MelanomaPhase 2NCT07574047
MELCHRONO: A Prospective Randomized Study Investigating Chrono-immunotherapy for Advanced Melanoma.
A Phase 2 study testing Immune Checkpoint Inhibitors in people with Melanoma and Advanced Melanoma, run by Swiss Cancer Institute at 9 sites in Switzerland.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma, Advanced Melanoma
- What is being tested?
- Immune Checkpoint Inhibitors
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 108 participants
- Where
- 9 sitesSwitzerland
- Study dates
- 12 Oct 2026to Jun 2032
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
Trial locations and contacts
9 sites in 1 country. Contact the study team or a site near you to ask about taking part.
9 sites in 1 country
Switzerland9 sites, 9 recruiting
- Recruiting
Universitätsspital Basel
Basel, 4058
Andreas Schmitt, MD, +41 61 328 69 92, andreasmichael.schmitt@usb.ch
Andreas Schmitt, MD
- Recruiting
Ente Ospedaliero Cantonale (EOC)
Bellinzona, 6500
Cristina Mangas de Arriba, MD, +41 91 811 94 11, cristina.mangas@eoc.ch
Cristina Mangas de Arriba, MD
- Recruiting
Inselspital, Bern
Bern, 3010
Berna Oezdemir, MD PhD, +41 31 632 81 95, berna.oezdemir@insel.ch
Berna Özdemir, MD
- Recruiting
HFR Fribourg
Fribourg, Canton of Fribourg, 1708
Bianca Gautron Moura, MD, +41 26 306 22 60, Bianca.gautronmoura@h-fr.ch
Bianca Gautron Moura, MD
- Recruiting
Hôpitaux Universitaires de Genève HUG
Geneva, 1205
Assma Ben Aissa, MD, +41 22 372 98 62, assma.benaissa@hug.ch
Assma Ben Aissa, MD
- Recruiting
Centre Hospitalier Universitaire Vaudois (CHUV)
Lausanne, 1011
Sofiya Latifyan, MD, +41 21 314 11 11, sofiya.latifyan@chuv.ch
Sofiya Latifyan, MD
- Recruiting
Spital Thurgau (Kantonsspital Münserlingen und Frauenfeld)
Münsterlingen, 8596
Ioannis Metaxas, MD, +41 58 144 78 50, ioannis.metaxas@stgag.ch
Ioannis Metaxas, MD
- Recruiting
HOCH Health Ostschweiz - Kantonsspital St. Gallen
Sankt Gallen, 9007
Tobias Peres, MD, +41 71 494 38 78, tobias.peres@h-och.ch
Tobias Peres, MD
- Recruiting
Universitätsspital Zürich USZ
Zurich, 8091
Joanna Mangana, MD, +41 44 255 11 11, johanna.mangana@usz.ch
Joanna Mangana, MD
About this study
Official title: MELCHRONO: A Prospective Randomized Study Investigating Chrono-immunotherapy for Advanced Melanoma. A Phase II 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.
Read the 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.
- Conditions
- Melanoma, Advanced Melanoma
- Being tested
- Immune Checkpoint Inhibitors
- Keywords
- Advanced melanoma, chrono-immunotherapy, phase IV, Nivolumab, Ipilimumab, relatlimab, Pembrplizumab, Opdivo, Keytruda, Opdualag, Yervoy, immune checkpoint inhibitor
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Immune Checkpoint InhibitorsDrug
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)
Immune Checkpoint InhibitorsDrug
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)
| Study group | Role | What they receive |
|---|---|---|
| ICI Infusions 8-12 h | Experimental | Participants will be randomized 1:1 to receive standard-of-care ICI therapy in an early (08:00 - 12:00) infusion time window. Receives: Drug: Immune Checkpoint Inhibitors |
| ICI Infusions 15-18 h | Active comparator | Participants will be randomized 1:1 to receive standard-of-care ICI therapy in a late (15:00 - 18:00) infusion time window. Receives: Drug: Immune Checkpoint Inhibitors |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: From randomization to Progressive Desease or death, up to 6 years
Secondary outcomes (2)
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.
Measured: 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.
Measured: At the end of trial treatment, up to 4 years from registration
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 May 2026
- Study start12 Oct 2026
- Primary completionJun 2030 (estimated)
- Study completionJun 2032 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for MelanomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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
- Masking
- None (open label)
- Enrolment
- 108 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Swiss Cancer Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Berna Özdemir, MD PhD, Study chair, Insel Gruppe AG, University Hospital Bern
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07574047
- Sponsor's protocol ID
- SCI-004_MELCHRONO
- Status last verified
- Oct 2026
- First submitted
- 1 May 2026
- Last updated
- 27 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 27 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- MELCHRONO: A Prospective Randomized Study Investigating Chrono-immunotherapy for Advanced Melanoma. A Phase II Trial.
- ClinicalTrials.gov ID
- NCT07574047
- Acronym / sponsor ID
- SCI-004_MELCHRONO
- Conditions
- Melanoma, Advanced Melanoma
- Keywords
- Advanced melanoma, chrono-immunotherapy, phase IV, Nivolumab, Ipilimumab, relatlimab, Pembrplizumab, Opdivo
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 108 participants (estimated)
- Lead sponsor
- Swiss Cancer InstituteUniversity, hospital or other
- Study start
- 12 Oct 2026 (actual)
- Primary completion
- Jun 2030 (estimated)
- Study completion
- Jun 2032 (estimated)
- First posted
- 7 May 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- 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
| Arm | Type | Receives |
|---|---|---|
| ICI Infusions 8-12 h | Experimental | Drug: Immune Checkpoint InhibitorsParticipants will be randomized 1:1 to receive standard-of-care ICI therapy in an early (08:00 - 12:00) infusion time window. |
| ICI Infusions 15-18 h | Active comparator | Drug: Immune Checkpoint InhibitorsParticipants will be randomized 1:1 to receive standard-of-care ICI therapy in a late (15:00 - 18:00) infusion time window. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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.
Key exclusion criteria (8 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Immune Checkpoint InhibitorsMorning 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 | ICI Infusions 8-12 h |
| Immune Checkpoint InhibitorsAfternooon 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 | ICI Infusions 15-18 h |
Primary outcome
Progression-free survival (PFS)
Time frame: 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.
2 secondary outcomes
Overall survival (OS)
Time frame: From randomization to death, up to 6 year
Objective response rate (ORR)
Time frame: At the end of trial treatment, up to 4 years from registration
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Oct 2026.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Berna Özdemir, MD PhD study chair
Insel Gruppe AG, University Hospital Bern
9 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Immune Checkpoint Inhibitors in people with Melanoma and Advanced Melanoma, run by Swiss Cancer Institute at 9 sites in Switzerland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 27 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 9 sites in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Lenka Vokalova, PhD (+41 31 389 91 91, trials@swisscancerinstitute.ch), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression-free survival (PFS) (time frame: From randomization to Progressive Desease or death, up to 6 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Oct 2026.