A Phase 2, Open Label, Single Arm, Clinical Trial of Neoadjuvant Relatlimab and Nivolumab in High Risk, Clinical Stage II Cutaneous Melanoma
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Pathological response rate
研究概览
简要总结
Neoadjuvant therapy is feasible in stage II melanoma, and the dual inhibition of the distinct LAG-3 and PD-1 checkpoint pathways with relatlimab and nivolumab has a synergistic effect in the tumour microenvironment leading to a pathological response after 2 doses of therapy.
详细描述
The incidence of stage II melanoma is significantly higher than for later stages of the disease, but stage II patients account for approximately 50% of all those who subsequently develop metastatic disease and die. Stage II melanomas have a Breslow thickness greater than 1.0 mm, with no clinical evidence of nodal, satellite or distant metastases. Pathological staging requires evaluation of the regional node basin after lymphatic mapping and sentinel node biopsy (SNB), which is required for N categorization of all >T1 melanomas. Compared to stage III disease, stage IIB and IIC have a worse prognosis than stage IIIA melanomas. Stage IIC even share the same poor prognosis as stage IIIB.
Global management guidelines highlight the importance of an initial diagnostic biopsy to confirm the diagnosis of melanoma and to pathologically stage the tumour. After the diagnosis and Breslow thickness and other features have been established by histological assessment of the initial excision biopsy, the definitive management of primary cutaneous melanoma consists of surgical excision with a safety margin of surrounding skin and subcutaneous tissue. Sentinel lymph node biopsy (SNB) should be considered for melanomas ≥ 1 mm thickness (≥ 0.8 mm if ulcerated or other high-risk features) in which case lymphoscintigraphy must be performed just prior to wider excision of the primary melanoma site.
Despite the equivalent risk, the current standard of care for stage IIB/C melanoma is observation only although this is expected to change given the results from recent studies investigating adjuvant drug therapy in this stage. Importantly, systemic adjuvant therapy is standard for stage IIIB/C/D disease. Although patients with stage II disease contribute the largest population to melanoma-specific mortality, under the current treatment guidelines, these patients represent a population less likely to be treated in the adjuvant setting and have no representation in the neoadjuvant setting.
Patients at low risk of recurrence with stage IIA disease (tumour >2-4 mm in thickness without ulceration [T3a], or >1 to 2 mm in thickness with ulceration [T2b]), have a high probability to be cured by surgery alone. However, the 5-year melanoma-specific survival (MSS) in stage IIA is 94%, which is comparable to the 93% of stage IIIB; patients with stage IIIA disease have a better prognosis than those with stage IIC disease. Patients diagnosed with higher risk stage IIB/C disease have thicker melanomas > 2.0 mm with ulceration, and > 4.0 mm with or without ulceration, respectively. These patients have an unmet clinical management need as there is no clear evidence for effective systemic adjuvant therapy to prevent disease recurrence once the primary tumour has been completely resected, which is the current standard of care for these patients. Approximately 15% to 20% of patients diagnosed with Stage IIB and 30% of patients diagnosed with Stage IIC melanoma will have a recurrence of their melanoma at 24 months. Within 5 years of surgical resection, approximately 25% of patients with Stage IIB disease and 40% of patients with Stage IIC disease will have disease recurrence. Among patients with stage IIB and IIC melanoma local recurrence occurs in 19 and 11% respectively; 45 and 58% experience regional recurrence and 44 and 39% have distant recurrence.
Patients who present with localized disease and primary tumours of less than 2.0 mm with ulceration (T2b), or primary tumour of >2.0 to 4.0 mm without ulceration (T3a) are categorised as having stage IIA melanoma. A subset of these patients have a high risk of recurrence and may benefit from adjuvant treatment. Melanoma Institute Australia has developed a risk prediction tool which will be used to select this additional high-risk population (i.e., those predicted to be at ≥ 20% recurrence at 5 years, melanomarisk.org.au). The high-risk group is identified using the following variables: mitotic rate, (count) presence of ulceration (yes/no), Breslow thickness (mm), lymphovascular invasion (present vs. absent), SNB status (negative vs not known), presence of tumour infiltrating lymphocytes (TILs), age (years), and sex (male vs. female).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The patient (or legally acceptable representative, if applicable) provides written informed consent for the trial.
- •Male/female patients who are at least 18 years of age on the day of signing informed consent.
- •Histologically confirmed primary cutaneous melanoma from a partial core biopsy, punch biopsy, or excisional biopsy with residual macroscopic disease.
- •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).
- •Synchronous primaries are acceptable if there is certainty that a lesion does not represent in-transit disease and consideration should be given to the need for multiple lymph mapping requirements.
- •Past history of a primary melanoma that has been completely excised. If a patient had an SNB, this must be negative.
- •Locoregional, nodal or metastatic spread must be ruled out with clinical examination, dermoscopy, RCM and LC-OCT, CT, MRI (or CT) brain, PET, SPECT/CT and lymphoscintigraphy (including ultrasound of draining nodal basin(s)). Patients with demonstrated clinical stage III melanoma are not eligible.
- •BRAF / NRAS mutant or wild type melanoma included.
- •Availability of the diagnostic tumour sample for translational studies.
- •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.
- •Eastern Cooperative Oncology Group (ECOG) status 0 to
- •Adequate haematological, hepatic, renal and endocrine function on blood pathology testing.
- •Anticipated life expectancy of >12 months.
- •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.
排除标准
- •Clinical or radiographic evidence of nodal, in-transit, satellite or microsatellite metastases or distant melanoma metastases.
- •Any contraindication to the administration of relatlimab or nivolumab.
- •A history of allergy or hypersensitivity to study treatment components.
- •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).
- •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:
- •Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc)
- •Inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if patient is on a stable dose
- •Non-absorbed intra-articular steroid injections.
- •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:
- •Type I diabetes mellitus
- •Residual autoimmune hypothyroidism on stable hormone replacement
- •Resolved childhood asthma or atopy
- •Psoriasis not requiring systemic treatment
- •Autoimmune conditions which are not expected to recur in the absence of an external trigger.
- •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:
- •Basal cell carcinoma of the skin
- •Squamous cell carcinoma of the skin
- •Carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy)
- •Prostatic intraepithelial neoplasia
- •Atypical melanocytic hyperplasia
- •Other malignancies for which the patient has been disease free for 1 year.
- •Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following:
- •Myocardial infarction 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 (such as poorly controlled atrial fibrillation, ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
- •QTc prolongation > 480 msec
- •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.
- •Troponin T (TnT) or I (TnI) >2 × institutional ULN. Participants with TnT or TnI levels between >1 to 2 × ULN will be permitted if repeat levels within 24 hours are ≤1 ULN. If TnT or TnI levels are between >1 to 2 × ULN within 24 hours, the participant may undergo a cardiac consultation and be considered for treatment, following cardiologist recommendation. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are <2 × ULN, the participant may undergo a cardiac consultation and be considered for treatment, following cardiologist recommendation. Notification of the decision to enrol the participant following cardiologist recommendation has to be made to the Investigator,
- •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.
- •Treatment with complementary medications (e.g., herbal supplements or traditional Chinese medicines).
- •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..
- •Active SARS-CoV-2 infection. The following are permitted
- •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.
- •At least 24 hours have passed since the last fever without the use of fever-reducing medications.
- •Acute symptoms (e.g., cough, shortness of breath) have resolved.
- •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.
- •Recommended negative follow-up SARS-CoV-2 RT-PCR or viral antigen test based on institutional / local guidelines.
- •Has a known history of Human Immunodeficiency Virus (HIV). Note: no testing for HIV is required unless mandated by local health authority.
- •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.
- •Has a known history of active TB (Bacillus Tuberculosis).
- •Pregnant or breast feeding females.
- •Concurrent medical or social conditions that may prevent the patient from attending assessments per schedule.
研究组 & 干预措施
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.
干预措施: Relatlimab and nivolumab fixed dose combination (FDC) (Drug)
结局指标
主要结局
Pathological response rate
时间窗: Week 6
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.
Feasibility of recruitment
时间窗: 2 years
1. Proportion of patients enrolled in the study from the population of patients presenting to the clinic with new stage II disease, and the reason(s) for exclusion. 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.
次要结局
- The melanoma-related event-free survival (EFS).(10 years)
- To assess surgical outcomes following neoadjuvant therapy(Baseline and Week 6)
- Recurrence of melanoma in the lymph node basin where the sentinel lymph node was biospied at week 6(1 year from surgery)
- Recurrence-free survival(From surgery to 10 years)
- Overall survival(10 years)
- Safety and tolerability of neoadjuvant and adjuvant treatment and surgical procedures.(100 days from last dose of study treatment)
- The positive sentinel node biopsy rate at surgery at week 6(Week 6)
- The difference in sentinel lymph node (SLN) mapping between baseline and surgery at week 6.(Week 6)
- Recurrence in the biopsied lymph node basin(1 year from surgery)
- Patient reported quality of life(1 year)
- Biomarker analyses(10 years)
- Microbiome analyses(10 years)
- Change in dermoscopy, reflectance confocal microscopy (RCM) and line field confocal optical coherence tomography (LC-OCT) images during neoadjuvant treatment.(Week 6)