Neo-adjuvant Immunotherapy in Patients With Localized Melanoma (NEOREM-NEO-1)

Neo-adjuvant Intratumoral Anti-CTLA4 + Anti-PD1 in Patients With Localized Melanoma

The success of anti-PD-1 and anti-CTLA-4 therapies has initiated a paradigm shift in oncology, with drugs now targeting the immune system rather than cancer cells to stimulate the antitumor immune response. Intratumoral (IT) delivery of immunostimulating agents reduces the systemic toxicity associated with monoclonal antibodies (mAbs) targeting immune checkpoints. Notably, IT injections of immune checkpoint blockade (ICB) have been shown to induce immune-mediated tumor responses both at the injected site and at distant, non-injected tumor sites. While surgery has traditionally been the preferred treatment for stage III and IV melanoma patients, neoadjuvant therapy with anti-CTLA-4 and anti-PD-1 agents has shown promising efficacy.

In patients with localized melanoma, it is hypothesized that IT administration of ipilimumab (anti-CTLA-4 Ab) combined with nivolumab (anti-PD-1 Ab) will provide the most effective and safe treatment combination.

The NEO-1 study is a proof-of-concept clinical trial designed as a sub-protocol of NEOREM master protocol (NCT07262489) to validate the intratumoral immunotherapy approach, aiming to maximize the dose/efficacy ratio of combined ipilimumab and nivolumab treatment while minimizing systemic adverse events. This is an academic, open-label, multicentric, phase II clinical trial evaluating the efficacy and safety of intratumoral injections of ipilimumab and nivolumab combination as neoadjuvant treatment in localized stage III resectable cutaneous or mucosal melanoma patients.

Baseline and on-treatment PORTRAIT profiling, as described in the NEOREM Master Protocol (NCT07262489), will be performed using fresh blood and tumor samples. This profiling will reveal the immune status of patients and support biomarker-driven preselection for future trials.

Study Overview

• Status: Recruiting
• Conditions: Mucosal Melanoma; Cutaneous Melanoma, Stage III
• Intervention / Treatment: Drug: Ipilimumab (YervoyTM, 50 mg/10 mL solution); Drug: Nivolumab (OpdivoTM, 40 mg/4mL solution)

Detailed Description

The combination of ipilimumab + nivolumab injected intravenously before resection of resectable stage III melanoma is more effective than adjuvant immunotherapy as recently demonstrated in a large phase III randomized controlled trial. However, the dual systemic immunotherapy gives rise to severe AEs (30% of patients had > grade 3 related AEs versus 14% in the adjuvant arm). NEO-1, a prospective, multicenter, phase II sub-protocol of the NEOREM master protocol (NCT07262489) focuses on evaluating the efficacy and safety of intratumoral neo-adjuvant treatment with ipilimumab and nivolumab in patients with resectable stage III melanoma.

NEO-1 is a proof-of-concept study designed to validate human intratumoral immunotherapy (HIT-IT) approach, which could maximize its dose/efficacy ratio of combined ipilimumab and nivolumab treatment while preventing systemic AEs. Image guided drug administration directly into tumor will increase the drug concentration at the tumor site leading to targeted drug action.

While evaluating the efficacy of intratumoral administration of ipilimumab in combination with nivolumab in melanoma patients, the NEO-1 study employs PORTRAIT profiling to analyze fresh blood and tumor samples collected at baseline and throughout treatment. This approach will reveal the features of the tumor microenvironment both before and after surgery, facilitating the identification of biomarkers that predict the efficacy of the proposed immunotherapy. The NEOREM master protocol (NCT07262489) allows the rapid analyses of the fresh samples collected, which enables an actual characterization of the immune landscape in patients prior to and during treatment.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Priyanka DEVI-MARULKAR, PhD, MBA; Phone Number: +33(0)662536043; Email: p-devi-marulkar@unicancer.fr

Study Locations

• France
  • Villejuif, France, 94805
    • Recruiting
    • Gustave Roussy
    • Principal Investigator: Caroline ROBERT, MD, PhD
    • Contact: Caroline ROBERT, MD, PhD; Phone Number: 33(0) 1 42 11 42 53; Email: Caroline.ROBERT@gustaveroussy.fr

Participation Criteria

Eligibility Criteria

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

Description

In addition to NEOREM Master Protocol inclusion and exclusion criteria, the following inclusion and exclusion criteria must be verified before inclusion in the NEO-1 trial:

Inclusion Criteria:

1. Patients ≥ 18 years old.
2. Patients with resectable and measurable (according to RECIST v1.1 criteria) stage III cutaneous and mucosal melanoma.
3. Patients who received anti-PD-1 and stopped treatment > 6 months prior to their inclusion in NEO-1 trial are eligible.
4. Patients who received target therapy and stopped treatment > 3 months prior to their inclusion in NEO-1 trial are eligible.

Exclusion Criteria:

1. Patients with clinically or radiologically detectable distant metastases.
2. Patients with uveal melanoma.
3. Patients with any hypersensitivity to the active ingredient or to any of the excipients of nivolumab and/ ipilimumab.
4. Patients without pathological evaluable disease according to RECIST v1.1 criteria.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Single Arm immunotherapy with Ipilimumab and nivolumab intra-tumoral administration; Patients will receive up to 3 doses of neo-adjuvant treatment with IT injections of ipilimumab (5mg/mL) & nivolumab (10mg/mL) at 3-week intervals (±3 days) for up to 6 weeks prior to surgery.

Drug: Ipilimumab (YervoyTM, 50 mg/10 mL solution); The 25 mg flat dose of the Ipilimumab will be administered by intra-tumoral injection. Injections will be performed under image guidance (the most adequate according to investigators preference). Ultrasound guidance will be privileged, as it is not using radiation. A maximum of 3 intratumoral procedures may occur with 3 weeks intervals prior to surgery.; Drug: Nivolumab (OpdivoTM, 40 mg/4mL solution); The 30 mg flat dose of the Nivolumab will be administered by intra-tumoral injection. Injections will be performed under image guidance (the most adequate according to investigators preference). Ultrasound guidance will be privileged, as it is not using radiation. A maximum of 3 intratumoral procedures may occur with 3 weeks intervals prior to surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary objective is to evaluate the tolerability of the intratumoral combination of ipilimumab and nivolumab in patients with resectable stage III cutaneous or mucosal melanoma.	The primary safety endpoint defined as the percentage of patients whose surgery was delayed by more than 2 weeks beyond the planned timeline, due to treatment-related adverse events.	Between 6 and 8 weeks upon end of the treatment
The primary objective is to evaluate the efficacy of the intratumoral combination of ipilimumab and nivolumab in terms of pCR or MPR in patients with resectable stage III cutaneous or mucosal melanoma.	The primary efficacy endpoint is defined as a pathological complete response (pCR) rate defined as the percentage of patients with pCR defined as the complete absence of viable tumor cells, or the major pathologic response (MPR) defined as less than 10% of surviving tumor cells in tumor biopsy of the surgical specimen.	Between 6 and 8 weeks upon end of the treatment

Collaborators and Investigators

• Sponsor: UNICANCER

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2026
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2033

Study Registration Dates

• First Submitted: September 26, 2025
• First Submitted That Met QC Criteria: November 14, 2025
• First Posted (Actual): November 17, 2025

Study Record Updates

• Last Update Posted (Actual): February 11, 2026
• Last Update Submitted That Met QC Criteria: February 6, 2026
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Melanoma; Neo-adjuvant Immunotherapy; Localized Cancers; Intra-tumoral treatment; Immune-checkpoint blockade
• 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; Pharmaceutical Preparations; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Nivolumab; Ipilimumab; Solutions
• Other Study ID Numbers: UC-IMM-2510; 2025-522127-95-00 (Ctis)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No