A phase 1, open-label, dose-escalation trial of oral TSR-011 in patients with advanced solid tumours and lymphomas
Autor: | Lorraine Hughes, Glen J. Weiss, Javier de Castro Carpeño, Wu Chou Su, Dmitri Bobilev, Monica M. Mita, Rafal Dziadziuszko, Sharon Lu, Chia-Chi Lin, Hendrik Tobias Arkenau, Jasgit C. Sachdev, Zhi Yi Zhang, Jian Chan |
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Přispěvatelé: | UAM. Departamento de Medicina |
Rok vydání: | 2019 |
Předmět: |
Oncology
Adult Male Cancer Research medicine.medical_specialty Lymphoma Maximum Tolerated Dose medicine.drug_class Medicina Article dose-escalation trial 03 medical and health sciences Electrocardiography 0302 clinical medicine Targeted therapies Refractory Pharmacokinetics Piperidines Internal medicine hemic and lymphatic diseases Neoplasms TSR-011 medicine Anaplastic lymphoma kinase Humans Anaplastic Lymphoma Kinase Lung cancer Adverse effect Protein Kinase Inhibitors Aged Aged 80 and over business.industry Middle Aged medicine.disease ALK inhibitor Clinical trial Tolerability 030220 oncology & carcinogenesis Benzamides Benzimidazoles Female business |
Zdroj: | Biblos-e Archivo. Repositorio Institucional de la UAM instname British Journal of Cancer Biblos-e Archivo: Repositorio Institucional de la UAM Universidad Autónoma de Madrid |
Popis: | Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers in non-small-cell lung cancer (NSCLC). TSR-011 is a dual ALK and tropomyosin-related kinase (TRK) inhibitor, active against ALK inhibitor resistant tumours in preclinical studies. Here, we report the safety, tolerability and recommended phase 2 dose (RP2D) of TSR-011 in patients with relapsed or refractory ALK- and TRK-positive advanced cancers. Methods: In this sequential, open-label, phase 1 trial (NCT02048488), patients received doses of 30 mg, escalated to 480 mg every 24 hours (Q24h), followed by an expansion cohort of patients with ALK-positive cancers. The primary objective was to evaluate safety and tolerability. Secondary objectives included pharmacokinetics. Results: TSR-011 320- and 480-mg Q24h doses exceeded the maximum tolerated dose. At the RP2D of 40 mg every 8 hours (Q8h), the most common grade 3–4 treatment-emergent adverse events occurred in 3.2–6.5% of patients. Of 14 ALK inhibitor-naive patients with ALK-positive NSCLC, 6 experienced partial responses and 8 had stable disease. Conclusions: At the RP2D (40 mg Q8h), TSR-011 demonstrated a favourable safety profile with acceptable QTc changes. Limited clinical activity was observed. Based on the competitive ALK inhibitor landscape and benefit/risk considerations, further TSR-011 development was discontinued This clinical trial was funded by TESARO |
Databáze: | OpenAIRE |
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