A phase 1, open-label, dose-escalation trial of oral TSR-011 in patients with advanced solid tumours and lymphomas

• Published in: British journal of cancer Vol. 121; no. 2; pp. 131 - 138
• Main Authors: Lin, Chia-Chi, Arkenau, Hendrik-Tobias, Lu, Sharon, Sachdev, Jasgit, de Castro Carpeño, Javier, Mita, Monica, Dziadziuszko, Rafal, Su, Wu-Chou, Bobilev, Dmitri, Hughes, Lorraine, Chan, Jian, Zhang, Zhi-Yi, Weiss, Glen J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-07-2019; Nature Publishing Group
• Subjects: 631/67/1059/602; 692/4028/67/1059/602; Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase - antagonists & inhibitors; Benzamides - administration & dosage; Benzamides - adverse effects; Benzamides - pharmacokinetics; Benzimidazoles - administration & dosage; Benzimidazoles - adverse effects; Benzimidazoles - pharmacokinetics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Drug Resistance; Electrocardiography - drug effects; Enzyme inhibitors; Epidemiology; Female; Humans; Lung cancer; Lymphoma; Lymphoma - drug therapy; Male; Maximum Tolerated Dose; Middle Aged; Molecular Medicine; Neoplasms - drug therapy; Non-small cell lung carcinoma; Oncology; Patients; Pharmacokinetics; Piperidines - administration & dosage; Piperidines - adverse effects; Piperidines - pharmacokinetics; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Protein-tyrosine kinase; Safety; Solid tumors; Tropomyosin; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-019-0503-9

Background
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.
Clinical trial registration number
NCT02048488.