letrozole + panobinostat

The combination of letrozole and panobinostat is being investigated for the treatment of metastatic breast cancer. Letrozole is an aromatase inhibitor that blocks estrogen production, while panobinostat (LBH589) is a pan-histone deacetylase inhibitor (HDACi)[1][2]. ## Clinical Development A Phase I study was conducted to determine the safety and efficacy of this combination. The recommended Phase II starting dose was established as panobinostat 20 mg orally three times weekly (Monday, Wednesday, Friday) and letrozole 2.5 mg orally daily[1][2]. The study found that this dose could be escalated to 30 mg three times weekly if no grade 3 toxicity developed, as partial responses were observed in patients receiving the 30 mg dose[1]. ## Mechanism of Action The combination works through complementary mechanisms: - Letrozole inhibits aromatase activity, reducing estrogen production - Panobinostat suppresses aromatase expression through promoters I.3/II[4] This dual approach allows for synergistic effects. In preclinical studies, the combination demonstrated the ability to suppress the proliferation of estrogen receptor-positive and aromatase-positive breast cancer cells in a synergistic manner[4]. The combination was particularly effective in patients with endocrine-resistant disease[2]. ## Clinical Results In the Phase I trial: - 12 patients were enrolled (6 at each dose level) - 2 patients experienced partial responses - 5 patients had stable disease - The most common severe adverse event was thrombocytopenia (in 4 of 12 patients)[1] The duration of response in these pre-treated patients was encouraging: - 5.6 months for patients with evaluable disease achieving stable disease - 5.1 months for patients achieving partial response - 3.7 months for patients with measurable disease achieving stable disease[2] The maximum tolerated dose was determined to be 20 mg of panobinostat, as dose-limiting toxicities occurred at the 30 mg dose level, including grade 3-4 thrombocytopenia and grade 3 diarrhea[1].