Histologically confirmed unresectable cutaneous stage III or stage IV melanoma. Note: Participants with central nervous system (CNS) metastases are eligible. * Participants with a previously treated other malignancy are eligible, if the risk of the prior malignancy interfering with either safety or efficacy endpoints is very low. * Measurable or evaluable disease. * Age ≥ 18 years. * Patients deemed suitable for ICI therapy based on the local investigator's clinical assessment. * ECOG performance status 0-2. * Women of childbearing potential must use effective contraception , not be pregnant or lactating and agree not to become pregnant during trial treatment and until 5 months after the last dose of trial treatment. A negative pregnancy test before inclusion into the trial is required for all women of childbearing potential. * Men agree not to donate sperm or to father a child during trial treatment and until 5 months after the last dose of trial treatment.
Exclusion criteria
* Prior treatment with any systemic anti-cancer therapy; with the exception of prior adjuvant anti-PD-1 or BRAF/MEK inhibitor therapy if the time from last dose to recurrence is more than 6 months. * Recent treatment (within 28 days prior to first dose) with any experimental drug. * Known history of allogeneic organ transplant. * Uveal or mucosal melanoma. * Receipt of live attenuated vaccine within 28 days prior to first dose. * Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information. * Known hypersensitivity to trial drug(s) or to any component of the trial drug(s). * Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned staging, treatment and follow-up, affect participant compliance or place the participant at high risk from treatment-related complications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) | From randomization to Progressive Desease or death, up to 6 years | Progression-free survival (PFS), defined as time from randomization to progression according to local assessment or death. Participants not experiencing an event will be censored at the date of the last available assessment before initiation of a new anti-cancer treatment, if any. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival (OS) | From randomization to death, up to 6 year | OS is defined as the time from randomization until death due to any cause. Participants not experiencing an event will be censored at the last date they were known to be alive. |
| Objective response rate (ORR) | At the end of trial treatment, up to 4 years from registration | Objective response rate (ORR) Objective response is defined as any complete response (CR) or partial response (PR) according to local assessment achieved during treatment. Any participant with CR or PR as best observed response during treatment will be considered as a success; otherwise, they will be considered as a failure. Participants without any tumor assessment, or with non-evaluable response (NE) during treatment, will be considered as failures for this endpoint. |
Countries
Switzerland
Contacts
CONTACTLenka Vokalova, PhD
CONTACTChristina Müller, PhD
STUDY_CHAIRBerna Özdemir, MD PhD
Insel Gruppe AG, University Hospital Bern
Outcome results
None listed