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

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.Peer reviewe

Understanding mechanisms of disease evolution in melanoma

Melanoma is a type of skin cancer that can be lethal. This study found that whilst melanoma is usually pigmented, depigmentation occurs as melanoma progresses, suggesting that depigmented cells outcompete pigmented cells, and that this is linked to expression of a protein called AXL. By modifying AXL levels and developing systems to evaluate how melanoma cells compete with one another, it was shown that AXL does not by itself reliably affect pigmentation, and that the role it plays in melanoma progression might vary from patient to patient. The findings provide insight into complex mechanisms of how melanoma cells compete and evolve as the disease progresses

Personalized Cancer Immunotherapy: Today's Challenge and Tomorrow's Promise

Precision medicine continues to be the benchmark toward which we strive in cancer research. Conventionally, it is the term applied to the use of genomic information to guide molecularly targeted therapy. However, the advent of clinically effective cancer immunotherapies has posed a challenge for this concept of precision medicine, as robust biomarkers that can differentiate responders from nonresponders have not been described. Here, we review the current scientific efforts using novel technologies to develop biomarkers for immunotherapeutics, to ultimately achieve “personalized immunotherapy.” We first examine the role of programmed death ligand 1 expression and tumor mutational burden, the two most-studied tumoral response biomarkers; and subsequently discuss innovative candidate biomarkers including integrated “omics” approaches utilizing serial tumor, blood, and microbiome sampling. We also detail the challenges in unifying these approaches into a patient-focused immunogram to truly personalize immunotherapy

Development of Molecularly Targeted Agents and Immunotherapies in Glioblastoma: A Personalized Approach

Over the past decade, precision cancer medicine has driven major advances in the management of advanced solid tumours with the identification and targeting of putative driver aberrations transforming the clinical outcomes across multiple cancer types. Despite pivotal advances in the characterization of genomic landscape of glioblastoma, targeted agents have shown minimal efficacy in clinical trials to date, and patient survival remains poor. Immunotherapy strategies similarly have had limited success. Multiple deficiencies still exist in our knowledge of this complex disease, and further research is urgently required to overcome these critical issues. This review traces the path undertaken by the different therapeutics assessed in glioblastoma and the impact of precision medicine in this disease. We highlight challenges for precision medicine in glioblastoma, focusing on the issues of tumour heterogeneity, pharmacokinetic-pharmacodynamic optimization and outline the modern hypothesis-testing strategies being undertaken to address these key challenges

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

Desenvolupament de fàrmacs; MelanomaDesarrollo de fármacos; MelanomaDrug development; MelanomaBackground 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.The study was sponsored by Orion Corporation, Orion Pharma, Espoo, Finland, the developer of ODM-207