Phase II Open-Label, Single-Arm Trial to Investigate the Efficacy and Safety of Topical Remetinostat Gel in Patients with Basal Cell Carcinoma

被引:8
作者
Kilgour, James M. [1 ]
Shah, Aatman [1 ,2 ]
Urman, Nicole M. [1 ]
Eichstadt, Shaundra [1 ,3 ]
Do, Hanh N. [1 ]
Bailey, Irene [1 ]
Mirza, Amar [1 ]
Li, Shufeng [1 ]
Oro, Anthony E. [1 ]
Aasi, Sumaira Z. [1 ]
Sarin, Kavita Y. [1 ]
机构
[1] Stanford Univ, Stanford Med Outpatient Ctr, Dept Dermatol, 450 Broadway,Pavil C,2nd Floor, Redwood City, CA 94063 USA
[2] Icahn Sch Med Mt Sinai, Dept Dermatol, New York, NY 10029 USA
[3] Tufts Med Ctr, Dept Dermatol, Boston, MA 02111 USA
关键词
NONMELANOMA SKIN-CANCER; RESISTANCE; US;
D O I
10.1158/1078-0432.CCR-21-0560
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: The mainstay of treatment for basal cell carcinoma (BCC) is surgical excision, which can result in significant associated morbidity, particularly for patients with recurrent tumors. We previously conducted a drug repositioning screen using molecular data from human BCCs and identified histone deacetylase (HDAC) inhibitors as a potential treatment for BCC. Here we conduct the first proof-of-principle study of a topical pan-HDAC inhibitor, remetinostat, in human BCC. Patients and Methods: We conducted a phase II, open-label, single-arm, single-institution trial of a topical HDAC inhibitor. Participants with at least one BCC were recruited. All participants applied 1% remetinostat gel three times daily for 6 weeks, with measurements of tumor diameter conducted at baseline and week 8. Surgical excision of the remaining tumor was conducted at the end of the study and microscopic evaluation was performed. Results: Thirty-three per-protocol tumors from 25 participants were included in the analysis. The overall response rate, defined as the proportion of tumors achieving more than 30% decrease in the longest diameter from baseline to week 8, was 69.7% 190% confidence interval (CI), 54%-82.595]. On pathologic examination, 54.8% of tumors demonstrated complete resolution. Pharmacodynamic analysis demonstrated similar levels of acetylated histone H3 in skin tissue before and after treatment, however, phosphorylation was increased. No systemic adverse events were reported. Conclusions: The HDAC inhibitor remetinostat is a well-tolerated and effective topical treatment for reducing BCC disease burden in a clinically significant manner. This provides in-human validation of HDAC inhibitors as a therapy for BCC.
引用
收藏
页码:4717 / 4725
页数:9
相关论文
共 31 条
  • [1] [Anonymous], 2017, Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
  • [2] Smoothened Variants Explain the Majority of Drug Resistance in Basal Cell Carcinoma
    Atwood, Scott X.
    Sarin, Kavita Y.
    Whitson, Ramon J.
    Li, Jiang R.
    Kim, Geurim
    Rezaee, Melika
    Ally, Mina S.
    Kim, Jinah
    Yao, Catherine
    Chang, Anne Lynn S.
    Oro, Anthony E.
    Tang, Jean Y.
    [J]. CANCER CELL, 2015, 27 (03) : 342 - 353
  • [3] Chiang A, J AM ACAD DERMATOL, V84, P1493
  • [4] Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma
    Coni, Sonia
    Mancuso, Anna Barbara
    Di Magno, Laura
    Sdruscia, Giulia
    Manni, Simona
    Serrao, Silvia Maria
    Rotili, Dante
    Spiombi, Eleonora
    Bufalieri, Francesca
    Petroni, Marialaura
    Kusio-Kobialka, Monika
    De Smaele, Enrico
    Ferretti, Elisabetta
    Capalbo, Carlo
    Mai, Antonello
    Niewiadomski, Pawel
    Screpanti, Isabella
    Di Marcotullio, Lucia
    Canettieri, Gianluca
    [J]. SCIENTIFIC REPORTS, 2017, 7
  • [5] Dummer Reinhard, 2020, Oncotarget, V11, P3473, DOI 10.18632/oncotarget.27735
  • [6] A phase 2 randomized study of SHAPE Gel (SHP-141) in patients with early-stage cutaneous T-cell lymphoma: Interim results.
    Duvic, Madeleine
    Kim, Youn H.
    LeBoeuf, Nicole R.
    Porcu, Pierluigi
    Hastings, Justin
    Bassuner, Juri
    Sowerby, Laura
    Posligua-Alban, Alba
    Guitart, Joan
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2016, 34 (15)
  • [7] Histone Deacetylase Inhibitors as Anticancer Drugs
    Eckschlager, Tomas
    Plch, Johana
    Stiborova, Marie
    Hrabeta, Jan
    [J]. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2017, 18 (07)
  • [8] New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)
    Eisenhauer, E. A.
    Therasse, P.
    Bogaerts, J.
    Schwartz, L. H.
    Sargent, D.
    Ford, R.
    Dancey, J.
    Arbuck, S.
    Gwyther, S.
    Mooney, M.
    Rubinstein, L.
    Shankar, L.
    Dodd, L.
    Kaplan, R.
    Lacombe, D.
    Verweij, J.
    [J]. EUROPEAN JOURNAL OF CANCER, 2009, 45 (02) : 228 - 247
  • [9] Basal cell carcinomas: attack of the hedgehog
    Epstein, Ervin H.
    [J]. NATURE REVIEWS CANCER, 2008, 8 (10) : 743 - 754
  • [10] Hedgehog pathway inhibition by topical patidegib to reduce BCC burden in patients with basal cell nevus (Gorlin) syndrome.
    Epstein, Ervin H.
    Lear, John
    Saldanha, Gillian
    Tang, Jean Y.
    Harwood, Catherine
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2018, 36 (15)