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
Přispěvatelé: UAM. Departamento de Medicina
Rok vydání: 2019
Předmět:
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