An Exploratory, Single-centre, Two-part Study to Describe Mycosis Fungoides Characteristics and Explore Novel Biomarkers With a Multi- Modal Patient Profiling Approach by Comparing MF Patients to Healthy Volunteers
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- Composite Assessment of Index Lesions Disease Severity Score (CAILS)
研究概览
简要总结
Mycosis fungoides (MF) is an ultra-orphan disease of which the etiology remains unknown. MF is diagnosed by correlating clinical appearance with histopathological analysis of often multiple invasive skin punch biopsies. To move patient care and the development of novel treatments for MF forward, objective, sensitive and reliable tools that are preferably non-invasive are desired. Therefore, the objective of the current study is to phenotype the early stages of mycosis fungoides in detail and to assess the response of chlormethine (CL) gel monotherapy. With this approach the investigators aim to detect novel biomarkers and to establish methodologies for the (non-)invasive monitoring of MF.
详细描述
In recent years, knowledge about the wide spectrum of cutaneous T-cell lymphomas (CTCL) has broadened. Mycosis fungoides (MF) comprises about 50-70% of all primary cutaneous T-cell lymphomas (Willemze et al, 2019). Many CTCL are misdiagnosed due to clinical and histopathological similarity to other skin conditions (such as psoriasis vulgaris, atopic dermatitis and tinea corpora), low prevalence of disease and a lack of reliable tools for detection of these diseases, resulting in delayed diagnosis with years of discomfort and possibly a worse prognosis. Furthermore, standard treatment has never been proven curative, has many side effects and exacerbations are frequent. To date, the etiology of mycosis fungoides remains unknown and little research has been conducted into the mechanisms underlying its development and its response to treatment.
Mycosis fungoides lesions change over time and differ between patients, consisting of three morphologically different stages: patches (erythematosquamous maculae), plaques (erythematosquamous, elevated and occasionally infiltrated lesions) and tumors (with or without ulceration). Only a relatively small group of patients advances to tumor stage MF during their lifetime. Mycosis fungoides is diagnosed by correlating clinical appearance with histopathological analysis of an invasive skin punch biopsy. Additionally, often multiple biopsies are required after diagnosis, e.g. when a lesion is clinically advancing to a different stage or if lesion origin is ambiguous. Currently no other biomarkers besides skin punch biopsies markers are available for the diagnosis of MF, the evaluation of a MF lesion over time, and the monitoring of a potential treatment effect. To advance MF patient care and the development of novel treatments for MF objective, sensitive and reliable (preferably non-invasive) tools are desired.
Therefore, the objective of the current study is to evaluate disease-related characteristics and biomarkers, the intra- and inter-patient variability of biomarkers, to evaluate biomarkers for disease-monitoring following CL gel treatment and to investigate and monitor skin-related adverse events that might develop after CL gel application in MF patients. With this approach the investigators aim to detect novel biomarkers and to establish methodologies for the (non-)invasive monitoring of MF.
For this purpose, a multi-modal patient profiling approach with in-depth characterization of cutaneous T-cell lymphomas will be performed. A clinical study will be conducted investigating the biology of the disease compared to healthy volunteers (part A) and patients' response to intervention (part B). The former to characterize objectively measured disease characteristics and mechanisms underlying its development, the latter to monitor the biomarker response associated to a MF-CTCL treatment, in this case CL gel. The study focusses on cellular, molecular, biophysical, imaging and microbiome analyses in comparison to healthy controls and between lesional and non-lesional skin of MF patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Chlormethine gel
Chlormethine gel 0.016% in 60mg tube, topical home administration from day 0 to day 155.
干预措施: Chlormethine (Drug)
结局指标
主要结局
Composite Assessment of Index Lesions Disease Severity Score (CAILS)
时间窗: from day -42 to day 155
CAILS is a composite score to quantify lesion severity and consists of scoring erythema, hypo-/hyperpigmentation, plaque elevation, desquamation and lesion size. The CAILS score of a single lesion ranges from 0 (unaffected) to 50 (severely affected).
Objective Response Rate (ORR)
时间窗: from day 43 to day 155
The Objective Response Rate (ORR) measures the lesional response as the change from baseline for the CAILS and mSWAT score. The ORR is the number of patients with complete response (100% clearance) + the number of patients with partial response (50%-99%) divided by the total number of patients.
Patient reported outcomes
时间窗: from day 0 to day 155
Patients will be asked to report on their condition through a Numerical Rating Scale (0 (better)- 100 (worse)) for itch, pain and sleeplessness.
Modified Severity Weighted Assessment Tool (mSWAT)
时间窗: from day -42 to day 155
mSWAT combines the assessment of the severity of lesions and the area affected into a single score ranging from 0 (unaffected) to 400 (severely affected).
SKINDEX-29: Quality of life (QoL)
时间窗: from day 0 to day 155
The Skindex-29 is a valid 29-item self-report measure that evaluates health-related QoL for patients with dermatological diseases. The score is subdivided in a domain for symptoms, emotions and fuctioning; domain scores range from 0 (no impact) to 100 (severely impacted). Total Skindex-29 score is calculated as a mean of the three domains, ranging from 0 (no impact on QoL) to 100 (QoL severely impacted).
Optical Coherence Tomography (OCT)
时间窗: from day 0 to day 155
OCT is a non-invasive assessment which visualizes skin morphology in vivo to a depth of 2 mm with the use of infrared light.
Lipidomics of the stratum corneum by liquid chromatography mass spectroscopy
时间窗: from day 0 to day 155
Tape stripping will be performed on (non-)lesional skin and lipids are subsequently extracted from the tape and analyzed using Liquid Chromatography-Mass Spectrometry (ng/cm2).
Patient genotyping
时间窗: day 43
A whole blood sample will be used to scan for common mutations in genes implicated in mycosis fungoides using next-generation sequencing.
Treatment Satisfaction Questionnaire for Medication (TSQM)
时间窗: from day 43 to day 155
TSQM consists of 14 questions and explores the subject satisfaction regarding the effectiveness, the side effects, convenience and global satisfaction of the investigational drug. The TSQM score ranges from 0 (lowest satisfaction) to 100 (highest satisfaction).
Laser Speckle Contrast Imaging (LSCI)
时间窗: from day 0 to day 155
The cutaneous microcirculation of (non-)lesional skin sites will be monitored over a 40 second timespan with a laser speckle contrast imager.
Cutaneous microbiome
时间窗: from day 0 to day 155
The cutaneous microbiome of (non-)lesional skin is collected by swabbing. The abundance of bacteria is thereafter determined using next-generation sequencing.
Faecal microbiome
时间窗: from day 43 to day 155
The bacterial composition of stool samples pre- and post-treatment will be determined using next-generation sequencing.
Itch Tracking by Derma Track
时间窗: from day 0 to day 155
Subjects are requested to wear a smartwatch during the night to register total duration of scratch movements.
User experience and subjective burden questionnaire
时间窗: from day 43 to day 155
Measures the user experience and subjective burden of the different imaging modalities used in this study. Scores ranging from 0 (no burden) to 100 (severe burden).
Blister immune cell subsets during dermatitis reactions
时间窗: from day 43 to day 155
Blisters will be induced on the lesional skin and the blister exudate aspirated. Blister exudate will be analyzed for the presence of immune cells (e.g. CD4+ and CD8+ T-Cells) using flow cytometry.
3D Multispectral imaging
时间窗: from day 0 to day 155
The redness and superficial morphology of (non-)lesional skin sites will be determined using a 3D multispectral imaging system.
Thermography
时间窗: from day 0 to day 155
Body surface temperature of (non-)lesional skin will be determined using a thermal imaging infrared camera.
Skin barrier function by Trans-Epidermal Water Loss (TEWL)
时间窗: from day 0 to day 155
The barrier status by trans epidermal water loss of (non-)lesional skin will be determined using TEWL. (g/m2/h)
Skin surface biomarkers
时间窗: from day 0 to day 155
Superficial protein biomarkers of (non-)lesional skin will be assessed by a non-invasive transdermal patch by FibroTx. The presence of protein biomarkers will be determined using ELISA. The following biomarkers will be assessed (ng/ul): IL-8, CXCL-2, IL-1A, IL-1RA, CCL-17 and CCL-27 and VEGF.
Blister immune cell subsets
时间窗: day 43
Blisters will be induced on the (non-)lesional skin and the blister exudate aspirated. Blister exudate will be analyzed for the presence of immune cells (e.g. CD4+ and CD8+ T-Cells) using flow cytometry.
Circulating protein biomarkers by PCR amplification
时间窗: from day 0 to day 155
Blood will be drawn using a venipuncture during visits and analyzed for the presence of various chemokines and cytokines (e.g. CCL20, CCL17, CXCL8).
Cells/ml; Circulating immune cell subsets
时间窗: from day 0 to day 155
Blood will be drawn using a venipuncture during visits and analyzed for the presence of immune cells (e.g. CD4+ and CD8+ T-Cells) using flow cytometry.
Change from baseline in blister protein biomarkers, by high-throughput, multiplex immunoassays of proteins by Proximity Estension Assay (PEA) technology
时间窗: day 43 and day 155
Blisters will be induced on the lesional skin and blister fluid aspirated. Blister fluid will be analyzed for the presence of various chemokines and cytokines using the Olink inflammation and immuno-oncology panel (96 proteins per panel, e.g. PD-L1, IL-4, IL-12, IL-13, ng/ml).
Erythema measurement of the skin
时间窗: from day 0 to day 155
Redness of the skin will be determined using a colorimeter
Immunohistochemistry and Imaging Mass Cytometry/VECTRA of biopsies
时间窗: from day 43 to day 155
Biopsies will be sectioned and stained for the determination of the cutaneous homeostasis and tumor micro-environment by visualising infiltration of cellular immune subsets (e.g. presence of CD4 and CD8).
Blister protein biomarkers by high-throughput, multiplex immunoassays of proteins by Proximity Estension Assay (PEA) technology
时间窗: from day 43 to day 155
Blisters will be induced on the lesional skin and blister fluid aspirated. Blister fluid will be analyzed for the presence of various chemokines and cytokines using the Olink inflammation and immuno-oncology panel (96 proteins per panel, e.g. PD-L1, IL-4, IL-12, IL-13, ng/ml).
Change from baseline in blister immune cell subsets after 16 weeks of treatment
时间窗: day 43 and day 155
Blisters will be induced on the lesional skin and the blister exudate aspirated. Blister exudate will be analyzed for the presence of immune cells (e.g. CD4+ and CD8+ T-Cells) using flow cytometry.
次要结局
未报告次要终点