Treatment of Cushing's Disease with Pituitary-Targeting Seliciclib.

CONTEXT: Preclinical studies show seliciclib (R-roscovitine) suppresses neoplastic corticotroph proliferation and pituitary adrenocorticotrophic hormone (ACTH) production.

OBJECTIVE: To evaluate seliciclib as an effective pituitary-targeting treatment for patients with Cushing's disease (CD).

DESIGN: Two prospective, open-label, phase 2 trials.

SETTING: Tertiary referral pituitary center.

PATIENTS: Adult patients with de novo, persistent, or recurrent CD.

INTERVENTION: Oral seliciclib 400 mg twice daily for 4 consecutive days each week for 4 weeks.

MAIN OUTCOME MEASURES: Primary endpoint in the proof-of-concept single-center study was normalization of 24-hour urinary free cortisol (UFC;  ≤ 50 µg/24 h) at study end; in the pilot multicenter study, primary endpoint was UFC normalization or ≥50% reduction in UFC from baseline to study end.

RESULTS: Sixteen patients were consented and 9 were treated. Mean UFC decreased by 42%, from 226.4 ± 140.3 µg/24 h at baseline to 131.3 ± 114.3 µg/24 h by study end. Longitudinal model showed significant UFC reductions from baseline to each treatment week. Three patients achieved ≥50% UFC reduction (range, 55% to 75%), and 2 patients exhibited 48% reduction; but none achieved UFC normalization. Plasma ACTH decreased by 19% (p = 0.01) in patients who achieved ≥48% UFC reduction. Three patients developed grade ≤2 elevated liver enzymes, anemia, and/or elevated creatinine, which resolved with dose interruption/reduction. Two patients developed grade 4 liver-related serious adverse events that resolved within 4 weeks of seliciclib discontinuation.

CONCLUSIONS: Seliciclib may directly target pituitary corticotrophs in CD and reverse hypercortisolism. Potential liver toxicity of seliciclib resolves with treatment withdrawal. The lowest effective dose requires further determination.