Overview

Eligibility

Design Details

Arms & Interventions

Outcome Measures

Trial Sites

Source: NCT05418972

Active, not recruiting

Neo ReNi II: A Phase 2 Clinical Trial of Neoadjuvant Relatlimab and Nivolumab in High Risk, Clinical Stage II Cutaneous Melanoma

Interventional

Phase 2

Melanoma Institute Australia

Sponsor: Melanoma Institute Australia

Last Updated: March 25, 2025
Notice- Information is sourced from public registries and may not reflect real-time changes at the local site.

Neoadjuvant therapy is feasible in stage II melanoma, and the dual inhibition of the distinct LAG-3 and PD-1 checkpoint pathways with relatlimab and nivolumab has a synergistic effect in the tumour microenvironment leading to a pathological response after 2 doses of therapy.

Show Detailed Description

Treatment Category

Checkpoint Inhibitors

Required Mutations

RAS, NRAS, BRAF, KRAS, HRAS

Trial Started

August 14, 2023

Last Updated by Sponsor

March 25, 2025

Estimated Completion

December 1, 2025

Contact Study

Name:Monica Osorio

Email:Monica.Osorio@melanoma.org.au

Phone:+612 9911 7296

Eligibility

Inclusion Criteria

1. The patient (or legally acceptable representative, if applicable) provides written informed consent for the trial.

2. Male/female patients who are at least 18 years of age on the day of signing informed consent.

3. AJCC (8th edition) clinical stage IIB (T3b and T4a) or IIC (T4b) melanoma, or stage IIA (T2b and T3a) melanoma with a ≥ 20% risk of recurrence at 5 years according to the MIA stage II risk calculator (melanomarisk.org.au). Staging and lymphoscintigraphy (including ultrasound of draining nodal basin(s) will be performed at baseline. Patients with demonstrated clinical stage III melanoma are not eligible.

4. Histologically confirmed primary cutaneous melanoma from a partial core biopsy, punch biopsy, or excisional biopsy with residual macroscopic disease.

5. BRAF / NRAS mutant or wild type melanoma included.

6. Availability of the diagnostic tumour sample for translational studies.

7. Surgery has been planned for sentinel node biopsy and complete resection of stage II disease. Only cases where a complete surgical resection leading to tumour free margins and which can be safely achieved without being overly morbid is considered "resectable". Resectability of each case has been agreed upon within the context of a Multi-Disciplinary Team (MDT) meeting.

8. Eastern Cooperative Oncology Group (ECOG) status 0 to 1.

9. Adequate haematological, hepatic, renal and endocrine function on blood pathology testing.

10. Anticipated life expectancy of >12 months.

11. Agreement to avoid pregnancy for the duration of treatment: Women of childbearing potential (WOCBP) must not be breastfeeding and must have a negative pregnancy test within 3 days prior to initiation of dosing. She must agree to use an acceptable method of birth control from the time of the negative pregnancy test, through the duration of treatment with the study combination plus 5 half-lives of study treatment for a total of 5 months post-treatment completion.

Exclusion Criteria

1. Clinical or radiographic evidence of nodal, in-transit, satellite or microsatellite metastases or distant melanoma metastases.

2. Any contraindication to the administration of relatlimab or nivolumab.

3. A history of allergy or hypersensitivity to study treatment components.

4. Prior immunotherapy for any malignancy (including, but not limited to: anti-PD-1, CTLA-4, PDL-1 or anti-LAG3 or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways).

5. Patients with a condition requiring chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 14 days prior to the first dose of study treatment. The following are permitted:

1. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc)

2. Inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if patient is on a stable dose

3. Non-absorbed intra-articular steroid injections.

6. Has active autoimmune disease that has required systemic treatment in the past 12 months (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). The following are permitted:

1. Vitiligo

2. Type I diabetes mellitus

3. Residual autoimmune hypothyroidism on stable hormone replacement

4. Resolved childhood asthma or atopy

5. Psoriasis not requiring systemic treatment

6. Autoimmune conditions which are not expected to recur in the absence of an external trigger.

7. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. The following malignancies, if undergone successful definitive resection or curative treatment, are permitted:

1. Basal cell carcinoma of the skin

2. Squamous cell carcinoma of the skin

3. Carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy)

4. Prostatic intraepithelial neoplasia

5. Atypical melanocytic hyperplasia

6. Other malignancies for which the patient has been disease free for 1 year.

8. Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following:

1. Myocardial infarction or stroke/transient ischemic attack within the 6 months prior to consent

2. Uncontrolled angina within the 3 months prior to consent

3. Any history of clinically significant arrhythmias (such as poorly controlled atrial fibrillation, ventricular tachycardia, ventricular fibrillation, or torsades de pointes)

4. QTc prolongation > 480 msec

5. History of other clinically significant cardiovascular disease (i.e., cardiomyopathy, congestive heart failure with New York Heart Association functional classification III-IV, pericarditis, significant pericardial effusion, significant coronary stent occlusion, poorly controlled venous thrombosis, etc)

(g) Cardiovascular disease-related requirement for daily supplemental oxygen (h) History of 2 or more M.I.s OR 2 or more coronary revascularization procedures (regardless of the number of stent placements during each procedure) (i) Patients with history of myocarditis, regardless of aetiology.

9. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis or current interstitial lung disease.

10. Has an active infection requiring systemic therapy.

11. Treatment with complementary medications (e.g., herbal supplements or traditional Chinese medicines).

12. Any live / live-attenuated vaccine (e.g., varicella, zoster, yellow fever, rotavirus, oral polio and measles, mumps, rubella [MMR]) within 30 days of first study treatment, during treatment and until 135 days post last dose. Inactivated / killed vaccines are permitted..

13. Active SARS-CoV-2 infection. The following are permitted

1. At least 10 days (4 weeks for severe/critical illness) have passed since symptoms first appeared or positive RT-PCR or viral antigen test result.

2. At least 24 hours have passed since the last fever without the use of fever-reducing medications.

3. Acute symptoms (e.g., cough, shortness of breath) have resolved.

4. In the opinion of the investigator, there are no COVID-19-related sequelae that may place the participant at a higher risk of receiving study treatment.

5. Recommended negative follow-up SARS-CoV-2 RT-PCR or viral antigen test based on institutional / local guidelines.

14. Has a known history of Human Immunodeficiency Virus (HIV). Note: no testing for HIV is required unless mandated by local health authority.

15. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.

16. Has a known history of active TB (Bacillus Tuberculosis).

17. Pregnant or breast feeding females.

18. Concurrent medical or social conditions that may prevent the patient from attending assessments per schedule.

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Design Details

AllocationN/A

Intervention ModelSingle Group Assignment

MaskingNone (Open Label)

Number to Enroll20

Arms & Interventions

Arms

Interventions

Type: Experimental

Description: NEOADJUVANT: All participants will receive neoadjuvant therapy with the fixed dose combination of intravenous relatlimab 160 mg and nivolumab 480 mg x 2 doses on days 1 and 29. SURGERY: All participants will have sentinel lymph node mapping and biopsy prior to a wide local excision of the primary melanoma between days 43 and 56. ADJUVANT: Participants with no pathological response or partial pathological response will receive the fixed dose combination of intravenous relatlimab 160 mg and nivolumab 480 mg for a further 11 doses.

Interventions:

Relatlimab and nivolumab fixed dose combination (FDC)

Outcome Measures

Primary Outcome Measures

Pathological response rateWeek 6

The primary endpoint is the pathological response rate at surgery (between days 43 and 56) from the first dose of neoadjuvant study treatment. The pathological response is categorised thus: * Complete pathological response (pCR) - 0% viable tumour cells in the surgical specimen * Near complete pathological response - (near pCR) - <10% viable tumour * Partial pathological response (pPR) - 10%-50% viable tumour * No pathological response (pNR) - >50% viable tumour The proportion of participants with a pCR, or near pCR will determine the pathological response rate.

Feasibility of recruitment2 years

1. Proportion of patients enrolled in the study from the population of patients presenting to the clinic with new stage II disease. 2. The proportion of stage II patients with residual disease following diagnostic biopsy. 3. Proportion of eligible patients who consent to the study. 4. The number of patients recruited per month compared to the expected 20 patients over 24 months or 0.84 per month.

Secondary Outcome Measures

Recurrence-free survivalFrom surgery to 10 years

The proportion of patients with an histologically confirmed diagnosis of disease recurrence (local, regional, and distant), as detected by the patient, on physical examination or during imaging surveillance, or death from any cause.

Overall survival10 years

The proportion of participants deceased from any cause.

Safety and tolerability of neoadjuvant and adjuvant treatment and surgical procedures.100 days from last dose of study treatment

The proportion of patients with adverse events as described in CTCAE version 5.0

Recurrence in the biopsied lymph node basin1 year from surgery

Incidence of recurrence in the biopsied lymph node basin

Patient reported quality of life1 year

The individual, summary and composite scores obtained from the validated EUROQOL QLQ-C30, EQ-5D, FACT-M and MCQ-28 questionnaires.

Biomarker analyses10 years

Identification of predictive or prognostic biomarkers from tumour and blood analyses at baseline, surgery and at recurrence, and correlated with pathological and clinical response and toxicity.

The positive sentinel node biopsy rate at surgery at week 6Week 6

1. The proportion of patients undergoing a sentinel node biopsy who have a positive result in the lymph node. 2. The number of sentinel nodes identified and the number harvested. 3. The proportion of patients with a positive sentinel node biopsy who undergo complete lymph node dissection.

The melanoma-related event-free survival (EFS).10 years

The proportion of patients with the earliest EFS outcome of: 1. Melanoma progression, from the initiation of study treatment prior to planned surgery (leading to unresectable stage III or stage IV disease). 2. Melanoma recurrence, from the date of surgery (local, regional or distant). 3. Study treatment-related death from the initiation of study treatment. 4. Melanoma-related death, from the initiation of study treatment.

Microbiome analyses10 years

From serial faecal samples and a baseline urine sample (testing gut permeability) 1. Correlation of bacterial diversity and abundance with treatment response and incidence of treatment-related toxicities. 2. Correlation of self-reported dietary habits (including use of oral probiotics) at baseline and impact on bacterial diversity in the gut. 3. The use of antibiotics during neoadjuvant treatment and the impact on intestinal bacterial diversity and abundance. 4. Correlation of gastrointestinal mucosal integrity with bacterial composition in stool samples and immune related adverse events and response.

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Trial Sites

This study has 1 trial site

Melanoma Institute Australia

Wollstonecraft, New South Wales, AU

Name:Monica Osorio

Email:monica.osorio@melanoma.org.au

Phone:+612 9911 7296

Recruiting

Wollstonecraft, New South Wales, 2065 AU

Melanoma Institute Australia

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