Abstract
BackgroundBromodomain and extra-terminal domain (BET) proteins are reported to be epigenetic anti-cancer drug targets. This first-in-human study evaluated the safety, pharmacokinetics and preliminary anti-tumour activity of the BET inhibitor ODM-207 in patients with selected solid tumours.MethodsThis was an open-label Phase 1 study comprised of a dose escalation part, and evaluation of the effect of food on pharmacokinetics. ODM-207 was administered orally once daily. The dose escalation part was initiated with a dose titration in the initial cohort, followed by a 3 + 3 design.ResultsThirty-five patients were treated with ODM-207, of whom 12 (34%) had castrate-resistant prostate cancer. One dose-limiting toxicity of intolerable fatigue was observed. The highest studied dose achieved was 2 mg/kg due to cumulative toxicity observed beyond the dose-limiting toxicity (DLT) treatment window. Common AEs included thrombocytopenia, asthenia, nausea, anorexia, diarrhoea, fatigue, and vomiting. Platelet count decreased proportionally to exposure with rapid recovery upon treatment discontinuation. No partial or complete responses were observed.ConclusionsODM-207 shows increasing exposure in dose escalation and was safe at doses up to 2 mg/kg but had a narrow therapeutic window.Clinical trial registrationThe clinical trial registration number is NCT03035591.
Highlights
Bromodomain and extra-terminal domain (BET) proteins are reported to be epigenetic anti-cancer drug targets
Evidence of the oncogenic nature of BRD4 is apparent in the rare and aggressive tumour known as nut midline carcinoma (NMC), which occurs as the result of a chromosomal translocation with a resultant fusion protein of BRD4 with nuclear protein in testis (NUT).[7]
Between 22 December 2016 and 10 May 2019, 36 patients were enrolled, and 35 patients were treated at doses ranging from 50 mg to 205 mg corresponding with a range of 0.6–2.0 mg/kg
Summary
Bromodomain and extra-terminal domain (BET) proteins are reported to be epigenetic anti-cancer drug targets. This first-in-human study evaluated the safety, pharmacokinetics and preliminary anti-tumour activity of the BET inhibitor ODM-207 in patients with selected solid tumours. The highest studied dose achieved was 2 mg/kg due to cumulative toxicity observed beyond the dose-limiting toxicity (DLT) treatment window. CONCLUSIONS: ODM-207 shows increasing exposure in dose escalation and was safe at doses up to 2 mg/kg but had a narrow therapeutic window. Evidence of the oncogenic nature of BRD4 is apparent in the rare and aggressive tumour known as nut midline carcinoma (NMC), which occurs as the result of a chromosomal translocation with a resultant fusion protein of BRD4 with nuclear protein in testis (NUT).[7]
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