Time-of-Day Specified Immunotherapy for Advanced Melanoma, The TIME Trial

NCT ID: NCT07155317

Last Updated: 2025-11-12

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE2

Total Enrollment

99 participants

Study Classification

INTERVENTIONAL

Study Start Date

2025-10-29

Study Completion Date

2027-12-31

Brief Summary

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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.

Detailed Description

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PRIMARY OBJECTIVE:

I. 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:

I. 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:

I. 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

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Advanced Acral Melanoma Advanced Cutaneous Melanoma Advanced Mucosal Melanoma Clinical Stage IV Cutaneous Melanoma AJCC v8 Metastatic Acral Melanoma Metastatic Cutaneous Melanoma Metastatic Mucosal Melanoma Unresectable Acral Melanoma Unresectable Cutaneous Melanoma Unresectable Mucosal Melanoma

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Arm I (nivolumab, ipilimumab)

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.

Group Type EXPERIMENTAL

Biopsy Procedure

Intervention Type PROCEDURE

Undergo tumor tissue biopsy

Biospecimen Collection

Intervention Type PROCEDURE

Undergo check swab and blood sample collection

Computed Tomography

Intervention Type PROCEDURE

Undergo CT

Ipilimumab

Intervention Type BIOLOGICAL

Given IV

Magnetic Resonance Imaging

Intervention Type PROCEDURE

Undergo MRI

Medical Device Usage and Evaluation

Intervention Type OTHER

Wear an actigraphy device

Nivolumab

Intervention Type BIOLOGICAL

Given IV

Questionnaire Administration

Intervention Type OTHER

Ancillary studies

Arm II (nivolumab, ipilimumab)

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.

Group Type EXPERIMENTAL

Biopsy Procedure

Intervention Type PROCEDURE

Undergo tumor tissue biopsy

Biospecimen Collection

Intervention Type PROCEDURE

Undergo check swab and blood sample collection

Computed Tomography

Intervention Type PROCEDURE

Undergo CT

Ipilimumab

Intervention Type BIOLOGICAL

Given IV

Magnetic Resonance Imaging

Intervention Type PROCEDURE

Undergo MRI

Medical Device Usage and Evaluation

Intervention Type OTHER

Wear an actigraphy device

Nivolumab

Intervention Type BIOLOGICAL

Given IV

Questionnaire Administration

Intervention Type OTHER

Ancillary studies

Arm III (nivolumab, ipilimumab)

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.

Group Type ACTIVE_COMPARATOR

Biopsy Procedure

Intervention Type PROCEDURE

Undergo tumor tissue biopsy

Biospecimen Collection

Intervention Type PROCEDURE

Undergo check swab and blood sample collection

Computed Tomography

Intervention Type PROCEDURE

Undergo CT

Ipilimumab

Intervention Type BIOLOGICAL

Given IV

Magnetic Resonance Imaging

Intervention Type PROCEDURE

Undergo MRI

Medical Device Usage and Evaluation

Intervention Type OTHER

Wear an actigraphy device

Nivolumab

Intervention Type BIOLOGICAL

Given IV

Questionnaire Administration

Intervention Type OTHER

Ancillary studies

Interventions

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Biopsy Procedure

Undergo tumor tissue biopsy

Intervention Type PROCEDURE

Biospecimen Collection

Undergo check swab and blood sample collection

Intervention Type PROCEDURE

Computed Tomography

Undergo CT

Intervention Type PROCEDURE

Ipilimumab

Given IV

Intervention Type BIOLOGICAL

Magnetic Resonance Imaging

Undergo MRI

Intervention Type PROCEDURE

Medical Device Usage and Evaluation

Wear an actigraphy device

Intervention Type OTHER

Nivolumab

Given IV

Intervention Type BIOLOGICAL

Questionnaire Administration

Ancillary studies

Intervention Type OTHER

Other Intervention Names

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Biopsy BIOPSY_TYPE Bx Biological Sample Collection Biospecimen Collected Specimen Collection CAT CAT Scan Computed Axial Tomography Computerized Axial Tomography Computerized axial tomography (procedure) Computerized Tomography Computerized Tomography (CT) scan CT CT Scan tomography Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody BMS 734016 BMS-734016 BMS734016 Ipilimumab Biosimilar CS1002 MDX 010 MDX-010 MDX-CTLA4 MDX010 Yervoy Magnetic Resonance Magnetic Resonance Imaging (MRI) Magnetic resonance imaging (procedure) Magnetic Resonance Imaging Scan Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance MR MR Imaging MRI MRI Scan MRIs NMR Imaging NMRI Nuclear Magnetic Resonance Imaging sMRI Structural MRI ABP 206 BCD-263 BMS 936558 BMS-936558 BMS936558 CMAB819 MDX 1106 MDX-1106 MDX1106 NIVO Nivolumab Biosimilar ABP 206 Nivolumab Biosimilar BCD-263 Nivolumab Biosimilar CMAB819 ONO 4538 ONO-4538 ONO4538 Opdivo

Eligibility Criteria

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Inclusion Criteria

* 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

Exclusion Criteria

* Immunosuppression (\> 10mg prednisone daily)
* Active autoimmune disease that would preclude the administration of immunotherapy
* Active leptomeningeal disease
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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National Cancer Institute (NCI)

NIH

Sponsor Role collaborator

Emory University

OTHER

Sponsor Role lead

Responsible Party

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Michael Lowe

Principal Investigator

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Michael Lowe, MD, MA

Role: PRINCIPAL_INVESTIGATOR

Emory University Hospital/Winship Cancer Institute

Locations

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Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, United States

Site Status RECRUITING

Emory Saint Joseph's Hospital

Atlanta, Georgia, United States

Site Status NOT_YET_RECRUITING

Countries

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United States

Central Contacts

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Michael C. Lowe, MD, MA

Role: CONTACT

Phone: 404-778-0680

Email: [email protected]

Zachary Buchwald, MD, PhD

Role: CONTACT

Email: [email protected]

Facility Contacts

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Tiffaney Roundtree

Role: primary

Tiffaney Roundtree

Role: primary

Other Identifiers

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NCI-2025-03025

Identifier Type: REGISTRY

Identifier Source: secondary_id

STUDY00008806

Identifier Type: OTHER

Identifier Source: secondary_id

WINSHIP6451-24

Identifier Type: OTHER

Identifier Source: secondary_id

P30CA138292

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STUDY00008806

Identifier Type: -

Identifier Source: org_study_id