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

研究成果: Article

摘要

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.

原文English
頁(從 - 到)131-138
頁數8
期刊British Journal of Cancer
121
發行號2
DOIs
出版狀態Published - 2019 七月 16

指紋

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

引用此文

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. 於: British Journal of Cancer. 2019 ; 卷 121, 編號 2. 頁 131-138.
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title = "A phase 1, open-label, dose-escalation trial of oral TSR-011 in patients with advanced solid tumours and lymphomas",
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, W-C, 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, 卷 121, 編號 2, 頁 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.

於: British Journal of Cancer, 卷 121, 編號 2, 16.07.2019, p. 131-138.

研究成果: Article

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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JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

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