Topical JAK-Inhibition of Early-Stage CTCL

This is an investigator-initiated, descriptive, proof-of-concept, open-label, single-arm phase II pilot study evaluating topical Janus kinase (JAK) inhibition with delgocitinib 20 mg/g cream (Anzupgo) in adults with stable, early-stage mycosis fungoides (MF stage IA, IB, or IIA), the most common subtype of cutaneous T-cell lymphoma (CTCL).

CTCL is a rare, incurable malignancy of unknown etiology. Dysregulated JAK/STAT signaling has repeatedly been linked to malignant T-cell proliferation, drug resistance, and skin barrier deterioration in CTCL. Delgocitinib is a pan-JAK inhibitor (JAK1, JAK2, JAK3, TYK2) already approved by the European Medicines Agency for chronic hand eczema, with a well-characterized local safety profile and minimal systemic absorption following topical application. This study investigates its off-label use in CTCL.

Approximately 15 participants will complete an up-to 4-week screening phase, a 16-week treatment phase with delgocitinib applied topically twice daily to affected skin areas, and a 4-week observational follow-up phase, for a total study duration of approximately 24 weeks per participant.

The primary objective is to evaluate the safety and tolerability of topical delgocitinib in this population, including incidence, severity, and causality of treatment-emergent adverse events and serious adverse events, local tolerability, and clinically relevant laboratory or vital sign abnormalities.

The secondary objective is to explore preliminary evidence of clinical activity and biological effects, including overall response rate. Exploratory mechanistic analyses will be performed on lesional and non-lesional skin biopsies to characterize malignant T-cell populations, the tumor microenvironment, and skin barrier changes in response to treatment.

There is no safety monitoring committee due to the small sample size; a certified dermatologist will monitor all adverse events, vital signs, and physical examination findings throughout the study. The study will be discontinued if more than three participants experience unacceptable adverse effects judged related to delgocitinib, or if more than seven participants experience disease progression requiring alternative therapy.

Inclusion criteria

• Men or women aged 18 or older at the time of consent
• Histologically confirmed diagnosis of mycosis fungoides (stage IA, IB, or IIA)
• Stable disease requiring palliative treatment
• No change in medication for 2 months prior to study entry
• Willing and able to give informed consent, obtained prior to any study-related procedures

Exclusion criteria

• Hypersensitivity to the active substance or to any of the excipients (Benzyl alcohol, Butylhydroxyanisole, Cetostearyl alcohol)
• Sézary syndrome (cancerous T-cells found in the blood)
• Concomitant treatment with other topical/skin-directed therapies (phototherapy, radiotherapy, chlormethine gel, topical corticosteroids)
• Psychiatric illness, disability, or social situation that would compromise subject safety or ability to provide consent
• History of non-melanoma skin cancer (NMSC)
• Atopic dermatitis or other clinically relevant dermatological diseases
• Other clinically significant medical conditions, including:
• Ongoing skin infections requiring antibiotics
• Physical, laboratory, or vital sign abnormalities that would, in the investigator's opinion, put the subject at undue risk or interfere with interpretation of study results
• Pregnancy or breastfeeding
• Women of childbearing potential must use a highly effective contraceptive method