Clinical Data Background: Painful and pruritic acneiform rash is a common treatment-limiting side effect of antibody and small molecule EGFRIs used to treat various cancers. Absent an approved product, off-label doxycycline, a tetracycline analog, has been used to prevent rash. Oral doxycycline, however, may cause limiting systemic side effects Methods: We conducted a Ph 2, randomized, double-blind, multicenter study investigating the safety and efficacy of self-applied, twice-daily, FDX104 in 24 patients receiving cetuximab or panitumumab for metastatic colon cancer. Each patient acted as her/his own control by applying FDX104 to one side of the face and matching foam vehicle (placebo) to the other side, beginning 1 week prior to starting the EGFRI. Patients were evaluated until 4 weeks after EGFRI initiation. Rash was quantified by an independent dermatologist using a Global Rash Severity (GRS) scale and by study investigators using a modified MASCC EGFRI Skin Toxicity Tool (MESTT). Maximum-grade rash severity on each side of the face at any visit was used in all analyses Results: Overall, 79% of patients developed rash. The most prominent rash-preventative effect was seen in the patients with severe (grade 3) rash. The overall difference in GRS grade 3 rash favored the FDX104 treatment side: grade 3 rash developed in 9 patients (37.5%) on the placebo side, but only 4 patients (16.7%) on the FDX104 side (P< .05). Four patients had a 2-grade difference in GRS scoring (severe vs mild) between sides. The time from EGFRI treatment initiation to first grade 3 rash trended in favor of FDX104 (hazard ratio = 0.2; P= .096), as did the probability of remaining free of severe rash over time (P= .096). MESTT-based analyses had similar but nonstatistically significant results. FDX104 was associated with mild, transient, localized skin reactions in 6 patients Conclusions: In patients receiving antibody EGFRIs, topical FDX104 was well tolerated and safe. FDX104 applied to skin caused no systemic side effects and had clinically meaningful EGFRI rash prevention activity. Topical FDX104 has the potential to improve patient quality of life, EGFRI compliance, and cancer outcomes and warrants additional studies Clinical trial information: NCT02239731