A Phase 1b Study Evaluating the Safety and Efficacy of Topical Administration of WP1220, an Inhibitor of STAT3 Activation, in Stage I, II or III Mycosis Fungoides (MF)
Authors: Sokołowska-Wojdyło Malgorzata , Blazewicz Izabela , Olszweska Berenika , Zak Ewa Maria , Klemp Walter , Silberman Sandra L , Priebe Waldemar 
Published: November 2019

Background: MF, the most common variant of cutaneous T-cell lymphoma (CTCL) is a disease in which T-cell lymphocytes become malignant, resulting in highly symptomatic, disfiguring skin lesions even in the earliest stages. Standard therapy for MF includes both local and systemic treatments that have shown efficacy, but some have considerable side effects. The recent understanding of the pathogenesis and signaling pathways promoting MF suggest that a focus on the development of targeted therapies could provide important advances for more effective treatment. The signal transducer and activator of transcription protein3 (STAT3) is an oncogenic transcription factor that drives invasion, angiogenesis, and immune suppression in many tumors. It has been identified as one of the key regulators of MF. STAT3 activation via phosphorylation of tyrosine 705 (p-STAT3) leads to increased proliferation and survival of tumor cells as well as suppression of the immune response. WP1220 is a synthetic analogue of caffeic acid benzyl ester (CABE) that potently inhibits p-STAT3 and effectively inhibits growth of CTCL cell lines in vitro.
Methods: This is the first clinical evaluation of WP1220, a p-STAT3 inhibitor in MF. This Phase 1b study was designed to demonstrate the safety and efficacy of topical treatment with a 10% (w/w) WP1220 ointment in adults with Stage I, II or III MF. Topical WP1220 is not absorbed and has no systemic effects. Patients were required to have histopathologic confirmation of the diagnosis of MF and have at least 2 lesions or more up to a maximum total skin area of ≤40cm2.Lesions were selected on the basis of progression despite at least one prior therapy, which could have been either systemic or topical. No concomitant topical therapies on index lesions to which WP1220 was applied was allowed. Patients were trained to apply ointment 2X daily for 3 months on these index lesions, which were evaluated on Days 7, 28, 56 and 84 using the same procedures/assessor throughout the study. The primary endpoint was absolute change from baseline CAILS (Composite Assessment of Index Lesion Severity) scores of the index lesions up to Day 84, with a follow up 1 month later (Day 112). Secondary objectives included monitoring of adverse events (AE) via patient diaries, and photographic documentation validated by independent dermatologic consultation. Biopsies from treated sites were obtained at baseline and at the end of the study to assess histopathology, as well as to perform exploratory evaluations of changes in STAT3 phosphorylation and pathway activation.
Results: There were 6 patients screened, and 5 patients enrolled between March and July 2019. Three are evaluable for both safety and efficacy after completing 3 months of treatment, with 2 ongoing and evaluable for safety. The only AE reported potentially related to study drug in one of the five patients was a mild contact dermatitis not requiring treatment. CAILS scores on index lesions were significantly decreased in the first 3 patients, who were stages IA, IB, and IIB, respectively, at entry. A composite score was obtained for all treated lesions for each patient, and percent changes were calculated from baseline to Day 84. There was a median reduction of 70.8% (range 62.1%-76.2%) for the 3 patients. Improvement was noted as early as 7 days after initiation of treatment, and maintenance of improvement was also shown at follow up (1 month after discontinuation, as per protocol). The fourth patient has also shown an initial reduction in the composite CAILS score after 56 days (26.7%), and is continuing on treatment. Independent dermatologic review based on photographic documentation, which will be provided, is in progress, as are evaluations of the biopsy samples for histopathology and status of p-STAT3 in treated lesions.
Conclusions: WP1220, an inhibitor of p-STAT3, has shown demonstrable safety and significant efficacy after at least 3 months of topical treatment in 3 patients with progressive MF, with a continuing trend towards improvement in additional patients currently in treatment. This is the first demonstration that inhibition of the STAT3 activation pathway with topical therapy has impacted the course of this disease. The trial is continuing, and updated and more comprehensive data from this study as well as assessment of STAT3 phosphorylation in treated lesions will be reported.

Disclosures
Klemp: Moleculin Biotech, Inc.: Employment, Equity Ownership. Silberman:Trovagene: Consultancy; Moleculin Biotech: Employment. Priebe:Moleculin Biotech, Inc.: Consultancy, Equity Ownership, Research Funding.