A Greek, Prospective Non-interventional Study Investigating the Effectiveness and the Mechanism of Action of Chlormethine (CL) Gel in the Treatment of MF-CTCL Adult Patients

1. RATIONALE Chlormethine is a topical alkylating agent whose role in MF-CTCL has been extensively studied over the last 40 years. While its efficacy is well established, many safety concerns have been raised due to high rates of delayed cutaneous hypersensitivity to aqueous solutions that limit the prolonged use of chlormethine in clinical practice. It has been shown that complete response to topical chlormethine is associated with lower risk of disease progression. Accordingly, the clinical data confirm that chlormethine gel is a safe and effective treatment, which be used in early and advanced stages of cutaneous lymphomas. In a study of 23 patients with stage IA-IIB mycosis fungoides from investigators' center an overall response of 65.22% at 9 months of treatment with topical chlormethine was recorded. Moreover in a recent multicenter greek study that included 58 patients with stage IA-IIB mycosis fungoides an overall response rate of 80.8% at 9 months of treatment was achieved. In the same study better response in patients with patches in comparison to plaques or tumors was also depicted. Unfortunately, the occurrence of skin drug reactions was the leading cause of treatment discontinuation in studies evaluating chlormethine irrespective of drug formulation, negatively affecting the achievement of a therapeutic response. In investigators' study, severe dermatitis was one of the main causes of treatment discontinuation, occuring in 15.5% of patients.

Taper of application frequency (as per SmPC) and topical steroid use represent strategies allowing the management of dermatitis in order to maintain patients on CL gel treatment and prevent treatment discontinuation. The presence or severity of dermatitis in the study population was not associated with ORR, indicating that the development of dermatitis did not affect the likelihood of response. It has previously been suggested that dermatitis may be a prognostic indicator for clinical response. These data highlight the unmet need to explain the significance of dermatitis after topical chlomethine application and the immunological changes behind and how these affect the clinical response. Additionally by standardizing a CyTOF technique in CTCL samples from skin biopsies of CTCL patients, investigators established the methodology for identification and enumeration of different cells populations in situ and their interactions with tumor microenvironment. Investigators' preliminary data demonstrated that the evaluation of MF-CTCL patients' immune profile revealed differences in cell proportion pinpointing the heterogeneity that characterizes different stages of MF.

Based on investigators' clinical and biological results investigators would like to further examine the change in the percentage as well as the profile of malignant and inflammatory cells by CyTOF analysis and further investigate the pathways (eg OX40, PDL1) involved in this process. 2. STUDY DESIGN 2.1 Study Description The proposed study is a non-interventional, prospective (data collection), open-label, single-arm study. Data collection will be done prospectively. The management of patients will be done in the classic framework of the management of adult patients with MF-CTCL in principal investigator's university hospital. 3. RESEARCH OBJECTIVES (CLINICAL, BIOLOGICAL AND PATIENT-REPORTED OUTCOMES - QUALITY OF LIFE) 3.1 Clinical objectives

3.1.1 Effectiveness of CL gel treatment in routine medical practice in MF patients by:

• Evaluation of clinical response by mSWAT

• Duration of response (defined as the interval from the time measurement criteria for CR and PR are first met until the first date that progressive disease is documented), time to next treatment (TNTT: defined as the time from the time the next treatment is recorded)
• Correlation between dermatitis occurrence and clinical response
• quality of life of the patients
• Chlormethine gel tube consumption
• safety and tolerability of the treatment with CL gel: frequency of skin side effects 3.2 Biological objectives For this part of the study the percentage change of malignant and inflammatory cells, profile of inflammatory (new and existing) and malignant cells in all MF patients treated with chlormethine gel (with or without dermatitis), cytokines and signaling pathways at a single cell level will be also measured.