Topical doxycycline foam 4% for prophylactic management of epidermal growth factor receptor inhibitor skin toxicity: an exploratory phase 2, randomized, double-blind clinical study

  • Einat Shacham Shmueli
  • Ravit Geva
  • Nirit Yarom
  • Ayala Hubert
  • Rita Keynan
  • Tal H. Kedem
  • Meir Eini
  • Dov Tamarkin
  • Mitchell ShirvanEmail author
Original Article



Acneiform rash, a common toxicity of epidermal growth factor receptor inhibitors (EGFRIs), can cause patient discomfort, warranting changes in treatment. This study investigated the safety, tolerability, and efficacy of a novel doxycycline foam, FDX104 4%, for managing EGFRI-related skin toxicity.


This was an exploratory phase 2, randomized, double-blind, placebo-controlled study. Subjects had metastatic colorectal cancer and were being treated with either cetuximab or panitumumab plus chemotherapy. Treatment (twice-daily topical FDX104 4% on one side of the face and vehicle foam on the other for 5 weeks) was initiated 7 ± 3 days prior to EGFRI therapy. Rash severity, safety, and tolerability were evaluated at 2 and 4 weeks after EGFRI start.


The mean maximal rash grade was lower with FDX104 4% vs vehicle, and fewer subjects developed moderate-to-severe (grades 2–3) rash. On the Global Severity Score scale, a statistically significant difference favored FDX104 4% over vehicle (P = .047). Adverse events (AEs) (n = 68) occurred in 20 subjects; most were mild or moderate. The most common AEs were oral mucositis, nausea, and vomiting, common to chemotherapy and EGFRI treatment. Study-drug–related AEs were experienced by five subjects and consisted of mild, local skin reactions. No study-drug–related systemic side effects were reported.


Twice-daily, topical administration of FDX104 4% as an adjunct to either cetuximab or panitumumab was safe and well tolerated, and appeared to prevent the onset of rash, especially severe rash. identifier

Trial Registration NCT02239731


Epidermal growth factor inhibitor Acneiform rash Skin toxicity Colorectal cancer Topical doxycycline foam FDX104 



The authors wish to thank Dr. Dror Rom, Prosoft Clinical, Wayne, PA, USA for the statistical analysis.

Funding information

This study was funded by Foamix Pharmaceuticals, Inc. Editorial support was provided by Giang Nguyen, PhD, of P value communications.

Compliance with ethical standards

Conflict of interest

This study was supported by Foamix Pharmaceuticals. Einat Shacham Shmueli served as principal investigator on this study and has received a grant from Foamix Pharmaceuticals. Ravit Geva, Nirit Yarom, and Ayala Hubert served as investigators on this study. Rita Keynan, Tal Hetzroni Kedem, Dov Tarmakin, and Mitchell Shirvan are employees of Foamix Pharmaceuticals. Meir Eini serves as a consultant for Foamix Pharmaceuticals. Mitchell Shirvan, Tal Hetzroni, and Meir Eini receive stock options from Foamix Pharmaceuticals. Ravit Geva reports other from MSD, Novartis, BMS, Roche, Janssen, Takeda, Medison, Merck, and Pfizer, outside the submitted work. The authors state that they have full control of all primary data, and they agree to allow the journal to review their data if requested.

Supplementary material

520_2018_4600_MOESM1_ESM.docx (1.5 mb)
ESM 1 (DOCX 1574 kb)


  1. 1.
    Chanprapaph K, Vachiramon V, Rattanakaemakorn P (2014) Epidermal growth factor receptor inhibitors: a review of cutaneous adverse events and management. Dermatol Res Pract 2014:734249. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Erbitux (cetuximab) Prescribing Information. Indianapolis, IN: Eli Lilly and Company; October 2016Google Scholar
  3. 3.
    Vectibix (panitumumab) Prescribing Information. 2015. Thousand Oaks, CA: Amgen, Inc; March 2015Google Scholar
  4. 4.
    Curry JL, Torres-Cabala CA, Kim KB, Tetzlaff MT, Duvic M, Tsai KY, Hong DS, Prieto VG (2014) Dermatologic toxicities to targeted cancer therapy: shared clinical and histologic adverse skin reactions. Int J Dermatol 53(3):376–384. CrossRefPubMedGoogle Scholar
  5. 5.
    Wagner LI, Lacouture ME (2007) Dermatologic toxicities associated with EGFR inhibitors: the clinical psychologist’s perspective. Impact on health-related quality of life and implications for clinical management of psychological sequelae. Oncology (Williston Park) 21(11 Suppl 5):34–36Google Scholar
  6. 6.
    Brown J, Su Y, Nelleson D, Shankar P, Mayo C (2016) Management of epidermal growth factor receptor inhibitor-associated rash: a systematic review. J Community Support Oncol 14(1):21–28. CrossRefPubMedGoogle Scholar
  7. 7.
    Califano R, Tariq N, Compton S, Fitzgerald DA, Harwood CA, Lal R, Lester J, McPhelim J, Mulatero C, Subramanian S, Thomas A, Thatcher N, Nicolson M (2015) Expert consensus on the management of adverse events from EGFR tyrosine kinase inhibitors in the UK. Drugs 75(12):1335–1348. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Lacouture ME, Anadkat MJ, Bensadoun RJ, Bryce J, Chan A, Epstein JB, Eaby-Sandy B, Murphy BA, Group MSTS (2011) Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer 19(8):1079–1095. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Lacouture ME, Mitchell EP, Piperdi B, Pillai MV, Shearer H, Iannotti N, Xu F, Yassine M (2010) Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol 28(8):1351–1357. CrossRefPubMedGoogle Scholar
  10. 10.
    Sinclair R (2014) Anticipating and managing the cutaneous side effects of epidermal growth factor receptor inhibitors. Asia Pac J Clin Oncol 10(Suppl 1):11–17. CrossRefPubMedGoogle Scholar
  11. 11.
    Smith K, Leyden JJ (2005) Safety of doxycycline and minocycline: a systematic review. Clin Ther 27(9):1329–1342. CrossRefPubMedGoogle Scholar
  12. 12.
    Scope A, Lieb JA, Dusza SW, Phelan DL, Myskowski PL, Saltz L, Halpern AC (2009) A prospective randomized trial of topical pimecrolimus for cetuximab-associated acnelike eruption. J Am Acad Dermatol 61(4):614–620. CrossRefPubMedGoogle Scholar
  13. 13.
    Lacouture ME, Maitland ML, Segaert S, Setser A, Baran R, Fox LP, Epstein JB, Barasch A, Einhorn L, Wagner L, West DP, Rapoport BL, Kris MG, Basch E, Eaby B, Kurtin S, Olsen EA, Chen A, Dancey JE, Trotti A (2010) A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCC skin toxicity study group. Support Care Cancer 18(4):509–522. CrossRefPubMedGoogle Scholar
  14. 14.
    Petrelli F, Borgonovo K, Cabiddu M, Coinu A, Ghilardi M, Lonati V, Barni S (2016) Antibiotic prophylaxis for skin toxicity induced by antiepidermal growth factor receptor agents: a systematic review and meta-analysis. Br J Dermatol 175(6):1166–1174. CrossRefPubMedGoogle Scholar
  15. 15.
    Boone SL, Rademaker A, Liu D, Pfeiffer C, Mauro DJ, Lacouture ME (2007) Impact and management of skin toxicity associated with anti-epidermal growth factor receptor therapy: survey results. Oncology 72(3–4):152–159. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Einat Shacham Shmueli
    • 1
  • Ravit Geva
    • 2
  • Nirit Yarom
    • 3
  • Ayala Hubert
    • 4
  • Rita Keynan
    • 5
  • Tal H. Kedem
    • 5
  • Meir Eini
    • 5
  • Dov Tamarkin
    • 5
  • Mitchell Shirvan
    • 5
    Email author
  1. 1.Sheba Medical CenterTel-HashomerIsrael
  2. 2.Tel Aviv Sourasky Medical CenterTel AvivIsrael
  3. 3.Assaf Harofeh Medical CenterTzrifinIsrael
  4. 4.Hadassah Medical CenterJerusalemIsrael
  5. 5.Foamix Pharmaceuticals Ltd.RehovotIsrael

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