Timing of Immunotherapy in Melanoma (TIME-NL)

Timing of Immunotherapy in Melanoma (TIME-NL): Dancing to the Beat of the Circadian Rhythm

The TIME-NL trial is a multicenter, randomized, open-label clinical trial in the Netherlands to assess the effect of the timing of the first administration of standard-of-care intravenous combination immunotherapy (early morning versus afternoon) in patients with metastatic melanoma. Patients will be randomized 1:1 to start standard-of-care ICI administration either before 10am (early morning arm; arm A) or after 1pm (afternoon arm; arm B). Patients will be stratified according to performance status and study center. The randomized clinical trial will be part of a hybrid design in which data from the randomized clinical trial will be combined with observational data.

Study Overview

• Status: Not yet recruiting
• Conditions: Melanoma
• Intervention / Treatment: Other: Timing of first administration (early morning); Other: Timing of immunotherapy (afternoon)

• Study Type: Interventional
• Enrollment (Estimated): 170
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Kalijn Bol, MD/PhD; Phone Number: +31243618800; Email: kalijn.bol@radboudumc.nl
• Study Contact Backup: Name: Mirte Meijerink; Email: studies.onco@radboudumc.nl

Study Locations

• Netherlands
  • Amsterdam, Netherlands
    • Amsterdam UMC
    • Contact: Fons van den Eertwegh
  • Amsterdam, Netherlands
    • Antoni van Leeuwenhoek
    • Contact: Hans van Thienen
  • Leiden, Netherlands
    • Leiden UMC
    • Contact: Ellen Kapiteijn
  • Rotterdam, Netherlands
    • ErasmusMC
    • Contact: Astrid van der Veldt

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histologically or cytologically confirmed cutaneous melanoma, classified as irresectable (stage III) or metastatic (stage IV) disease.
• At least 18 years of age.
• World Health Organization (WHO) Performance Status 0-1.
• Measurable disease according to RECIST 1.1.
• Starting treatment with standard-of-care combination immunotherapy (ipilimumab+nivolumab) as first line treatment.
• Signed informed consent form

Exclusion Criteria:

• Uveal or mucosal melanoma (unknown primary melanoma is allowed).
• Use of systemic immunosuppressive medications. Inhaled or topical steroids are permitted.
• Use of adrenal replacement medications, e.g. hydrocortisone.
• Use of melatonin agonists.
• Prior systemic therapy for irresectable/metastatic melanoma (prior T-VEC is allowed)
• Prior systemic therapy for resectable melanoma in the last 6 months (neo-adjuvant and adjuvant treatment is allowed if at least 6 months ago).
• Use of investigational drugs.

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
Active Comparator: A: early morning immunotherapy; Standard-of-care immune checkpoint inhibition with ipilimumab + nivolumab with the first administration starting before 10am	Other: Timing of first administration (early morning); The timing of the first administration of combination immunotherapy starting before 10am
Active Comparator: B: afternoon immunotherapy; Standard-of-care immune checkpoint inhibition with ipilimumab + nivolumab with the first administration starting after 1pm	Other: Timing of immunotherapy (afternoon); The timing of the first administration of combination immunotherapy starting after 1pm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best overall response rate	Best overall response rate (radiological complete or partial response according to RECIST 1.1)	from enrollment to 1year

Collaborators and Investigators

• Sponsor: Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Estimated): July 16, 2026
• Primary Completion (Estimated): September 30, 2029
• Study Completion (Estimated): September 30, 2033

Study Registration Dates

• First Submitted: July 6, 2026
• First Submitted That Met QC Criteria: July 6, 2026
• First Posted (Actual): July 10, 2026

Study Record Updates

• Last Update Posted (Actual): July 10, 2026
• Last Update Submitted That Met QC Criteria: July 6, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: melanoma; timing; chronoimmunotherapy
• 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
• Other Study ID Numbers: R0128980; NL-011107 (Other Identifier: CCMO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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