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

NCT07504796 | Recruiting Phase 4 DMC FDA Drug FDA Device

• 1 other identifier: 25-00592
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Metastatic Melanoma; Advanced Melanoma

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Objective response rate (CR+PR)

  Month 6

• Incidence of immune-related adverse events (irAEs) with ipilimumab, relatlimab, and nivolumab triplet therapy administered after prior nivolumab plus relatlimab doublet therapy.

  Up to 2 years

• Progression-free survival in Cohorts A and C

  Month 6

• Progression-free survival

  Month 12

• Progression-free survival

  Month 24

Study Arms (4)

Cohort A: Undetectable ctDNA

EXPERIMENTAL

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; Drug: Relatlimab; Device: Signatera genome MRD assay

Cohort B: Positive ctDNA without early progresson (continue treatment)

ACTIVE COMPARATOR

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; Drug: Relatlimab; Device: Signatera genome MRD assay

Cohort B: Positive ctDNA without early progression (switch treatment)

EXPERIMENTAL

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; Drug: Relatlimab; Drug: Ipilimumab; Device: Signatera genome MRD assay

Cohort C: Positive ctDNA with early progression

EXPERIMENTAL

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; Drug: Relatlimab; Drug: Ipilimumab; Device: Signatera genome MRD assay

Interventions

Nivolumab DRUG

480 mg Nivolumab every 4 weeks

Cohort A: Undetectable ctDNA; Cohort B: Positive ctDNA without early progression (switch treatment); Cohort B: Positive ctDNA without early progresson (continue treatment); Cohort C: Positive ctDNA with early progression

Relatlimab DRUG

160 mg Relatlimab every 4 weeks

Cohort A: Undetectable ctDNA; Cohort B: Positive ctDNA without early progression (switch treatment); Cohort B: Positive ctDNA without early progresson (continue treatment); Cohort C: Positive ctDNA with early progression

Ipilimumab DRUG

50 mg (1 mg/kg) intravenously every 8 weeks

Cohort B: Positive ctDNA without early progression (switch treatment); Cohort C: Positive ctDNA with early progression

Signatera genome MRD assay DEVICE

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".

Cohort A: Undetectable ctDNA; Cohort B: Positive ctDNA without early progression (switch treatment); Cohort B: Positive ctDNA without early progresson (continue treatment); Cohort C: Positive ctDNA with early progression

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient must be ≥ 18 years old.
• 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.
• Patients must be willing and able to comply with scheduled visits, laboratory tests, and other requirements of the study.
• 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.
• Patient must have melanoma originating from cutaneous, acral-lentiginous, or mucosal primary sites. Patients with melanoma of unknown primary site are eligible.
• Patient must have at least one lesion for measurable disease per RECIST 1.1 guidelines (refer to section 8.1 for more information).
• 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)
• Patient must be planned to initiate standard of care first-line therapy for metastatic disease
• 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).
• 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).
• 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.).
• 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.
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• 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.
• 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.

You may not qualify if:

• Patients with carcinomatosis meningitis or a history of current ocular/uveal melanoma are excluded.
• Patients with a history of myocarditis.
• 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.
• 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.
• 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.
• 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.
• Known hypersensitivity to monoclonal antibodies
• Pregnancy
• 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.
• 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

Sponsors & Collaborators

• NYU Langone Health: lead

Study Sites (1)

NYU Langone Health

New York, New York, 10016, United States

RECRUITING

MeSH Terms

Conditions

Melanoma

Interventions

Nivolumab; relatlimab; Ipilimumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Janice M. Mehnert, MD

  NYU Langone Health

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Janice M. Mehnert, MD

CONTACT

212-731-5431; janice.mehnert@nyulangone.org

Cancer Trials Office

CONTACT

cancertrials@nyulangone.org

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 26, 2026
• First Posted: April 1, 2026
• Study Start: April 13, 2026
• Primary Completion (Estimated): May 1, 2029
• Study Completion (Estimated): May 1, 2031
• Last Updated: April 21, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• 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.
• 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.

Locations

US (1)