A Phase II, Multicentre, Open Label, Randomised Clinical Trial of Nivolumab and Ipilimumab Combined With Relatlimab for Patients With Resectable Advanced Melanoma Identified as Poor Responders to Immunotherapy Neo IRENIE (NEOadjuvant Ipilimumab, RElatlimab, NIvolumab Evaluation)

Study Purpose

This clinical trial is for patients with stage 3 cutaneous melanoma and patients with mucosal melanoma who are able to have surgery to remove all tumour deposits. To improve the chance that melanoma will not recurr, new experimental combinations of a type of treatment called immunotherapy will be given before surgery.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion Criteria

COMMON Inclusion Criteria Applicable to all 3 cohorts.

Inclusion Criteria:

  • - 1.
Written informed consent.
  • - 2.
Male or female patients who are at least 18 years of age on the day of signing informed consent.
  • - 3.
Clinically detectable disease, and/or RECIST version 1.1 defined disease, and/or disease confirmed on PET imaging.
  • - 4.
Fully resectable disease defined as having no significant vascular, central nervous system or bony involvement. Only cases where a complete surgical resection leading to tumour free margins and which is safely achieved is considered "resectable".
  • - 5.
Concurrent primary disease and lymph node metastases acceptable provided completely resectable.
  • - 6.
Up to 3 in-transit metastases are permitted as long as these are fully resectable.
  • - 7.
Tumour that is amenable to a newly obtained core biopsy for performance of the multi-omic predictive biomarker model.
  • - 8.
ECOG performance status of 0 to 1.
  • - 9.
Adequate haematological, hepatic, renal and endocrine function.
  • - 10.
An anticipated life expectancy of >12 months.
  • - 11.
Women of child bearing potential (WOCBP) must agree to avoid pregnancy or breast feeding for the duration of study treatment. Inclusion Criteria
  • - Cohort 1 only.
  • - a.
Histologically confirmed diagnosis of cutaneous melanoma or unknown primary melanoma.
  • - b.
AJCC 8th Ed Stage IIIB, IIIC, IIID cutaneous melanoma.
  • - c.
No prior systemic treatment for cutaneous melanoma.
  • - d.
Completion of the multi-omic predictive biomarker model within 14 days (7-10 business days) of planned randomisation. Inclusion Criteria
  • - Cohort 2 only.
  • - a.
Histologically confirmed diagnosis of cutaneous melanoma or unknown primary melanoma.
  • - b.
AJCC 8th Ed Stage IIIB, IIIC, IIID cutaneous melanoma.
  • - c.
Disease progression on neoadjuvant anti-PD-1 monotherapy, where progressed disease is completely resectable or, disease recurrence on adjuvant anti-PD-1 monotherapy, where recurrent disease is completely resectable.
  • - d.
No prior treatment with CTLA-4 or LAG-3 inhibitors. Inclusion Criteria
  • - Cohort 3 only.
  • - a.
Histologically confirmed diagnosis of mucosal melanoma.
  • - b.
Any stage of disease provided it is fully resectable.
  • - c.
No prior systemic treatment for mucosal melanoma.COMMON Exclusion Criteria Applicable to all 3 cohorts.
  • - 1.
Uveal melanoma.
  • - 2.
Any contraindication to the administration of relatlimab, ipilimumab or nivolumab.
  • - 3.
No prior systemic therapy, including treatment with prior anti-PD1/L1, anti-CTLA-4 or anti-LAG-3 therapy (cohorts 1 and 3), except for cohort 2 which will have received anti-PD1 monotherapy only.
  • - 4.
A diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 14 days of randomisation. 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.
  • - 5.
An 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.
  • - 6.
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. In situ melanoma. 6. Atypical melanocytic hyperplasia. 7. Multiple primary melanomas. 8. Other malignancies for which the patient has been disease free for 1 year.
  • - 7.
A known CNS metastases and/or carcinomatous meningitis.
  • - 8.
Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis or current interstitial lung disease.
  • - 9.
Has an active infection requiring systemic therapy.
  • - 10.
Has a known history of Human Immunodeficiency Virus (HIV). Note: no testing for HIV is required unless mandated by local health authority.
  • - 11.
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.
  • - 12.
Has a known history of active TB (Bacillus Tuberculosis).
  • - 13.
Uncontrolled or significant cardiovascular disease including, but not limited to any of the following: 1. Myocardial infarction (MI) 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 ms. 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) 6. Cardiovascular disease-related requirement for daily supplemental oxygen. 7. History of 2 or more M.I.s OR 2 or more coronary revascularisation procedures (regardless of the number of stent placements during each procedure) 8. Patients with history of myocarditis, regardless of aetiology.
  • - 14.
Patients with a >1+ proteinuria on urine dipstick testing unless a 24-hour urine collection for quantitative assessment indicates that the urine protein is <1 g/24 hours.
  • - 15.
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
  • - 16.
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • - 17.
Pregnant or breast feeding females.
  • - 18.
Concurrent medical or social conditions that may prevent the patient from attending assessments per schedule

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT06999980
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 2
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Melanoma Institute Australia
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Georgina Long
Principal Investigator Affiliation Melanoma Institute Australia
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Other
Overall Status Not yet recruiting
Countries Australia
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Cutaneous Melanoma, Mucosal Melanoma
Additional Details

This clinical trial is for patients with cutaneous melanoma which has spread to the lymph nodes (known as stage 3 melanoma) and for patients with any stage of mucosal melanoma. The study is for those patients who have disease that can be surgically removed. The standard treatment for these patients is surgery to remove the affected tumour, lymph nodes, and any other deposits of melanoma, followed by drug therapy (known as adjuvant therapy). The most common drug therapy used to treat melanoma after surgery is known as 'immunotherapy'. Immunotherapy works by boosting the body's own immune system to better recognise and kill cancer cells. The aim of the study is to offer new immunotherapy combinations to 3 cohorts of patients who are known to be poor responders to standard immunotherapy regimens. Three cohorts of patients will be included: 1. Patients with resectable stage 3 cutaneous melanoma who have a predictive biomarker test result that indicates they will be poor responders to standard anti-PD-1 immunotherapy. 2. Patients with resectable stage 3 cutaneous melanoma who have had a recurrence of melanoma despite having standard anti-PD-1 based immunotherapy. 3. Patients with resectable mucosal melanoma, at any stage of disease. Mucosal melanoma is known to respond poorly to stabdard immunotherapy. This research will test three new combinations of immunotherapy which are given before surgery. Treatment given before surgery is known as 'neoadjuvant' treatment. Neoadjuvant treatment is standard for many cancers, including melanoma. The purpose of neoadjuvant immunotherapy is to increase the body's natural immune response by training it to recognise the evasive cancer cells before they are removed at surgery, and to shrink or destroy the melanoma, which may make surgery easier. This has been shown to reduce the chance of melanoma recurring after surgery. The drugs used in this study are called 'nivolumab', 'relatlimab', and 'ipilimumab'. In this trial, there are three different study treatment combinations. Each combination uses different mechanisms to potentially overcome the predicted resistance to standard immunotherapy. There are 4 phases to the study: 1. Neoadjuvant treatment with one of the new immunotherapy combinations. 2. Surgery. 3. Aadjuvant treatment with standard immunotherapy, IF the neoadjuvant therapy has not been effective enough to clear more than 10% of cancer cells. 4. Follow up for recurrence and survival to the end of 10 years.The main goal is to learn which of the new immunotherapy combinations are most effective at destroying the melanoma cells before surgery for each cohort of patients. The other important goals are to learn which treatment is best at preventing the return of melanoma over 10 years and which increases survival from melanoma. We also want to evaluate the side effects patients may have to treatment and how this affects the quality of life. We will also continue to research biomarkers in blood, tumour tissue and stools to identify possible mechanisms for better response to therapy. The study will be conducted in Australia and internationally and in total, 297 patients will be involved.

Arms & Interventions

Arms

Experimental: Treatment Arm A

Ipilimumab at 3 mg per kg with nivolumab at 1 mg per kg will be administered on days 1 and 22 (Q3W) in the neoadjuvant period for a total of 2 doses.

Experimental: Treatment Arm B

Ipilimumab 1mg per kg and the fixed dose combination nivolumab 480 mg and relatlimab 160 mg will be administered on days 1 and 29 (Q4W) for a total of 2 doses.

Experimental: Treatment Arm C

Fixed dose combination of nivolumab 480 mg and relatlimab 160 mg alone, to be administered on days 1 and 29 (Q4W) for a total of 2 doses.

Interventions

Drug: - Ipilimumab 3mg/kg and nivolumab 1mg/kg

Neoadjuvant for 2 doses on days 1 and 22

Drug: - Nivolumab 480mg and relatlimab 160mg and ipilimumab 1mg/kg

Neoadjuvant for 2 doses at days 1 and 29

Drug: - Nivolumab 480mg and relatlimab 160mg

Neoadjuvant for 2 doses on days 1 and 29

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

International Sites

Melanoma Institute Australia, Wollstonecraft, New South Wales, Australia

Status

Address

Melanoma Institute Australia

Wollstonecraft, New South Wales, 2065

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