Neoadjuvant Nivolumab and Relatlimab in Merkel Cell Carcinoma

Merkel Cell Carcinoma Clinical Trial

Official title:

A Phase 2, Open Label, Single Arm Clinical Trial of Neoadjuvant Nivolumab and Relatlimab in Stage I To III Resectable Merkel Cell Carcinoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06151236
• Other study ID #: MIA2023/489
• Secondary ID: CA224-1064
• Status: Recruiting
• Phase: Phase 2
• Start date: March 11, 2024
• Est. completion date: April 2034

Study information

• Verified date: March 2024
• Source: Melanoma Institute Australia
• Contact: Monica Osorio
• Phone: + 61 2 9911 7296
• Email: monica.osorio[@]melanoma.org.au
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: April 2034
• Est. primary completion date: April 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Merkel Cell
• Merkel Cell Carcinoma

Intervention

Drug:
• Nivolumab 240 mg / Relatlimab 80 mg in a fixed dose combination
Dual inhibition of the distinct LAG3 and PD-1 checkpoint pathways

Locations

Country	Name	City	State
Australia	Melanoma Institute Australia	Wollstonecraft	New South Wales
Australia	Melanoma Institute Australia	Wollstonecraft	New South Wales

Sponsors (2)

Lead Sponsor	Collaborator
Melanoma Institute Australia	Bristol-Myers Squibb

Country where clinical trial is conducted

Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Polyomavirus positivity	Proportion of patients with and without polyomavirus in tumour tissue and/or in blood samples at baseline. Correlate Merkel cell polyomavirus viral positivity (MCPyV+) in stage I-III MCC with pathological response.	Week 6
Other	Biomarkers of response, resistance, toxicity	Morphological assessment H&E, including viable MCC cells, Ki67, TILs density, % fibrosis, % necrosis, compared with paired baseline measures.; Tumour PD-L1 expression status (+ve status = =1% tumour cells positive staining using Dako 28-8 PD-L1 IHC assay).; Characterisation of immune profile in tumour microenvironment using multiplex immunohistochemistry and Imaging mass cytometry.; RNA sequencing - gene expression profile including potential to perform single cell analysis on dissection specimen from tumour dissociates (single cell RNA seq).; Characterisation of peripheral immune profile through Cytometry by time of flight.; DNA sequencing to determine tumour mutational burden and key somatic mutations.; Response to treatment using circulating tumour DNA in peripheral blood using droplet digital PCR to quantify tumour DNA (copies/ml plasma) of known mutation in MCC tissue.	Week 6
Other	Correlation of gut microbiome on outcomes	Correlation of bacterial diversity and abundance with treatment response and incidence of treatment-related toxicities; Correlation of self-reported dietary habits (including use of oral probiotics) at baseline and impact on bacterial diversity in the gut; The use of antibiotics and/or steroids during neoadjuvant treatment and the impact on intestinal bacterial diversity and abundance	Week 6
Other	Correlation of outcome measures	Proportion of patients with concordance in pathological response, RECIST response and metabolic response (PERCIST)	Week 6
Other	Assessment of concordance between RECIST and immune-related response criteria	Proportion of patients with CR, PR, SD and PD as measured with both response criteria	Week 6
Other	Comparison of outcomes against CheckMate	Comparison of primary and secondary efficacy outcomes to those reported in the Checkmate 358 trial	10 years
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Recurrence-free survival	The proportion of patients alive and disease free from the time of surgery	10 years
Secondary	Disease progression rate	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.; Disease progression which leads to unresectable MCC.	Week 6
Secondary	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
Secondary	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
Secondary	Patient reported quality of life	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.; The correlation of patient-rated quality of life scores with adverse events.	1 year
Secondary	Study treatment completion rate	Proportion of patients receiving full neoadjuvant drug treatment per schedule and number of treatments missed.; Proportion of patients undergoing planned surgery at week 6.; Reasons for incomplete study treatment e.g. adverse event, withdrawn consent, , disease progression, patient lost to follow-up.	Week 8