Advanced Acral MelanomaPhase 2NCT07155317
Time-of-Day Specified Immunotherapy for Advanced Melanoma, The TIME Trial
A Phase 2 study testing Biopsy Procedure, Biospecimen Collection and Computed Tomography in people with Advanced Acral Melanoma and Advanced Cutaneous Melanoma, run by Emory University at 2 sites in United States.
Trial summary
This phase II trial tests the safety and effectiveness of giving ipilimumab and nivolumab in the morning compared to other times of day in treating patients with melanoma that is stage IV or that cannot be removed by surgery (unresectable). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced Acral Melanoma, Advanced Cutaneous Melanoma, Advanced Mucosal Melanoma
- What is being tested?
- Biopsy Procedure, Biospecimen Collection and Computed Tomography
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 99 participants
- Where
- 2 sitesUnited States
- Study dates
- 29 Oct 2025to 31 Dec 2027
- Phase
- Phase 2
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
- Pathologically confirmed American Joint Committee on Cancer (AJCC) 8th edition stage IV unresectable cutaneous, acral, or mucosal melanoma
- No uveal melanoma
- Patients with asymptomatic, non-hemorrhagic brain metastases < 2 cm are eligible
- No prior immunotherapy within 1 year, (serine/threonine-protein kinase B-raf [BRAF]/mitogen-activated protein kinase [MEK] inhibitors allowed)
- Eastern Cooperative Oncology Group (ECOG) 0-1
- Age ≥ 18
- Adequate organ function to receive ipilimumab/nivolumab
Who cannot join
- Immunosuppression (> 10mg prednisone daily)
- Active autoimmune disease that would preclude the administration of immunotherapy
- Active leptomeningeal disease
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Zachary Buchwald, MD, PhD contact
United States2 sites, 2 recruiting
- Recruiting
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, 30322
Tiffaney Roundtree, tiffaney.laquinta.roundtree@emory.edu
Michael C. Lowe, MD, MA
- Not yet recruiting
Emory Saint Joseph's Hospital
Atlanta, Georgia, 30342
Tiffaney Roundtree, tiffaney.laquinta.roundtree@emory.edu
Michael C. Lowe, MD, MA
About this study
Official title: The TIME Trial - Phase II Randomized Controlled Trial of Time-of-Day Specified Immunotherapy for Advanced Melanoma
This phase II trial tests the safety and effectiveness of giving ipilimumab and nivolumab in the morning compared to other times of day in treating patients with melanoma that is stage IV or that cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the tumor and may interfere with the ability of tumor cells to grow and spread. While some patients have impressive outcomes with both of these drugs, over 40% of patients do not experience any clinical benefit. Studies have shown that the time of day that vaccines and other therapies are given have had an impact on response and survival. It is not known, however, whether time of day has an impact on response to immune checkpoint inhibitors, such as ipilimumab and nivolumab. Giving ipilimumab and nivolumab earlier in the day compared to later in the day may improve response to treatment and survival in patients with stage IV or unresectable melanoma.
Read the detailed description
PRIMARY OBJECTIVE:
- To compare the progression-free survival (PFS) following administration of immunotherapy at different time-of-day intervals for previously untreated unresectable or metastatic melanoma.
SECONDARY OBJECTIVES:
- To compare adverse events (AEs). II. Rate of receiving all immunotherapy doses as scheduled. III. Objective response rate. IV. Melanoma specific survival (MSS) and overall survival (OS). V. Patient-reported quality of life (QOL).
TERTIARY/EXPLORATORY OBJECTIVE:
- To explore immune biomarkers associated with clinical efficacy (PFS, OS).
OUTLINE: Patients are randomized to 1 of 3 arms.
ARM I: Patients receive nivolumab intravenously (IV) over 60 minutes and ipilimumab IV over 90 minutes at 0800-1100 on day 1 of each cycle. Cycles repeat every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance nivolumab for up to a total of 2 years. Patients wear an actigraphy device for 5-7 days at enrollment prior to first infusion and for up to 4 weeks then over 3 weeks starting with visit 4. Patients also undergo check swab and blood sample collection, computed tomography (CT) or magnetic resonance imaging (MRI) and MRI or CT of brain throughout the study. Additionally, patients may optionally undergo tumor tissue biopsy throughout the study.
ARM II: Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes at 1100-1400 on day 1 of each cycle. Cycles repeat every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance nivolumab for up to a total of 2 years. Patients wear an actigraphy device for 5-7 days at enrollment prior to first infusion and for up to 4 weeks then over 3 weeks starting with visit 4. Patients also undergo check swab and blood sample collection, CT or MRI and MRI or CT of brain throughout the study. Additionally, patients may optionally undergo tumor tissue biopsy throughout the study.
ARM III: Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes at 1400-1700 on day 1 of each cycle. Cycles repeat every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance nivolumab for up to a total of 2 years. Patients wear an actigraphy device for 5-7 days at enrollment prior to first infusion and for up to 4 weeks then over 3 weeks starting with visit 4. Patients also undergo check swab and blood sample collection, CT or MRI and MRI or CT of brain throughout the study. Additionally, patients may optionally undergo tumor tissue biopsy throughout the study.
After completion of study treatment, patients are followed up every 3 months for 12 months, then for up to year 5.
- Conditions
- Advanced Acral Melanoma, Advanced Cutaneous Melanoma, Advanced Mucosal Melanoma, Clinical Stage IV Cutaneous Melanoma AJCC v8, Metastatic Acral Melanoma, Metastatic Cutaneous Melanoma
- Being tested
- Biopsy Procedure, Biospecimen Collection, Computed Tomography, Ipilimumab, Magnetic Resonance Imaging
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Biopsy ProcedureProcedure or surgery
Also called Biopsy, BIOPSY_TYPE, Bx
Undergo tumor tissue biopsy
Biospecimen CollectionProcedure or surgery
Also called Biological Sample Collection, Biospecimen Collected, Specimen Collection
Undergo check swab and blood sample collection
Computed TomographyProcedure or surgery
Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography
Undergo CT
IpilimumabBiological
Also called Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS 734016, BMS-734016, BMS734016
Given IV
Magnetic Resonance ImagingProcedure or surgery
Also called Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan
Undergo MRI
Medical Device Usage and EvaluationOther
Wear an actigraphy device
NivolumabBiological
Also called ABP 206, BCD-263, BMS 936558, BMS-936558
Given IV
Questionnaire AdministrationOther
Ancillary studies
| Study group | Role | What they receive |
|---|---|---|
| Arm I (nivolumab, ipilimumab) | Experimental | Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes at 0800-1100 on day 1 of each cycle. Cycles repeat every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance nivolumab for up to a total of 2 years. Patients wear an actigraphy device for 5-7 days at enrollment prior to first infusion and for up to 4 weeks then over 3 weeks starting with visit 4. Patients also undergo check swab and blood sample collection, CT or MRI and MRI or CT of brain throughout the study. Additionally, patients may optionally undergo tumor tissue biopsy throughout the study. Receives: Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Biological: Ipilimumab; Procedure: Magnetic Resonance Imaging; Other: Medical Device Usage and Evaluation; Biological: Nivolumab; Other: Questionnaire Administration |
| Arm II (nivolumab, ipilimumab) | Experimental | Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes at 1100-1400 on day 1 of each cycle. Cycles repeat every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance nivolumab for up to a total of 2 years. Patients wear an actigraphy device for 5-7 days at enrollment prior to first infusion and for up to 4 weeks then over 3 weeks starting with visit 4. Patients also undergo check swab and blood sample collection, CT or MRI and MRI or CT of brain throughout the study. Additionally, patients may optionally undergo tumor tissue biopsy throughout the study. Receives: Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Biological: Ipilimumab; Procedure: Magnetic Resonance Imaging; Other: Medical Device Usage and Evaluation; Biological: Nivolumab; Other: Questionnaire Administration |
| Arm III (nivolumab, ipilimumab) | Active comparator | Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes at 1400-1700 on day 1 of each cycle. Cycles repeat every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance nivolumab for up to a total of 2 years. Patients wear an actigraphy device for 5-7 days at enrollment prior to first infusion and for up to 4 weeks then over 3 weeks starting with visit 4. Patients also undergo check swab and blood sample collection, CT or MRI and MRI or CT of brain throughout the study. Additionally, patients may optionally undergo tumor tissue biopsy throughout the study. Receives: Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Biological: Ipilimumab; Procedure: Magnetic Resonance Imaging; Other: Medical Device Usage and Evaluation; Biological: Nivolumab; Other: Questionnaire Administration |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression-Free Survival (PFS) A versus (vs.) C and B vs. C
Will be determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Will be compared between arms with a log rank test. The hazard ratio and the corresponding 95% confidence interval (CI) for the A vs. C and B vs. C comparisons will be estimated in a Cox proportional hazards model using the randomized arm as a single covariate. The PFS curves for each randomized arm will be estimated using the Kaplan-Meier (KM) method. In addition, PFS rates at specific time points will be estimated using KM estimates on the PFS curve for each randomized arm. Associated 2-sided 95% CIs will be calculated using the Greenwood formula (using log-log transformation).
Measured: From randomization to progression or death, assessed up to 5 years
Secondary outcomes (6)
Incidence of Treatment-Related Adverse Events (AE)
Will be determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5. Frequencies and percentages will be used to summarize safety events. All treatment-associated AE event rates, as well as treatment-associated grade 3 or higher AE event rates will be reported. Event rates will be compared between arms using a Chi-square test. Differences in event rates will be reported, and 95% CIs will be estimated.
Measured: Up to 100 days after last dose of study treatment
Objective Response Rate (ORR)
Will be defined as complete response and/or partial response assessed using RECIST 1.1 criteria. Will be estimated as a proportion, with an exact 95% CI estimated using the Clopper-Pearson method. ORR will be compared between arms using a Chi-square test.
Measured: Up to 3 months
Overall Survival (OS)
Will be compared between arms with a log rank test. The hazard ratio and the corresponding 95% CIs for the A vs. C and B vs. C comparisons will be estimated in a Cox proportional hazards model using the randomized arm as a single covariate. The OS curves for each randomized arm will be estimated using the KM method. In addition, OS rates at specific time points will be estimated using KM estimates on the OS curve for each randomized arm. Associated 2-sided 95% CIs will be calculated using the Greenwood formula (using log-log transformation).
Measured: From randomization to death from any cause, assessed up to 5 years
PFS A vs. B
Will be determined using RECIST 1.1. PFS will be compared between arms with a log rank test. The hazard ratio and the corresponding 95% CI for the A vs. B comparison will be estimated in a Cox proportional hazards model using the randomized arm as a single covariate. The PFS curves for each randomized arm will be estimated using the KM method. In addition, PFS rates at specific time points will be estimated using KM estimates on the PFS curve for each randomized arm. Associated 2-sided 95% CIs will be calculated using the Greenwood formula (using log-log transformation).
Measured: From randomization to progression or death, assessed up to 5 years
Disease Specific Survival
To explore immune biomarkers associated with clinical efficacy from the pre-treatment and post-treatment melanoma biopsy specimens and peripheral blood.
Measured: Up to 5 years
Rate of Receiving all Immunotherapy Doses as Scheduled
To compare rate of receiving all immunotherapy doses as scheduled, of subjects with previously untreated unresectable or metasatic melanoma who receive immunotherapy infusions at different time-of-day intervals, and impact of quality of life on timing of infusion.
Measured: Up to 4 cycles (cycle length = 3 weeks)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Sep 2025
- Study start29 Oct 2025
- Primary completion31 Dec 2026 (estimated)
- Study completion31 Dec 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Advanced Acral MelanomaStudies of the same condition, open and under way.
- More trials run by Emory UniversityThe sponsor's other registered studies.
- 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
- Masking
- None (open label)
- Enrolment
- 99 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Emory University
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Principal investigator, Michael Lowe, Emory University
- Investigators
- Michael Lowe, MD, MA, Principal investigator, Emory University Hospital/Winship Cancer Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07155317
- Sponsor's protocol ID
- STUDY00008806
- Other IDs
- NCI-2025-03025, STUDY00008806, WINSHIP6451-24, P30CA138292
- Status last verified
- Nov 2025
- First submitted
- 21 Aug 2025
- Last updated
- 12 Nov 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No