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

Chia Chi Lin, Hendrik Tobias Arkenau, Sharon Lu, Jasgit Sachdev, Javier de Castro Carpeño, Monica Mita, Rafal Dziadziuszko, Wu Chou Su, Dmitri Bobilev, Lorraine Hughes, Jian Chan, Zhi Yi Zhang, Glen J. Weiss

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)131-138
Number of pages8
JournalBritish Journal of Cancer
Volume121
Issue number2
DOIs
Publication statusPublished - 2019 Jul 16

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Lymphoma
Neoplasms
Safety
Non-Small Cell Lung Carcinoma
Maximum Tolerated Dose
anaplastic lymphoma kinase
Gene Rearrangement
Pharmacokinetics
Clinical Trials

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Lin, C. C., Arkenau, H. T., Lu, S., Sachdev, J., de Castro Carpeño, J., Mita, M., ... Weiss, G. J. (2019). A phase 1, open-label, dose-escalation trial of oral TSR-011 in patients with advanced solid tumours and lymphomas. British Journal of Cancer, 121(2), 131-138. https://doi.org/10.1038/s41416-019-0503-9
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. / A phase 1, open-label, dose-escalation trial of oral TSR-011 in patients with advanced solid tumours and lymphomas. In: British Journal of Cancer. 2019 ; Vol. 121, No. 2. pp. 131-138.
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abstract = "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.",
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Lin, CC, Arkenau, HT, Lu, S, Sachdev, J, de Castro Carpeño, J, Mita, M, Dziadziuszko, R, Su, WC, Bobilev, D, Hughes, L, Chan, J, Zhang, ZY & Weiss, GJ 2019, 'A phase 1, open-label, dose-escalation trial of oral TSR-011 in patients with advanced solid tumours and lymphomas', British Journal of Cancer, vol. 121, no. 2, pp. 131-138. https://doi.org/10.1038/s41416-019-0503-9

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

In: British Journal of Cancer, Vol. 121, No. 2, 16.07.2019, p. 131-138.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A phase 1, open-label, dose-escalation trial of oral TSR-011 in patients with advanced solid tumours and lymphomas

AU - Lin, Chia Chi

AU - Arkenau, Hendrik Tobias

AU - Lu, Sharon

AU - Sachdev, Jasgit

AU - de Castro Carpeño, Javier

AU - Mita, Monica

AU - Dziadziuszko, Rafal

AU - Su, Wu Chou

AU - Bobilev, Dmitri

AU - Hughes, Lorraine

AU - Chan, Jian

AU - Zhang, Zhi Yi

AU - Weiss, Glen J.

PY - 2019/7/16

Y1 - 2019/7/16

N2 - 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.

AB - 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.

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