ctDNA-guided Addition of Ipilimumab to Patients Receiving Nivolumab and Relatlimab

A Multi-center Trial Evaluating the ctDNA-guided Addition of Ipilimumab to Patients Receiving Nivolumab and Relatlimab for Advanced Melanoma

The purpose of this study is to investigate the use of ctDNA measurements to guide first-lien therapy choice for patients with advanced or metastatic melanoma. Primary endpoints include progression-free survival. Secondary study endpoints include objective response rate and incidence and severity of immune-related adverse events.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Melanoma; Advanced Melanoma
• Intervention / Treatment: Drug: Nivolumab; Drug: Relatlimab; Device: Signatera genome MRD assay; Drug: Ipilimumab

Detailed Description

This study's approach seeks to rationally, rather than empirically, choose one treatment approach over another, as well as to develop methods to predict disease recurrence at earlier time points. The combination of ipilimumab and nivolumab is the standard of care for first-line treatment of advanced melanoma. This study instead seeks to pioneer treatment choice based on evidence of molecular relapse, and to determine whether this results in superior outcomes compared with the current standard of care to treat until evidence of radiologic progression. Patients with sustained "zeroconversion" may not require an immediate switch, while patients whose ctDNA levels are detectable and/or rising may benefit from an earlier therapeutic switch. The overall goal is to improve patient selection for therapy, thus sparing the therapeutic and financial toxicities from therapies that have stopped working (i.e. patients with rising ctDNA levels) or are perhaps not necessary (patients who have sustained zeroconversion).

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Janice M. Mehnert, MD; Phone Number: 212-731-5431; Email: janice.mehnert@nyulangone.org
• Study Contact Backup: Name: Cancer Trials Office; Email: cancertrials@nyulangone.org

Study Locations

• United States
  • New York
    • New York, New York, United States, 10016
      • Recruiting
      • NYU Langone Health

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Patient must be ≥ 18 years old.
2. Patients must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written informed consent from (ICF) in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal patient care.
3. Patients must be willing and able to comply with scheduled visits, laboratory tests, and other requirements of the study.
4. Patient must have active advanced melanoma, defined as unresectable stage IIIB-IV by American Joint Committee on Cancer (AJCC) 8th edition. Patients with mucosal melanoma defined as unresectable stage III or regional/distant metastatic disease are eligible.
5. Patient must have melanoma originating from cutaneous, acral-lentiginous, or mucosal primary sites. Patients with melanoma of unknown primary site are eligible.
6. Patient must have at least one lesion for measurable disease per RECIST 1.1 guidelines (refer to section 8.1 for more information).
7. Patients must have specimen required for study procedures, including either archived tumor tissue or fresh tissue and whole blood available, at baseline to send to Natera as part of screening for Signatera testing to be completed. (refer to section 8.2 for more information)
8. Patient must be planned to initiate standard of care first-line therapy for metastatic disease
9. Patients must not have received prior anticancer treatment for metastatic disease (for example, but not limited to, systemic, local, radiation, radiopharmaceutical). Exceptions: Surgery for melanoma and/or post-resection brain radiotherapy (RT) if central nervous system (CNS) metastases and adjuvant RT for locoregional disease after resection. Prior treatment with the following therapies in the adjuvant setting: interferon (IFN)-alpha therapy, BRAF/MEK therapy (e.g. dabrafenib and trametinib), anti-PD-1 therapy (e.g. pembrolizumab or nivolumab), or anti-CTLA-4 therapy (e.g. ipilimumab) is allowed if therapy has been completed for 6 months (see criterion 10).
10. All patients must have their disease status documented by a complete physical examination and imaging studies within 4 weeks prior to the first dose of study drug. Imaging studies must include computerized tomography (CT) scan of chest, abdomen, pelvis, and all known sites of resected disease in the setting of Stage IIIB/C/D or Stage IV disease, and brain magnetic resonance imaging ([MRI]; brain CT is allowable if MRI is contraindicated).
11. The complete set of baseline radiographic images must be available before treatment initiation. Prior treatment with adjuvant IFN-alpha, adjuvant ipilimumab and/or nivolumab or pembrolizumab or BRAF/MEK therapy (e.g. dabrafenib and trametinib) are allowed if recurrence of disease occurred more than 6 months from the last dose of adjuvant therapy; that is, a patient must have recurred with unresectable disease at least 6 months or more after finishing adjuvant therapy; combination adjuvant therapies with nivolumab or pembrolizumab are also allowed (vaccines, bempegaldesleukin, relatlimab, etc.).
12. Patients must have detectable ctDNA at baseline. A blood sample will be collected during the screening phase in order to determine if patients are eligible based on presence of ctDNA. Patients are permitted to start treatment with nivolumab/relatlimab cycle 1 while awaiting results.
13. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
14. Patients with prior or concurrent nonmelanoma malignancies whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this study.
15. Asymptomatic brain metastases are permitted. Patients who have received/will receive gamma knife radiotherapy or stereotactic body radiation therapy (SBRT) treated lesions are also eligible. Patients must be on < 10 mg of prednisone or equivalent at the time of treatment.

16. All baseline laboratory requirements will be assessed and should be obtained within 14 days of C1D1. Screening laboratory values must meet the following criteria:

    • white blood cells (WBCs) ≥ 2000/μL
    • Neutrophils ≥ 1500/μL
    • Platelets ≥ 100 × 10³/μL
    • Hemoglobin ≥ 9.0 g/dL
    • Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or creatinine clearance > 40 mL/minute (using Cockcroft/Gault formula)
    • Aspartate Aminotransferase (AST) ≤ 1.5 × ULN
    • Alanine Aminotransferase (ALT) ≤ 1.5 × ULN
    • Total bilirubin ≤ 1.5 × ULN (except patients with Gilbert Syndrome who must have total bilirubin < 3.0 mg/dL)
    • Coagulation : Prothrombin Time (PT), Partial Thromboplastin Time (PTT), International Normalized Ratio (INR)

Exclusion Criteria:

1. Patients with carcinomatosis meningitis or a history of current ocular/uveal melanoma are excluded.
2. Patients with a history of myocarditis.
3. Patients with active, known, or suspected autoimmune disease requiring immunosuppression beyond 10 mg daily of prednisone. Patients with type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, or skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll. For any cases of uncertainty, it is recommended that the Principal Investigator be consulted prior to signing informed consent.
4. Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of C1D1. Inhaled or topical steroids are permitted in the absence of active autoimmune disease.
5. Patients must not be receiving concurrent anti-tumor therapies in addition to the standard of care anti-PD-1 regimens. Patients who are receiving bisphosphonates and RANKL inhibitors for management of bone metastases are eligible.
6. Any serious or uncontrolled medical disorder or active infection that, in the opinion of the Investigator, may increase the risk associated with or would otherwise affect study participation.
7. Known hypersensitivity to monoclonal antibodies
8. Pregnancy
9. Prior therapy for melanoma with the following exceptions which are allowed: 1) surgery for the melanoma lesion(s), 2) adjuvant RT after neurosurgical resection for CNS lesions or for resected locoregional disease, and 3) prior adjuvant therapy as long as concluded 6 months prior.

10. Any of the following laboratory abnormalities:

    • Absolute Neutrophil Count (ANC) < 1,500/μL or WBC < 2,000 μL
    • Platelet count < 100,000/μL
    • Hematologic growth factors are not allowed at screening or during the first cycle of treatment
    • Hemoglobin < 9 g/dL (< 5.5 mmol/L; previous red blood cell (RBC) transfusion is permitted)
    • Creatinine > 1.5 × ULN
    • AST or ALT > 1.5 × ULN. For patients with liver metastasis AST or ALT > 3 × ULN
    • Serum total bilirubin > 1.5 mg/dL or > 3 × ULN for patients with hereditary benign hyperbilirubinemia

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A: Undetectable ctDNA; Patients will be treated with 2 doses of nivolumab 480 mg/relatlimab 160 mg given every 28 days. Patients with undetectable ctDNA ("zeroconversion") will continue on this regimen until radiologic progression or death for up to 2 years, per standard of care.	Drug: Nivolumab; 480 mg Nivolumab every 4 weeks; Drug: Relatlimab; 160 mg Relatlimab every 4 weeks; Device: Signatera genome MRD assay; SignateraTM is a personalized, tumor-informed circulating tumor DNA (ctDNA)-based test of molecular residual disease (MRD). The Signatera Designed on Genome test is a qualitative and quantitative test that reports the presence or absence of ctDNA as "ctDNA Positive" or "ctDNA Not Detected".
Active Comparator: Cohort B: Positive ctDNA without early progresson (continue treatment); Patients will be treated with 2 doses of nivolumab 480 mg/relatlimab 160 mg given every 28 days. Patients who exhibit positive ctDNA at week 6, who do not exhibit "zeroconverson" at week 6 will be randomized to one of two treatment arms in Cohort B. In this arm patients continue treatment with 2 doses of nivolumab 480 mg/relatlimab 160 mg at 4 week intervals.	Drug: Nivolumab; 480 mg Nivolumab every 4 weeks; Drug: Relatlimab; 160 mg Relatlimab every 4 weeks; Device: Signatera genome MRD assay; SignateraTM is a personalized, tumor-informed circulating tumor DNA (ctDNA)-based test of molecular residual disease (MRD). The Signatera Designed on Genome test is a qualitative and quantitative test that reports the presence or absence of ctDNA as "ctDNA Positive" or "ctDNA Not Detected".
Experimental: Cohort B: Positive ctDNA without early progression (switch treatment); Patients will be treated with 2 doses of nivolumab 480 mg/relatlimab 160 mg given every 28 days. Patients who exhibit positive ctDNA at week 6, who do not exhibit "zeroconverson" at week 6 will be randomized to one of two treatment arms in Cohort B. In this arm patients receive 1 dose of ipilimumab at 1 mg/kg in 8 week intervals in addition to 2 doses of nivolumab 480 mg/relatlimab 160 mg at 4 week intervals.	Drug: Nivolumab; 480 mg Nivolumab every 4 weeks; Drug: Relatlimab; 160 mg Relatlimab every 4 weeks; Device: Signatera genome MRD assay; SignateraTM is a personalized, tumor-informed circulating tumor DNA (ctDNA)-based test of molecular residual disease (MRD). The Signatera Designed on Genome test is a qualitative and quantitative test that reports the presence or absence of ctDNA as "ctDNA Positive" or "ctDNA Not Detected".; Drug: Ipilimumab; 50 mg (1 mg/kg) intravenously every 8 weeks
Experimental: Cohort C: Positive ctDNA with early progression; Patients will be treated with 2 doses of nivolumab 480 mg/relatlimab 160 mg given every 28 days. Patients with positive ctDNA and progressive disease (early progression) on scans at week 6 will switch to ipilimumab at 1 mg/kg in 8-week intervals in addition to 2 doses of nivolumab 480 mg/relatlimab 160 mg at 4-week intervals. Cohort C patients will continue on this regimen until radiologic progression or death for up to 2 years, per standard of care.	Drug: Nivolumab; 480 mg Nivolumab every 4 weeks; Drug: Relatlimab; 160 mg Relatlimab every 4 weeks; Device: Signatera genome MRD assay; SignateraTM is a personalized, tumor-informed circulating tumor DNA (ctDNA)-based test of molecular residual disease (MRD). The Signatera Designed on Genome test is a qualitative and quantitative test that reports the presence or absence of ctDNA as "ctDNA Positive" or "ctDNA Not Detected".; Drug: Ipilimumab; 50 mg (1 mg/kg) intravenously every 8 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival rate in patients randomized in Cohort B	Progression-free survival (PFS), defined as the time from first treatment administration until progressive disease (PD) according to RECIST v1.1 (with irRECIST used as a supportive criterion) or death from any cause, whichever occurs earlier.	Month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (CR+PR)	Objective response rate (ORR) (CR+PR) by RECIST 1.1, with irRECIST supportive, reported as the percentage of patients achieving response in all cohorts. Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of the longest diameters (LD) of target lesions, taking as reference the baseline sum LD; Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. The ORR is the response recorded from the start of the treatment until month 6	Month 6
Incidence of immune-related adverse events (irAEs) with ipilimumab, relatlimab, and nivolumab triplet therapy administered after prior nivolumab plus relatlimab doublet therapy.	From the first treatment administration until final on-treatment visit.	Up to 2 years
Progression-free survival in Cohorts A and C	Progression-free survival (PFS), defined as the time from first treatment administration until progressive disease (PD) according to RECIST v1.1 (with irRECIST used as a supportive criterion) or death from any cause, whichever occurs earlier.	Month 6
Progression-free survival	Progression-free survival (PFS), defined as the time from first treatment administration until progressive disease (PD) according to RECIST v1.1 (with irRECIST used as a supportive criterion) or death from any cause, whichever occurs earlier.	Month 12
Progression-free survival	Progression-free survival (PFS), defined as the time from first treatment administration until progressive disease (PD) according to RECIST v1.1 (with irRECIST used as a supportive criterion) or death from any cause, whichever occurs earlier.	Month 24

Collaborators and Investigators

• Sponsor: NYU Langone Health
• Investigators: Principal Investigator: Janice M. Mehnert, MD, NYU Langone Health

Study record dates

Study Major Dates

• Study Start (Actual): April 13, 2026
• Primary Completion (Estimated): May 1, 2029
• Study Completion (Estimated): May 1, 2031

Study Registration Dates

• First Submitted: March 26, 2026
• First Submitted That Met QC Criteria: March 26, 2026
• First Posted (Actual): April 1, 2026

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: April 17, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• 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; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Nivolumab; Ipilimumab; relatlimab
• Other Study ID Numbers: 25-00592

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The de-identified participant data from the final research dataset will be shared upon reasonable request beginning 9 to 36 months after publication or as required by a condition of awards or supporting agreements, provided the requesting investigator executes a data use agreement with NYU Langone Health. This instance of data sharing will also require separate IRB review as well as review from NYU Langone s Data Sharing Strategy Board (DSSB). Requests should be directed to: cancertrials@nyulangone.org. The protocol and statistical analysis plan will be posted on Clinicaltrials.gov only as required by federal regulation or supporting awards and agreements.
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.
• IPD Sharing Access Criteria: The investigator who proposes to use the data will be granted access upon reasonable request. Requests should be directed to: cancertrials@nyulangone.org. To gain access, data requestors will need to sign a data access agreement. This instance of data sharing will also require separate IRB review as well as review from NYU Langone's DSSB.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes