Neo-adjuvant Immunotherapy in Patients With Localized Melanoma

NCT ID: NCT07230613

Last Updated: 2025-11-17

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-12-01
• Study Completion Date: 2033-12-31

Brief Summary

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 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, 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.

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 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 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.

Conditions

Cutaneous Melanoma, Stage III; Mucosal Melanoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Ipilimumab (YervoyTM, 50 mg/10 mL solution)

Intervention Type: DRUG

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.

Nivolumab (OpdivoTM, 40 mg/4mL solution)

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

UNICANCER

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Central Contacts

Priyanka DEVI-MARULKAR, PhD, MBA

Role: CONTACT

p-devi-marulkar@unicancer.fr

+33(0)605541300

Other Identifiers

UC-IMM-2510

Identifier Type: -

Identifier Source: org_study_id

2025-522127-95-00

Identifier Type: CTIS

Identifier Source: secondary_id