This article is more than 5 years old. Information may no longer be current.
Antifungal agent demonstrated activity in basal cell carcinoma
Click Here to Manage Email Alerts
The oral antifungal drug itraconazole reduced cell proliferation and hedgehog pathway activity in patients with basal cell carcinoma, according to phase 2 study results.
Prior studies showed itraconazole inhibited the hedgehog pathway — often malignantly activated in basal cell carcinoma (BCC) — and reduced BCC growth in mice, according to background information provided by researchers.
The current analysis included 29 patients with one or more basal cell carcinoma tumor ˃4 mm. Three patients had previously received vismodegib (Erivedge, Genentech).
Researchers assigned 19 of the 29 patients to itraconazole. They received either 200-mg doses twice a day for 1 month, or 100-mg doses twice a day for a mean of 2.3 months. The other 10 patients served as controls.
Researchers conducted biomarker analyses — including changes in Ki67 tumor proliferation and hedgehog pathway activity (GLI1 mRNA) — among patients who received 200-mg doses.
Among patients in this arm who had not received vismodegib, itraconazole decreased Ki67 cell proliferation by 45% compared with baseline levels (P=.04). These patients also demonstrated a 65% reduction of GLI1 mRNA levels compared with baseline levels (P=.028).
Among all vismodegib-naive patients, itraconazole was associated with a 24% reduction in tumor size (95% CI, 18.2-30). Change in tumor size was comparable between both itraconazole treatment arms (P=.435).
Among eight evaluable patients, four achieved partial response and four demonstrated stable disease.
“Tumors from untreated control patients and from those previously treated with vismodegib showed no significant changes in proliferation or tumor size,” the researchers wrote.
Two patients discontinued itraconazole treatment due to adverse events — one due to grade 2 fatigue and another due to grade 4 congestive heart failure.
“Itraconazole can reduce basal cell carcinoma tumor size via inhibition of the hedgehog-signaling pathway after 1 month of treatment,” the researchers concluded. “As demonstrated by in vitro signaling assays, the efficacy of itraconazole is dose dependent, and future studies should examine whether higher doses of itraconazole administered over longer treatment periods can approach the efficacy seen with vismodegib and other smoothened antagonists.”
Data interpretation is limited by the fact the 200-mg dose arm included only four patients, Luc Dirix, MD, PhD, of the Sint-Augustinus Cancer Center at Antwerp University Hospital in Belgium, wrote in an accompanying editorial.
“This leaves the questions of optimal dosing of itraconazole unanswered,” Dirix wrote. “This might be important given that 600 mg itraconazole per day in patients with castrate-refractory prostate cancer was substantially more effective than 200 mg daily in achieving hedgehog pathway downregulation in the skin. This observation and the absence of any pharmacokinetic-pharmacodynamics data make it impossible to give any advice on optimal dosing itraconazole in untreated patients or, more importantly, patients with vismodegib-refractory disease.”
For more information:
Disclosure: One researcher reports a consultant/advisory role with Genentech.