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

Br J Cancer. 2019 Jul;121(2):131-138. doi: 10.1038/s41416-019-0503-9. Epub 2019 Jun 20.


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.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Electrocardiography / drug effects
  • Female
  • Humans
  • Lymphoma / drug therapy*
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms / drug therapy*
  • Piperidines / administration & dosage
  • Piperidines / adverse effects*
  • Piperidines / pharmacokinetics
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects*
  • Protein Kinase Inhibitors / pharmacokinetics


  • Benzamides
  • Benzimidazoles
  • Piperidines
  • Protein Kinase Inhibitors
  • Anaplastic Lymphoma Kinase
  • belizatinib

Associated data

  • ClinicalTrials.gov/NCT02048488