ODM-207

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.

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.

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.

ODM-207 shows increasing exposure in dose escalation and was safe at doses up to 2 mg/kg but had a narrow therapeutic window.

The clinical trial registration number is NCT03035591.

Background: The upregulated expression of BET proteins is closely associated with the occurrence and development of hematological malignancies and solid tumors. Several BET inhibitors have been developed, and some have been in phase I/II of clinical trials. Here, the safety, efficacy, and pharmacodynamics of ten BET inhibitors currently in clinical trials were evaluated.Methods: We retrieved and reviewed published reports on the clinical trials of twelve BET inhibitors including AZD5153, ABBV-075, BMS-986158, CPI-0610, GSK525762, OTX-015, PLX51107, INCB054329, INCB057643, FT-1101, CC-90010, and ODM-207 for patients with hematological malignancies and solid tumors and summarized their published target genes.Results: In the monotherapy of BET inhibitors, the most common and severe (grade ≥3) hematological adverse events (AEs) are thrombocytopenia, anemia, and neutropenia. The most common non-hematological syndromes are diarrhea, nausea, fatigue, dysgeusia, and decreased appetite, while the most severe AE is pneumonia. Additionally, Tmax of these BET inhibitors was between 0.5–6 h, but the range for T1/2 varied significantly. According to published data, the rates of SD, PD, CR and PR were 27.4%, 37.6%, 3.5%, and 5.7%, respectively, which is not very satisfactory. In addition to BRD4, oncogene MYC is another common target gene of these BET inhibitors. Ninety-seven signaling pathways may be regulated by BET inhibitors.Conclusion: All BET inhibitors reviewed in our study exhibited exposure-dependent thrombocytopenia, which may limit their clinical application. Moreover, further efforts are necessary to explore the optimal dosing schemes and combinations to maximize the efficacy of BET inhibitors.