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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT05418972




Registration number
NCT05418972
Ethics application status
Date submitted
9/06/2022
Date registered
15/06/2022

Titles & IDs
Public title
A Phase 2 Clinical Trial of Neoadjuvant Relatlimab and Nivolumab in High Risk, Clinical Stage II Cutaneous Melanoma
Scientific title
A Phase 2, Open Label, Single Arm, Clinical Trial of Neoadjuvant Relatlimab and Nivolumab in High Risk, Clinical Stage II Cutaneous Melanoma
Secondary ID [1] 0 0
MIA2022/CT/432, CA224-137
Universal Trial Number (UTN)
Trial acronym
Neo ReNi II
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Stage II Melanoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Relatlimab and nivolumab fixed dose combination (FDC)

Experimental: Neoadjuvant immunotherapy +/- Adjuvant immunotherapy - 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.


Treatment: Drugs: Relatlimab and nivolumab fixed dose combination (FDC)
Lymphocyte activation gene-3 (LAG-3) and programmed death-1 (PD-1) are two distinct inhibitory immune checkpoints that are often co-expressed on tumor-infiltrating lymphocytes, thus contributing to tumor-mediated T-cell exhaustion. The combination of nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) results in increased T-cell activation compared to the activity of either antibody alone.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Pathological response rate
Assessment method [1] 0 0
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.
Timepoint [1] 0 0
Week 6
Primary outcome [2] 0 0
Feasibility of recruitment
Assessment method [2] 0 0
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.
Timepoint [2] 0 0
2 years
Secondary outcome [1] 0 0
The positive sentinel node biopsy rate at surgery at week 6
Assessment method [1] 0 0
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.
Timepoint [1] 0 0
Week 6
Secondary outcome [2] 0 0
The melanoma-related event-free survival (EFS).
Assessment method [2] 0 0
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.
Timepoint [2] 0 0
10 years
Secondary outcome [3] 0 0
Recurrence-free survival
Assessment method [3] 0 0
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.
Timepoint [3] 0 0
From surgery to 10 years
Secondary outcome [4] 0 0
Overall survival
Assessment method [4] 0 0
The proportion of participants deceased from any cause.
Timepoint [4] 0 0
10 years
Secondary outcome [5] 0 0
Safety and tolerability of neoadjuvant and adjuvant treatment and surgical procedures.
Assessment method [5] 0 0
The proportion of patients with adverse events as described in CTCAE version 5.0
Timepoint [5] 0 0
100 days from last dose of study treatment
Secondary outcome [6] 0 0
Recurrence in the biopsied lymph node basin
Assessment method [6] 0 0
Incidence of recurrence in the biopsied lymph node basin
Timepoint [6] 0 0
1 year from surgery
Secondary outcome [7] 0 0
Patient reported quality of life
Assessment method [7] 0 0
The individual, summary and composite scores obtained from the validated EUROQOL QLQ-C30, EQ-5D, FACT-M and MCQ-28 questionnaires.
Timepoint [7] 0 0
1 year
Secondary outcome [8] 0 0
Biomarker analyses
Assessment method [8] 0 0
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.
Timepoint [8] 0 0
10 years
Secondary outcome [9] 0 0
Microbiome analyses
Assessment method [9] 0 0
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.
Timepoint [9] 0 0
10 years

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Not applicable
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
14/08/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/12/2035
Actual
Sample size
Target
20
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Melanoma Institute Australia - Wollstonecraft
Recruitment postcode(s) [1] 0 0
2065 - Wollstonecraft

Funding & Sponsors
Primary sponsor type
Other
Name
Melanoma Institute Australia
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Bristol-Myers Squibb
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Public notes

Contacts
Principal investigator
Name 0 0
Georgina Long
Address 0 0
Melanoma Institute Australia
Country 0 0
Phone 0 0
Email 0 0
Contact person for public queries
Name 0 0
Monica Osorio
Address 0 0
Country 0 0
Phone 0 0
+612 9911 7296
Email 0 0
Monica.Osorio@melanoma.org.au
Contact person for scientific queries

Data sharing statement


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT05418972