Neo IRENIE (NEOadjuvant Ipilimumab, RElatlimab, NIvolumab Evaluation)
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.
Study 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.
The investigators also want to evaluate the side effects patients may have to treatment and how this affects the quality of life. The investigators 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.
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
Inclusion criteria
- Written informed consent
- Male or female patients who are at least 18 years of age on the day of signing informed consent.
- Clinically detectable disease, and/or RECIST version 1.1 defined disease, and/or disease confirmed on PET imaging.
- 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'.
- Concurrent primary disease and lymph node metastases acceptable provided completely resectable.
- Up to 3 in-transit metastases are permitted as long as these are fully resectable.
- Tumour that is amenable to a newly obtained core biopsy for performance of the multi-omic predictive biomarker model
- ECOG performance status of 0 to 1.
- Adequate haematological, hepatic, renal and endocrine function
- An anticipated life expectancy of >12 months.
- Women of child bearing potential (WOCBP) must agree to avoid pregnancy or breast feeding for the duration of study treatment.
- Histologically confirmed diagnosis of cutaneous melanoma or unknown primary melanoma
- AJCC 8th Ed Stage IIIB, IIIC, IIID cutaneous melanoma
- No prior systemic treatment for cutaneous melanoma
- Completion of the multi-omic predictive biomarker model within 14 days (7-10 business days) of planned randomisation.
- Histologically confirmed diagnosis of cutaneous melanoma or unknown primary melanoma
- AJCC 8th Ed Stage IIIB, IIIC, IIID cutaneous melanoma
- 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
- No prior treatment with CTLA-4 or LAG-3 inhibitors.
- Histologically confirmed diagnosis of mucosal melanoma
- Any stage of disease provided it is fully resectable
- No prior systemic treatment for mucosal melanoma
Exclusion criteria
- Uveal melanoma
- Any contraindication to the administration of relatlimab, ipilimumab or nivolumab
- 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.
- 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.
- 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).
- A known additional malignancy that is progressing or has required active treatment within the past 3 years.
- A known CNS metastases and/or carcinomatous meningitis
- Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis or current interstitial lung disease.
- Has an active infection requiring systemic therapy.
- Has a known history of Human Immunodeficiency Virus (HIV).
- 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.
- Has a known history of active TB (Bacillus Tuberculosis).
- Uncontrolled or significant cardiovascular disease including, but not limited to any of the following.
- 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.
- 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.
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- Pregnant or breast feeding females
- Concurrent medical or social conditions that may prevent the patient from attending assessments per schedule
Eligibility
Age eligible for study : NA
Healthy volunteers accepted : No
Gender eligible for study: ALL
Things to know
Study dates
Study start:
Primary completion:
Study completion finish:
Study type
TREATMENT
Phase
- PHASE2
Study ID
NCT06999980
Intervention or treatment
DRUG: Ipilimumab 3mg/kg and nivolumab 1mg/kg
DRUG: Nivolumab 480mg and relatlimab 160mg and ipilimumab 1mg/kg
DRUG: Nivolumab 480mg and relatlimab 160mg
Conditions
- Cutaneous Melanoma
- Mucosal Melanoma
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Research sites nearby
Closest Location:
Melanoma Institute Australia
Select from list below to view details:
Melanoma Institute Australia
Wollstonecraft, New South Wales, Australia
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Who is running the clinical trial?
Melanoma Institute Australia
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
| Participant Group/Arm | Intervention/Treatment |
|---|---|
EXPERIMENTAL: Treatment Arm A
| Drug: Ipilimumab 3mg/kg and nivolumab 1mg/kg |
EXPERIMENTAL: Treatment Arm B
| Drug: Ipilimumab 1mg/kg Nivolumab 480mg and relatlimab 160mg |
EXPERIMENTAL: Treatment Arm C
| Drug: Nivolumab 480mg and relatlimab 160mg |
ACTIVE_COMPARATOR: Treatment Arm D (Cohort 1a)
| Drug: Ipilimumab 1mg/kg and nivolumab 3mg/kg |
ACTIVE_COMPARATOR: Treatment Arm E (Cohort 1b)
| Drug: Ipilimumab 1mg/kg and nivolumab 3mg/kg |
ACTIVE_COMPARATOR: Treatment Arm F
| Drug: Pembrolizumab 200 mg |
What is the study measuring?
Primary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| Pathological response rate | The primary endpoint is the pathological response rate at surgery (between days 43 and 56) from the first dose of neoadjuvant study treatment for each of cohorts 1b, 2 and 3. 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. | Week 6 |
Secondary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| Event-free survival (EFS) | The proportion of patients with the earliest EFS outcome of: (a) Melanoma progression, from the initiation of study treatment prior to planned surgery (leading to unresectable disease). (b) Disease recurrence, from the date of surgery (local, regional or distant). (c) Study treatment-related death from the initiation of study treatment. (d) Melanoma-related death, from the initiation of study treatment. | 10 years |
| Objective response rate | RECIST version 1.1 defined objective response at week 6 for patients with RECIST-measurable disease at baseline | Week 6 |
| Metabolic response rate | PERCIST defined metabolic response | Week 6 |
| Loco-regional relapse-free survival | Time from surgery to the date of loco-regional recurrence | 10 years |
| Distant metastases-free survival | Time from surgery to the earliest date of distant recurrence, treatment-related death, or melanoma-related death | 10 years |
| Overall survival | Time from randomisation to death | at 1, 2, 5 and 10 years |
| Type, frequency and severity of drug-related toxicities | The number, type, and grade of treatment-related adverse events per CTCAE version 5.0 | 30 days from last dose of study treatment |
| Surgical adverse outcomes | The number and grade of surgical complications according to the Clavien-Dindo Classification assessed at 3, 12 and 48 weeks post-operatively | At 3, 12 and 48 weeks post-operatively |
| Health related quality of life | The individual, summary and composite scores obtained from the validated EUROQOL QLQ-C30, EQ-5D, FACT-M (questions M10 to M17) | 1 year |
| Comparison of the actual pathologocal response to each immunotherapy arm with the predicted pathological response to neoadjuvant immunotherapy based on the multi-omic predictive biomarker model | Correlation of the actual pathological response with the predicted response to combination neoadjuvant immunotherapy based on the multi-omic predictive biomarker model | Week 6 |
References
Clinical Trials Gov: Neo IRENIE (NEOadjuvant Ipilimumab, RElatlimab, NIvolumab Evaluation)Other trials to consider
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