{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T18:18:12Z","timestamp":1767205092815,"version":"build-2238731810"},"reference-count":61,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T00:00:00Z","timestamp":1647302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cancers"],"abstract":"<jats:p>Mycosis fungoides (MF) is a subtype of CTCL with a low incidence and high medical need for novel treatments. The objective of this randomized, placebo-controlled, double-blinded, first-in-human study was to evaluate safety, efficacy, cutaneous and systemic pharmacokinetics (PK) of topical bimiralisib in healthy volunteers (HVs) and MF patients. In this trial, a total of 6 HVs and 19 early-stage MF patients were treated with 2.0% bimiralisib gel and\/or placebo. Drug efficacy was assessed by the Composite Assessment of Index Lesion Severity (CAILS) score, supported by objective measuring methods to quantify lesion severity. PK blood samples were collected frequently and cutaneous PK was investigated in skin punch biopsies on the last day of treatment. Local distribution of bimiralisib in HVs showed a mean exposure of 2.54 \u00b5g\/g in the epidermis. A systemic concentration was observed after application of a target dose of 2 mg\/cm2 on 400 cm2, with a mean Cavg of 0.96 ng\/mL. Systemic exposure of bimiralisib was reached in all treated MF patients, and normalized plasma concentrations showed a 144% increased exposure compared to HVs, with an observed mean Cavg of 4.49 ng\/mL and a mean cutaneous concentration of 5.3 \u00b5g\/g. No difference in CAILS or objective lesion severity quantification upon 42 days of once-daily treatment was observed in the MF patient group. In general, the treatment was well tolerated in terms of local reactions as well as systemic adverse events. In conclusion, we showed that topical bimiralisib treatment leads to (i) meaningful cutaneous drug levels and (ii) well-tolerated systemic drug exposure in MF patients and (iii) a lack of clinical efficacy, in need of further exploration due to numerous unknown factors, before depreciation of topical bimiralisib as a novel therapeutic drug for CTCLs.<\/jats:p>","DOI":"10.3390\/cancers14061510","type":"journal-article","created":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T03:34:13Z","timestamp":1647401653000},"page":"1510","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Topical Bimiralisib Shows Meaningful Cutaneous Drug Levels in Healthy Volunteers and Mycosis Fungoides Patients but No Clinical Activity in a First-in-Human, Randomized Controlled Trial"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1064-4198","authenticated-orcid":false,"given":"Selinde","family":"Wind","sequence":"first","affiliation":[{"name":"Centre for Human Drug Research, 2333 CL Leiden, The Netherlands"},{"name":"Department of Dermatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manon","family":"Jansen","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research, 2333 CL Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie","family":"Rijsbergen","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research, 2333 CL Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michiel","family":"van Esdonk","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research, 2333 CL Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitrios","family":"Ziagkos","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research, 2333 CL Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wing","family":"Cheng","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research, 2333 CL Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tessa","family":"Niemeyer-van der Kolk","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research, 2333 CL Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Korsten","sequence":"additional","affiliation":[{"name":"Charles River Laboratories Den Bosch B.V., 5231 DD Den Bosch, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agnieszka","family":"Gruszka","sequence":"additional","affiliation":[{"name":"Charles River Laboratories Den Bosch B.V., 5231 DD Den Bosch, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debora","family":"Schmitz-Rohmer","sequence":"additional","affiliation":[{"name":"PIQUR Therapeutics AG, 4057 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Bonnel","sequence":"additional","affiliation":[{"name":"MS Imaging Department, ImaBiotech, 59120 Lille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raphael","family":"Legouffe","sequence":"additional","affiliation":[{"name":"MS Imaging Department, ImaBiotech, 59120 Lille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florian","family":"Barr\u00e9","sequence":"additional","affiliation":[{"name":"MS Imaging Department, ImaBiotech, 59120 Lille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcel","family":"Bekkenk","sequence":"additional","affiliation":[{"name":"Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ellen","family":"de Haas","sequence":"additional","affiliation":[{"name":"Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koen","family":"Quint","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2280-8161","authenticated-orcid":false,"given":"Harald","family":"Schnidar","sequence":"additional","affiliation":[{"name":"SCARLETRED Holding GmbH, 1030 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie","family":"Rolli","sequence":"additional","affiliation":[{"name":"PIQUR Therapeutics AG, 4057 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8054-5785","authenticated-orcid":false,"given":"Henk","family":"Streefkerk","sequence":"additional","affiliation":[{"name":"PIQUR Therapeutics AG, 4057 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7912-0918","authenticated-orcid":false,"given":"Jacobus","family":"Burggraaf","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research, 2333 CL Leiden, The Netherlands"},{"name":"Department of Dermatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"},{"name":"Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5872-4613","authenticated-orcid":false,"given":"Maarten","family":"Vermeer","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Rissmann","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research, 2333 CL Leiden, The Netherlands"},{"name":"Department of Dermatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"},{"name":"Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"adv00013","DOI":"10.2340\/00015555-3367","article-title":"Early-stage 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