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Neoadjuvant Nivolumab and Relatlimab in Merkel Cell Carcinoma

PHASE2RECRUITING

The goal of this clinical trial is to test neoadjuvant dual immunotherapy in Merkel cell carcinoma with the aim to improve recurrence-free survival.

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Study details:

This is a phase 2, open label, single cohort, single centre, clinical trial of neoadjuvant immunotherapy with dual inhibition of PD-1 and LAG-3 immune checkpoint pathways. The hypothesis is that neoadjuvant therapy produces a higher pathological response rate (pCR) and a longer recurrence-free survival in a cohort of treatment-naïve patients with resectable stage I (≥10 mm) to stage III Merkel cell carcinoma compared to neoadjuvant nivolumab monotherapy in Checkmate 358 (n=123, NCT02488759, historical control).

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

Aged ≥ 18 years

Written consent Histologically confirmed, resectable Merkel cell carcinoma with AJCC (8th ed) clinical stage I (≥ 10 mm), II, or III

In-transit metastases are permitted if they are completely resectable

Measurable disease according to RECIST 1.1 criteria

Tumour amenable to core biopsy

Previous radiotherapy permitted if there is RECIST-measurable progression of disease since the completion of radiotherapy

ECOG 0-1

Adequate organ function on blood pathology

Life expectancy >12 months

Female patients to use effective contraception during study treatment and for 5 months after last dose.

Exclusion criteria

Clinical or radiographic evidence of distant metastases

Contraindication to nivolumab and / or relatlimab

Prior anti-PD-1, CTLA-4, PDL-1 or LAG 3 antibody exposure, or an agent directed to another stimulatory or co-inhibitory T-cell receptor for any disease or any chemotherapy or experimental local or systemic drug treatment

Active autoimmune disease or requirement for chronic steroid therapy other than hormone replacement therapy

A diagnosis of immunodeficiency or chronic steroid therapy >10 mg OD prednisone or equivalent

Additional malignancy active within past 3 years; patients with chronic lymphocytic leukaemia can be included in this study.

Uncontrolled cardiovascular disease or history of myocarditis - Has had an allogenic tissue/solid organ transplant

Active Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.

Known HIV

Pregnant or breast feeding females

Concurrent medical or social conditions that may prevent the patient attending assessments or procedures per schedule

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2024-03-11

Primary completion: 2026-04-01

Study completion finish: 2034-04-01

Study type

TREATMENT

Phase

PHASE2

Trial ID

NCT06151236

Intervention or treatment

DRUG: Nivolumab 240 mg / Relatlimab 80 mg in a fixed dose combination

Conditions

• Merkel Cell Carcinoma

Condition: Merkel Cell Carcinoma
DRUG: Nivolumab 240 mg / Relatlimab 80 mg in a fixed dose combination
Wollstonecraft, New South Wales, Australia
Sponsor: Melanoma Institute Australia

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Find a site

Closest Location:

Melanoma Institute Australia

Research sites nearby

Select from list below to view details:

Melanoma Institute Australia
Wollstonecraft, New South Wales, 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: Neoadjuvant Treatment Nivolumab and relatlimab will be administered in a fixed dose combination (FDC). The FDC product contains nivolumab and relatlimab in a protein-mass ratio of 3:1 (nivolumab 240 mg and relatlimab 80 mg): in a 20 mL concentrate solution per single vial. The dose and dosing regimen for this study is nivolumab 480 mg and relatlimab 160 mg - 2 vials per infusion. This was primarily based on the observed benefit/risk profile observed in metastatic melanoma patients from Study CA224-020 pharmacokinetics (PK), pharmacodynamics, and extensive nivolumab monotherapy clinical experience. In addition, the Phase 2/3 Study CA224-047 established this dose as active in unresectable and metastatic melanoma. This study is open label and single arm, with all patients scheduled to receive two doses of nivolumab and relatlimab FDC prior to surgery on days 1 and 29.	DRUG: Nivolumab 240 mg / Relatlimab 80 mg in a fixed dose combination Dual inhibition of the distinct LAG3 and PD-1 checkpoint pathways

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Neoadjuvant Treatment

Nivolumab and relatlimab will be administered in a fixed dose combination (FDC). The FDC product contains nivolumab and relatlimab in a protein-mass ratio of 3:1 (nivolumab 240 mg and relatlimab 80 mg): in a 20 mL concentrate solution per single vial. The dose and dosing regimen for this study is nivolumab 480 mg and relatlimab 160 mg - 2 vials per infusion. This was primarily based on the observed benefit/risk profile observed in metastatic melanoma patients from Study CA224-020 pharmacokinetics (PK), pharmacodynamics, and extensive nivolumab monotherapy clinical experience. In addition, the Phase 2/3 Study CA224-047 established this dose as active in unresectable and metastatic melanoma.
This study is open label and single arm, with all patients scheduled to receive two doses of nivolumab and relatlimab FDC prior to surgery on days 1 and 29.

DRUG: Nivolumab 240 mg / Relatlimab 80 mg in a fixed dose combination

Dual inhibition of the distinct LAG3 and PD-1 checkpoint pathways

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Pathological complete response rate	Proportion of patients with a pathological complete response, as determined on the week 6 surgical specimen using the guidelines published by the International Neoadjuvant Melanoma Consortium: Complete pathological response (pCR) = 0% viable tumour cells in the surgical specimen	Week 6

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Pathological non-complete response rate to neoadjuvant immunotherapy	Proportion of patients with each non-pCR response category, as determined on the week 6 surgical specimen using the guidelines published by the International Neoadjuvant Melanoma Consortium: * Near complete pathological response - (near pCR) - \>0% - ≤10% viable tumour * Partial pathological response (pPR) - \>10 - ≤50% viable tumour * Non pathological response (pNR) - \>50% viable tumour	Week 6
Toxicity and tolerability of neoadjuvant immunotherapy and surgery	The proportion of patients with adverse events (AE) as described in CTCAE version 5.0, from the initiation of study treatment until at least 135 days after the end of treatment. Outcome measures include the proportion of patients with: * An AE by CTCAE term and grade and duration * AEs attributable to neoadjuvant study treatment * Grade 3/4/5 AEs by AE term * A requirement to interrupt study treatment and/or delay surgery within time limit due to an AE * A requirement to discontinue study treatment early due to an AE * A requirement for oral or parenteral steroid treatment for immune-related adverse events. * Post-operative complications (e.g. seroma formation, wound infection or lymphoedema) and duration of events. * and the Surgeon's assessment of 'operability' from baseline and at surgery.	Week 24
Objective response rate to neoadjuvant immunotherapy	The proportion of patients within each response category, as assessed using RECIST version 1.1, comparing week 6 to baseline CT and MRI. Objective response rate= CR and PR	Week 6
Metabolic response rate to neoadjuvant immunotherapy	The proportion of patients within each response category, as assessed using PERCIST (standardised uptake value \[SUV\]) comparing week 6 to baseline PET. Metabolic response rate = CMR and PMR.	Week 6
Recurrence-free survival	The proportion of patients alive and disease free from the time of surgery	10 years
Disease progression rate	1. The proportion of patients alive and with RECIST-defined progression of disease from the date of consent to the first radiographical evidence of local, regional or distant progression. 2. Disease progression which leads to unresectable MCC.	Week 6
Event-free survival rate	The proportion of patients alive and disease free from the date of consent to the first radiographical evidence of local, regional or distant progression	10 years
Overall survival rate	The proportion of patients alive at years 1, 2, 5 and 10, and to actual date of death (in months), from the initiation of study treatment.	10 years
Patient reported quality of life	1. Changes in patient rated quality of life scores using QLQ-C30 and EQ-5D-5L from date of consent to 6 -12 weekly intervals until the end of year 1. 2. The correlation of patient-rated quality of life scores with adverse events.	1 year
Study treatment completion rate	1. Proportion of patients receiving full neoadjuvant drug treatment per schedule and number of treatments missed. 2. Proportion of patients undergoing planned surgery at week 6. 3. Reasons for incomplete study treatment e.g. adverse event, withdrawn consent, , disease progression, patient lost to follow-up.	Week 8

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References

Clinical Trials Gov: Neoadjuvant Nivolumab and Relatlimab in Merkel Cell Carcinoma