Neoadjuvant Nivolumab and Relatlimab in Cutaneous Squamous Cell Carcinoma
PHASE2RECRUITING
The goal of this study is to test neoadjuvant therapy with the dual inhibition of Programmed cell death protein 1 (PD-1) and lymphocyte activation gene 3 (LAG-3) immune checkpoint pathways in a cohort of treatment-naïve, resectable stage II to IV cutaneous squamous cell carcinoma on the pathological response rate (pCR) and recurrence-free survival.
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 II to IV (M0) cutaneous squamous cell carcinoma compared to neoadjuvant cemiplimab monotherapy in Checkmate 358 (n=123, NCT02488759, historical control).
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
Inclusion criteria
- ≥ 18 years of age
- Written informed consent
- Histologically confirmed, resectable stage II to IV cutaneous squamous cell carcinoma defined as: Non-head and neck cuSCC: stage II (T2, N0, M0); stage III (T3, N0, M0; or T1-3, N1, M0); stage IV (T1-3, N2 or N3, M0; or T4a or T4b, any N, M0); Cutaneous head and neck CC: stage II (T2, N0, M0); stage III (T3, N0, M0); stage IV (T4a or T4b, any N, M0)
- In-transit metastases (ITM) are permitted if they are completely resectable.
- Measurable disease according to RECIST version 1.1 criteria (≥10 mm longest diameter for primary lesions and / or ≥15 mm in shortest diameter for lymph nodes as determined by CT imaging) within 2 weeks of the start of study treatment.
- Tumour amenable to a newly obtained core biopsy of a lesion which has not been previously irradiated.
- Previous radiotherapy permitted if performed at a prior site of disease not seen at baseline.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- Documented adequate haematological, hepatic, renal, and thyroid function determined by blood pathology
- Anticipated life expectancy of > 12 months
- Women of childbearing potential must have a negative serum pregnancy test within 24 hours of the first dose of study treatment or within 72 hours if this is not feasible. Effective contraception should be used for the duration of study treatment and for 5 half-lives (or 5 months) after the last dose.
Exclusion criteria
- Clinical or radiographic evidence of distant metastasis
- SCC of the eyelid, vulva, penis and perianus
- Any contraindication to the administration of nivolumab and / or relatlimab
- Prior anti-PD-1, CTLA-4 (Cytotoxic T-lymphocyte associated protein 4), PDL-1 (Programmed death-ligand 1) or LAG 3 (Lymphocyte-Activation Gene 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 a requirement for chronic steroid therapy other than hormone replacement therapy
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in doses 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.
- Known additional malignancies (unless adequately treated) active within the previous 3 years, except for locally curable cancers that have been apparently cured.
- Uncontrolled or significant cardiovascular disease including, but not limited to any of the following: Myocardial infarction (MI) or stroke/transient ischemic attack within the 6 months prior to consent; Uncontrolled angina within the 3 months prior to consent; Any history of clinically significant arrhythmias; QTc (corrected QT interval) prolongation > 480 ms; History of other clinically significant cardiovascular disease.
- Troponin T (TnT) or I (TnI) >2 × institutional ULN (upper limit of normal).
- 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 had an allogenic tissue/solid organ transplant
- Has a known history of Human Immunodeficiency Virus (HIV).
- Has a known history of Hepatitis B or known active Hepatitis C virus infection.
- 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
NCT06288191
Intervention or treatment
DRUG: Nivolumab 240 mg / Relatlimab 80 mg in a fixed dose combination
Conditions
- Cutaneous Squamous Cell Carcinoma
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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?
MIA
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: Neoadjuvant Treatment
| Drug: Nivolumab 240 mg / Relatlimab 80 mg in a fixed dose combination |
What is the study measuring?
Primary Outcome
| Measure | Description | 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
| Measure | Description | Time Frame |
|---|---|---|
| Pathological near pathological response (near pCR), partial response (pPR) and pathological non-response (pNR) rate | 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 (INMC): * Major pathological response (pCR + near-pCR), * 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) per Common Terminology Criteria for Adverse Events (CTCAE), from initiation of study treatment until at least 135 days after the end of treatment. Outcome measures include the proportion of patients with each of the following measures: 1. An AE by CTCAE term / grade 2. AEs attributable to neoadjuvant treatment 3. Grade 3/4/5 AEs by AE term 4. The duration of events reported in (a) 5. Delayed study treatment and/or delay surgery due to an AE 6. A requirement to discontinue study treatment early due to an AE 7. Oral or parenteral steroid treatment for immune-related adverse events. 8. Post-operative complications (e.g. seroma formation, wound infection or lymphoedema) and duration of events. 9. Post-operative complications at 3 weeks and one year using the Clavien-Dindo Classification. 10. Surgeon's assessment of 'operability' and morbidity from baseline and at surgery per INMC questionnaires. | Week 24 |
| Objective response rate to neoadjuvant therapy | 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 the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) and the standardised uptake value (SUV) comparing week 6 to baseline positron emission tomography (PET) scan. Metabolic response rate = Complete metabolic response (CMR) and partial metabolic response (PMR). | Week 6 |
| Recurrence-free survival | The proportion of patients alive and disease free from the time of surgery | 10 years |
| 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 cutaneous squamous cell carcinoma (cuSCC) | Week 6 |
| Event-free survival rate | Proportion of patients with EFS defined as the earliest of any of the following events: 1. Time from 1st dose study treatment to disease progression (unresectable stage III or stage IV disease), 2. Time of surgery to recurrence of cuSCC (local, regional or distant) 3. Treatment related death 4. Disease related death | 10 years |
| Overall survival | The proportion of patients alive at years 1, 2, 5 and 10, and to actual date of death (in months), from the first dose of study treatment. | 10 years |
| Patient reported quality of life (QLQ-C30) | The published scoring for: The European Organization for the Research and Treatment of Cancer Quality of Life of Cancer Patients Questionnaire (QLQ-C30). A 30 item instrument where a higher score represents a higher ("better") level of functioning, or a higher ("worse") level of symptoms. Changes in patient rated quality of life (QOL) scores using QLQ-C30 are recorded at baseline (within 7 days of first dose of study treatment) and at 6 -12 weekly intervals until the end of year 1 will be measured. The correlation of the QLQ-C30 scores with adverse events will be measured. | 1 year |
| Patient reported quality of life (EQ-5L-5D) | The published scoring for: The European Quality of Life (EQ-5L-5D). Each dimension has 5 levels: no problems, some problems, extreme problems. The EQ visual analogue scale (VAS records) the respondent's self-rated health on a vertical, visual analogue scale where the endpoints are labelled 'Best imaginable, health state' and 'Worst imaginable health state'. Changes in patient rated quality of life (EQ-5D-5L) scores recorded at baseline (within 7 days of first dose of study treatment) and at 6 -12 weekly intervals until the end of year 1 will be measured. The correlation of the EQ-5L-5D scores with adverse events will be measured. | 1 year |
| Study treatment completion rate and the causes of any missed treatments | 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 |
| De-escalation of adjuvant radiotherapy. | Proportion of patients where adjuvant radiotherapy was planned at baseline but who did not need radiotherapy as a result of pathological response and pathologically clear surgical margins. | Week 8 |
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References
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