Merkel Cell Carcinoma
Conditions
Brief 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
Detailed 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).
Interventions
Dual inhibition of the distinct LAG3 and PD-1 checkpoint pathways
Sponsors
Melanoma Institute Australia
Bristol-Myers Squibb
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open label, single centre clinical trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Aged ≥ 18 years 2. Written consent 3. Histologically confirmed, resectable Merkel cell carcinoma with AJCC (8th ed) clinical or pathological stage I (≥ 10 mm), IIA, or IIB or III disease 4. In-transit metastases are permitted if they are completely resectable 5. Measurable disease according to RECIST 1.1 criteria 6. Previous radiotherapy permitted if there is RECIST-measurable progression of disease since the completion of radiotherapy 7. At least one of either, archival tissue from a primary or nodal MCC lesion (if applicable) for the current diagnosis and/or a newly obtained core biopsy of a lesion which has not been previously irradiated. 8. ECOG 0-1 9. Adequate organ function on blood pathology 10. Life expectancy \>12 months 11. Female patients to use effective contraception during study treatment and for 5 months after last dose.
Exclusion criteria
1. Clinical, radiographic or pathological evidence of distant metastases 2. Contraindication to nivolumab and / or relatlimab 3. 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 4. Active autoimmune disease or requirement for chronic steroid therapy other than hormone replacement therapy 5. A diagnosis of immunodeficiency or chronic steroid therapy \>10 mg OD prednisone or equivalent 6. Additional malignancy active within past 3 years; patients with chronic lymphocytic leukaemia can be included in this study. 7. Uncontrolled cardiovascular disease or history of myocarditis 8. Has had an allogenic tissue/solid organ transplant 9. Troponin T (TnT) or I (TnI) \>2 × institutional ULN 10. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis or current interstitial lung disease 11. Has an active infection requiring systemic therapy 12. Active Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection. 13. Known HIV 14. Pregnant or breast feeding females 15. Concurrent medical or social conditions that may prevent the patient attending assessments or procedures per schedule
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological complete response rate | Week 6 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient reported quality of life | 1 year | 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. |
| Pathological non-complete response rate to neoadjuvant immunotherapy | Week 6 | 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 |
| Toxicity and tolerability of neoadjuvant immunotherapy | Week 24 | The treatment related adverse events (AE) as described in CTCAE version 5.0, from the initiation of study treatment up to 135 days after the last dose of study treatment |
| Objective response rate to neoadjuvant immunotherapy | Week 6 | 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 |
| Metabolic response rate to neoadjuvant immunotherapy | Week 6 | 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. |
| Recurrence-free survival | 10 years | The proportion of patients alive and disease free from the time of surgery |
| Disease progression rate | Week 6 | 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. |
| Event-free survival (EFS) rate | 10 years | The proportion of patients with EFS defined as from the time of first dose of study treatment to the earliest of: 1. Disease progression to unresectable stage III or stage IV disease) 2. Recurrence of MCC 3. Treatment-related death 4. Disease related death |
| Study treatment completion rate | Week 8 | 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. |
| Overall survival rate | 10 years | 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. |
| Surgical-related adverse events | 12 weeks | — |
Countries
Australia
Contacts
CONTACTMonica Osorio
PRINCIPAL_INVESTIGATORGeorgina V Long
Melanoma Instiute Australia
Outcome results
None listed