Fimepinostat, Combination HDAC and Pi3-kinase Inhibitor Tumor-Directed Therapy for Cushing Disease (IND 168501 - 07/31/2023) - Abstract Cushing Disease (CD) a life-threatening “orphan disease” with an annual US incidence of ~8 cases per million. It is caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, which drives excess adrenal-derived cortisol production. The annual health care cost of CD patients is > 7 times higher than average patients, and there is a large unmet medical need in treatment for this “orphan disease”. In a systematic high throughput screen of 200,000 compounds, we identified the dual PI3K + HDAC inhibitor, fimepinostat (CUDC-907) as an incredibly potent inhibitor of murine and human corticotroph tumor POMC transcription and ACTH secretion in both in vitro and in vivo models of CD. Supported by our pre-clinical data, we hypothesize that Fimepinostat suppresses pituitary corticotroph tumor growth and ACTH production to normalize cortisol levels in patients with CD. We now propose a pilot, short-term (4 weeks) phase II single- center study to demonstrate the safety and efficacy of Fimepinostat in the treatment of patients with de novo, persistent, and/or recurrent CD recruited at the University of California, Los Angeles. This Phase 2 open-label adaptive study has 2 specific aims: Aim 1 will assess the efficacy and Aim 2 the safety respectively of Fimepinostat in 20 subjects with de novo, persistent, or recurrent CD from UCLA outpatient clinics. Subjects will be randomized to either Fimepinostat 60mg (two 30mg capsules once a day, 10 subjects) or 30mg (single 30mg capsule daily in 10 subjects). Fimepinostat will be administered days 3-7 of each week and then 2 days off for a total of 4 weeks. Drug efficacy in both treatment arms will be determined based on the response rate of subjects exhibiting normalization and/or >50% reduction of 24-hour urinary free cortisol (24h UFC) levels (mean of 3 consecutive samples) after treating 10 subjects in each treatment dose arm. As further efficacy assessment, we will compare several secondary endpoints including normalization of 24h UFC (days 23-28 inclusive), plasma ACTH, serum and salivary cortisol levels (D29) to the subject’s baseline levels (Days -1 to - 5). Changes in clinical signs and symptoms of hypercortisolism, including reductions in body weight, body mass index, and blood pressure along with changes in health-related QOL and depression scores from baseline to 4 weeks will also be assessed although we acknowledge that some of these parameters may take longer to change than our 4 week study. A DSMB will carefully monitor all aspects of safety and assess any adverse and/or serious adverse events. This study will determine the most effective and least toxic dose regimen of Fimepinostat in the treatment of CD and pave the way for larger longer-term clinical trials in Cushing disease.
