First-in-human Phase 1 open label study of the BET inhibitor ODM-207 in patients with selected solid tumours

• Published in: British journal of cancer Vol. 123; no. 12; pp. 1730 - 1736
• Main Authors: Ameratunga, Malaka, Braña, Irene, Bono, Petri, Postel-Vinay, Sophie, Plummer, Ruth, Aspegren, John, Korjamo, Timo, Snapir, Amir, de Bono, Johann S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.12.2020; Nature Publishing Group
• Subjects: 631/154/433; 631/67/1059/153; 631/67/1347; 631/67/1813/1634; 631/67/589/466; Administration, Oral; Adolescent; Adult; Aged; Anorexia; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Asthenia; Biological Availability; Biomedical and Life Sciences; Biomedicine; Blood Platelets - drug effects; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cancer Research; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Clinical trials; Diarrhea; Drug Administration Schedule; Drug Resistance; Epidemiology; Epigenetics; Fatigue; Fatigue - chemically induced; Female; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lymphoma, Non-Hodgkin - drug therapy; Lymphoma, Non-Hodgkin - metabolism; Male; Maximum Tolerated Dose; Melanoma - drug therapy; Melanoma - metabolism; Middle Aged; Molecular Medicine; Nausea; Neoplasms - drug therapy; Neoplasms - metabolism; Oncology; Oral administration; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Oxazoles - administration & dosage; Oxazoles - adverse effects; Oxazoles - pharmacokinetics; Patients; Pharmacokinetics; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Proteins - antagonists & inhibitors; Pyridines - administration & dosage; Pyridines - adverse effects; Pyridines - pharmacokinetics; Quinolines - administration & dosage; Quinolines - adverse effects; Quinolines - pharmacokinetics; Sarcoma - drug therapy; Sarcoma - metabolism; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - metabolism; Solid tumors; Therapeutic targets; Thrombocytopenia; Titration; Toxicity; Tumors; Vomiting; Young Adult
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-020-01077-z

Background 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. Methods This 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. Results Thirty-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. 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. Clinical trial registration The clinical trial registration number is NCT03035591.