MELCHRONO: A Prospective Randomized Study Investigating Chrono-immunotherapy for Advanced Melanoma.

MELCHRONO: A Prospective Randomized Study Investigating Chrono-immunotherapy for Advanced Melanoma. A Phase IV Trial.

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Melanoma; Advanced Melanoma
• Intervention / Treatment: Drug: Immune Checkpoint Inhibitors; Drug: Immune Checkpoint Inhibitors

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.

• Study Type: Interventional
• Enrollment (Estimated): 108
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Christina Müller, PhD; Phone Number: +41 31 389 91 91; Email: trials@swisscancerinstitute.ch
• Study Contact Backup: Name: Lenka Vokalova, PhD; Phone Number: +41 31 389 91 91; Email: trials@swisscancerinstitute.ch

Study Locations

• Switzerland
  • Bellinzona, Switzerland, 6500
    • Ente Ospedaliero Cantonale (EOC)
    • Contact: Cristina Mangas de Arriba, MD; Phone Number: +41 91 811 94 11; Email: cristina.mangas@eoc.ch
    • Principal Investigator: Cristina Mangas de Arriba, MD
  • Bern, Switzerland, 3010
    • Inselspital, Bern
    • Contact: Berna Oezdemir, MD; Phone Number: +41 31 632 81 95; Email: berna.oezdemir@insel.ch
    • Principal Investigator: Berna Özdemir, MD
  • Geneva, Switzerland, 1211
    • Hôpitaux Universitaires de Genève HUG
  • Lausanne, Switzerland, 1011
    • Centre Hospitalier Universitaire Vaudois (CHUV)
    • Contact: Sofiya Latifyan, MD; Phone Number: +41 21 314 11 11; Email: sofiya.latifyan@chuv.ch
    • Principal Investigator: Sofiya MD Latifyan
  • Münsterlingen, Switzerland, 8596
    • Spital Thurgau (Kantonsspital Münserlingen und Frauenfeld)
    • Principal Investigator: Ioannis Metaxas, MD
    • Contact: Ioannis Metaxas, MD; Phone Number: +41 58 144 78 50; Email: ioannis.metaxas@stgag.ch
  • Sankt Gallen, Switzerland, 9007
    • HOCH Health Ostschweiz - Kantonsspital St. Gallen
    • Contact: Tobias Peres, MD; Phone Number: +41 71 494 38 78; Email: tobias.peres@h-och.ch
    • Principal Investigator: Tobias Peres, MD
  • Zurich, Switzerland, 8091
    • Universitätsspital Zürich USZ
  • Canton of Fribourg
    • Fribourg, Canton of Fribourg, Switzerland, 1708
      • Hfr Fribourg
      • Contact: Bianca Gautron Moura, MD; Phone Number: +41 26 306 22 60; Email: Bianca.gautronmoura@h-fr.ch
      • Principal Investigator: Bianca Gautron Moura, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ICI Infusions 8-12 h; Participants will be randomized 1:1 to receive standard-of-care ICI therapy in an early (08:00 - 12:00) infusion time window.	Drug: Immune 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); Drug: Immune Checkpoint Inhibitors; Afternooon 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)
Active Comparator: ICI Infusions 15-18 h; Participants will be randomized 1:1 to receive standard-of-care ICI therapy in a late (15:00 - 18:00) infusion time window.	Drug: Immune 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); Drug: Immune Checkpoint Inhibitors; Afternooon 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	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.	From randomization to Progressive Desease or death, up to 6 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	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.	From randomization to death, up to 6 year
Objective response rate (ORR)	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.	At the end of trial treatment, up to 4 years from registration

Collaborators and Investigators

• Sponsor: Swiss Cancer Institute
• Investigators: Study Chair: Berna Özdemir, MD et phil., Insel Gruppe AG, University Hospital Bern

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): June 1, 2030
• Study Completion (Estimated): June 1, 2032

Study Registration Dates

• First Submitted: May 1, 2026
• First Submitted That Met QC Criteria: May 1, 2026
• First Posted (Actual): May 7, 2026

Study Record Updates

• Last Update Posted (Actual): May 7, 2026
• Last Update Submitted That Met QC Criteria: May 1, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Nivolumab; Ipilimumab; Keytruda; relatlimab; Opdivo; Advanced melanoma; immune checkpoint inhibitor; phase IV; Yervoy; Opdualag; chrono-immunotherapy; Pembrplizumab
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Skin and Connective Tissue Diseases; Melanoma; Antineoplastic Agents, Immunological; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Therapeutic Uses; Immune Checkpoint Inhibitors
• Other Study ID Numbers: SCI-004_MELCHRONO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No