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.

• delgocitinib (Drug), also known as Anzupgo: Delgocitinib is a pan-Janus kinase (JAK1, JAK2, JAK3, TYK2) inhibitor formulated as a 20 mg/g topical cream, marketed as Anzupgo and approved by the European Medicines Agency for chronic hand eczema. In this study, delgocitinib cream is applied topically to affected skin areas twice daily for 16 weeks, off-label, for the treatment of early-stage cutaneous T-cell lymphoma.

Primary outcomes

• Incidence of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [Safety and Tolerability of Topical Delgocitinib] [From baseline (day 0) to end of treatment week 16 (day 112)]: Severity and causal relationship to study treatment will be assessed for all TEAEs and SAEs. Local tolerability will be evaluated based on application-site reactions. Vital signs, physical examination findings, and laboratory parameters will be assessed for clinically relevant abnormalities

Secondary outcomes

• Overall Response Rate (mSWAT) [From baseline (day 0) to end of treatment (day 112)]: Proportion of participants achieving complete response (CR), partial response (PR), or stable disease (SD), based on clinical and molecular assessment using the modified Severity-Weighted Assessment Tool (mSWAT). The mSWAT is a clinician-assessed measure of skin disease burden calculated from body surface area (BSA) affected by patches, plaques, and tumors, weighted by lesion type (patch ×1, plaque ×2, tumor ×4). Scores range from 0 (no skin involvement) to a theoretical maximum of 400 (100% BSA, all tumor), with higher scores indicating more extensive/severe skin disease (worse outcome)
• Change in Patient-Reported Pruritus (NRS) [From baseline (day 0) to end of treatment, week 16 (day 112)]: Change from baseline in pruritus intensity, assessed using the Numeric Rating Scale (NRS), a patient-reported single-item scale ranging from 0 (no itch) to 10 (worst itch imaginable), with higher scores indicating greater itch severity (worse outcome).
• Change in Skin-Related Quality of Life (Skindex-29) [From baseline (day 0) to end of treatment, week 16 (day 112)]: Change from baseline in skin-related quality of life, assessed using the Skindex-29, a 29-item dermatology-specific quality-of-life questionnaire covering three domains (symptoms, emotions, and functioning). Each domain score is standardized to a 0-100 scale, where 0 indicates no impact on quality of life and 100 indicates maximum negative impact, with higher scores indicating worse skin-related quality of life.
• Change in Immune Cell Infiltrate Density by Immunohistochemistry [From baseline (day 0) to end of treatment, week 16 (day 112)]: Change from baseline in density of immune cell markers, including malignant T-cell markers, in lesional and non-lesional skin biopsies, assessed by immunohistochemistry (IHC). Reported as cells per mm² and/or percentage of positively stained area.
• Change in Spatial Gene and Protein Expression Profile by Spatial Transcriptomics [From baseline (day 0) to end of treatment, week 16 (day 112)]: Change from baseline in spatially resolved gene and protein expression in lesional and non-lesional skin biopsies, assessed by spatial transcriptomics platforms (Nanostring GeoMx digital spatial profiling and 10x Genomics Xenium in situ analysis), used to characterize the tumor microenvironment and skin barrier gene expression changes. Reported as normalized expression counts per region of interest.
• Change in Immune Cell Composition by Imaging Mass Cytometry [From baseline (day 0) to end of treatment, week 16 (day 112)]: Change from baseline in single-cell protein marker expression and immune cell subset composition in lesional and non-lesional skin biopsies, assessed by imaging mass cytometry (Hyperion). Reported as percentage of cells positive for each marker and/or cells per mm².
• Malignant T-Cell Clonality and Immune Cell Subset Composition by CITE-Seq [From baseline (day 0) to end of treatment, week 16 (day 112)]: Change from baseline in malignant T-cell clonality and immune cell subset composition in lesional and non-lesional skin biopsies, assessed by CITE-seq (single-cell RNA sequencing combined with surface protein detection and T-cell receptor clonotyping). Reported as percentage of clonal T-cell frequency and relative frequency of immune cell subsets.

Sex: All, ages: 18 Years to any

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

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• Rikke Bech, MD, PhD, Study director, Department of Dermatology and Venerology, Aarhus University Hospital
• Elisabeth Linde Grove, MD, Principal investigator, Department of Dermatology and Venerology, Aarhus University Hospital

NIH grants: 2025