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Clinical Trial
. 2022 Sep 1;158(9):1031-1039.
doi: 10.1001/jamadermatol.2022.2749.

Efficacy and Safety of Topical Hypericin Photodynamic Therapy for Early-Stage Cutaneous T-Cell Lymphoma (Mycosis Fungoides): The FLASH Phase 3 Randomized Clinical Trial

Ellen J Kim  1 , Aaron R Mangold  2 , Jennifer A DeSimone  3 , Henry K Wong  4 , Lucia Seminario-Vidal  5 , Joan Guitart  6 , James Appel  7   8 , Larisa Geskin  9 , Edward Lain  10 , Neil J Korman  11 , Nathalie Zeitouni  12 , Neda Nikbakht  13 , Kenneth Dawes  14 , Oleg Akilov  15 , Joi Carter  16 , Michi Shinohara  17 , Timothy M Kuzel  18 , Warren Piette  18 , Neal Bhatia  19 , Amy Musiek  20 , David Pariser  21 , Youn H Kim  22 , Dirk Elston  23 , Erin Boh  24 , Madeleine Duvic  25 , Auris Huen  25 , Theresa Pacheco  26 , Jeffrey P Zwerner  27 , Seung Tae Lee  28 , Michael Girardi  29 , Christiane Querfeld  30 , Kimberly Bohjanen  31 , Elise Olsen  32 , Gary S Wood  33 , Adam Rumage  34 , Oreola Donini  34 , Andrea Haulenbeek  34 , Christopher J Schaber  34 , Richard Straube  34 , Christopher Pullion  34 , Alain H Rook  1 , Brian Poligone  35
Affiliations
Clinical Trial

Efficacy and Safety of Topical Hypericin Photodynamic Therapy for Early-Stage Cutaneous T-Cell Lymphoma (Mycosis Fungoides): The FLASH Phase 3 Randomized Clinical Trial

Ellen J Kim et al. JAMA Dermatol. .

Abstract

Importance: Given that mycosis fungoides-cutaneous T-cell lymphoma (MF/CTCL) is chronic, there is a need for additional therapies with minimal short- and long-term adverse effects. Topical synthetic hypericin ointment, 0.25%, activated with visible light is a novel, nonmutagenic photodynamic therapy (PDT).

Objectives: To determine the efficacy and safety of topical synthetic hypericin ointment, 0.25%, activated with visible light as a nonmutagenic PDT in early-stage MF/CTCL.

Design, settings, and participants: This was a multicenter, placebo-controlled, double-blinded, phase 3 randomized clinical trial (FLASH study) conducted from December 2015 to November 2020 at 39 academic and community-based US medical centers. Participants were adults (≥18 years) with early-stage (IA-IIA) MF/CTCL.

Interventions: In cycle 1, patients were randomized 2:1 to receive hypericin or placebo to 3 index lesions twice weekly for 6 weeks. In cycle 2, all patients received the active drug for 6 weeks to index lesions. In cycle 3 (optional), both index and additional lesions received active drug for 6 weeks.

Main outcomes and measures: The primary end point was index lesion response rate (ILRR), defined as 50% or greater improvement in modified Composite Assessment of Index Lesion Severity (mCAILS) score from baseline after 6 weeks of therapy for cycle 1. For cycles 2 and 3, open label response rates were secondary end points. Adverse events (AEs) were assessed at each treatment visit, after each cycle, and then monthly for 6 months. Data analyses were performed on December 21, 2020.

Results: The study population comprised 169 patients (mean [SD] age, 58.4 [16.0] years; 96 [57.8%] men; 120 [72.3%] White individuals) with early-stage MF/CTCL. After 6 weeks of treatment, hypericin PDT was more effective than placebo (cycle 1 ILRR, 16% vs 4%; P = .04). The ILRR increased to 40% in patients who received 2 cycles of hypericin PDT (P < .001 vs cycle 1 hypericin) and to 49% after 3 cycles (P < .001 vs cycle 1 hypericin). Significant clinical responses were observed in both patch and plaque type lesions and were similar regardless of age, sex, race, stage IA vs IB, time since diagnosis, and number of prior therapies. The most common treatment-related AEs were mild local skin (13.5%-17.3% across cycles 1-3 vs 10.5% for placebo in cycle 1) and application-site reactions (3.2%-6.9% across cycles 1-3 vs 4% for placebo in cycle 1). No drug-related serious AEs occurred.

Conclusion and relevance: The findings of this randomized clinical trial indicate that synthetic hypericin PDT is effective in early-stage patch and plaque MF/CTCL and has a favorable safety profile.

Trial registration: ClinicalTrials.gov Identifier: NCT02448381.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr E. Kim reported grants from Innate Pharma and Galderma; consulting/advisory fees from Almirall, Galderma, and Helsinn; and honoraria from Ology and UpToDate, all outside the submitted work. Dr Mangold reported grants from Crispr Therapeutics, Elorac, Kyowa Hakko Kirin, and Sun Pharmaceuticals; consulting/advisory fees from UCB, Eli Lilly, Regeneron, PHLEC, Corbus, Incyte, Pfizer, Novartis, Jansen, Argenx, Akari, and Castle Biosciences, all outside the submitted work. Dr Seminario-Vidal reported grants from Kyowa Kirin, and personal fees from Kyowa Kirin, Novartis, Boehringer Ingelheim, Helsinn, Regeneron, Blueprint, Eli Lilly, Soligenix, Helsinn, Eisai, AbbVie, Bristol Myers Squibb, Celgene, Glenmark, Amgen, AnaptysBio, and Innate Pharma outside the submitted work; and being a faculty member at the University of South Florida during the conduct of the study. Dr Guitart reported personal fees from Kirin Kyowa and Elorac outside the submitted work. Dr Korman reported consulting and advisory fees from AbbVie, Amgen, Argenx, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, ChemoCentryx, Dermavant, Dermira, Eli Lilly, Galderma, Genentech, GlaxoSmithKline, Immune, Janssen, Kyowa Hakko Kirin Pharma, Leo Pharma, Menlo Therapeutics, Novartis, Pfizer, Principia, Prothena, Regeneron, Rhizen, Soligenix, Sun Pharma, Syntimmune, Trevi Therapeutics, UCB, Valeant, and XBiotech, outside the submitted work. Dr Zeitouni reported grants from Sun Pharma, Biofrontera, and speaking honoraria from Biofrontera outside the submitted work. Dr Nikbakht reported consulting fees and serving as a member of Helsinn Advisory Board. Dr Shinohara reported grants from Elorac, Cabaletta Bio, and Astex, and serving on the board of the US Cutaneous Lymphoma Consortium outside the submitted work. Dr Piette reported a grant through Rush Medical University from Soligenix outside the submitted work. Dr Kuzel reported grants from Eisai and speaker’s honoraria from Kyowa Kirin. Dr Musiek reported personal fees and grants from Kyowa, Elorac, UpToDate, ADD Board Prep Plus Author, Pfizer, Bristol Myers Squibb, and Aristea Therapeutics, all outside the submitted work. Dr Pariser reported consulting fees from Biofrontera, Dermira, Novartis, Regeneron, Bickel Biotechnology, and Sanofi; and serving as a DSMB member of Bristol Myers Squibb, on the advisory board for Pfizer, and a researcher for Almirall, Amgen, AOBiome, Asana Biosciences, Bickel Biotech, Celgene, Dermira, Eli Lilly, Leo Pharma, Menlo Therapeutics, Novartis, Novo Nordisk, Ortho Dermatologics, Pfizer, and Regeneron, all outside the submitted work. Dr Olsen reports receiving consulting fees from Kyowa Kirin, UpToDate, Molecular Biotech, Helsinn, Soligenix and served on data safety monitoring board for Affimed. Dr Boh reported grants through the Tulane School of Medicine during the conduct of the study. Dr Duvic reported serving on the Soligenix scientific advisory board during the conduct of the study; and personal fees from Eisai, Bionz Consulting, and Bausch scientific advisory board outside the submitted work. Dr Huen reported grants from Kyowa Kirin, Trillium, Galderma, Innate, Eisai, and Seattle Genetics; and personal fees from Kyowa Kirin, Rhizen, Stemline, Helsinn, all outside the submitted work. Dr Querfeld reported advisory board fees from Helsinn, Kyowa Kirin, Mallinckrodt, Stemline, Helsinn, Celgene, and speaking fees from Helsinn, all outside the submitted work. Dr Wood reported serving on the scientific advisory board of Soligenix. Dr Rumage reported equity in Soligenix and a grant from the US National Cancer Institute (NCI), outside the submitted work. Dr Schaber reported a grant from NCI during the conduct of the study and being the co-investor and holding a patent for the hypericin process. Dr Straube reported a grant from NCI during the conduct of the study. Dr Pullion reported personal fees from Soligenix outside the submitted work. Dr Rook reported serving on the scientific advisory board of Soligenix and speaking fees from Mallinckrodt. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Schema
Abbreviation: ITT, intent-to-treat population.
Figure 2.
Figure 2.. Clinical Responses to Hypericin PDT, by Treatment Time, Disease Stage, and Prior Therapy
A, Week 8 represents the patient outcomes of cycle 1 with hypericin PDT (n = 116) or placebo (n = 50) for 6 wks plus a 2-wk rest period before evaluation; week 16, outcomes for patients who received hypericin PDT in cycle 1 and for 6 wks in cycle 2 (n = 44 of 110) plus another 2-wk rest; and week 24, outcomes for patients who received hypericin PDT in cycles 1 and 2 and continued with optional cycle 3 (n =  38 of 78) plus a 2-wk rest. The statistical significance of the RR comparison at the end of cycle 1 was calculated by logistic regression describing responder status when ≥50% improvement in cumulative mCAILS scores from baseline was seen as a function of treatment assignment and baseline mCAILS score. Errors bars describe the 95% CIs using the method of Clopper-Pearson. RRs in cycle 2 for patients who initially received placebo in cycle 1 (22%) were similar to the RRs in the patients receiving hypericin PDT in cycle 1 (16%); data not shown. B, Treatment RRs after 16 wk of hypericin PDT for patients receiving hypericin PDT in both cycles 1 and 2, as a function of disease stage (stages IA and IB; owing to small sample size, stage IIA data are not included) and previous CTCL therapy. Treatment RR was similar across these defined subpopulations. CTCL refers to cutaneous T-cell lymphoma; mCAILS, modified Composite Assessment of Index Lesion Severity; PDT, photodynamic therapy; and RRs, response rates.
Figure 3.
Figure 3.. Consolidated Response Rates Across All Individual Index Lesions, Patch vs Plaque
Consolidated response rate of individual lesions (total vs patch vs plaque) at end of cycles 1 and 2 (all data are reported as a percentage of lesions achieving 50% or more improvement relative to baseline).
See this image and copyright information in PMC

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