Phase (Ph) 1/2 study of TSR-011, a potent inhibitor of ALK and TRK, including crizotinib-resistant ALK mutations.

Weiss, Glen J.; Sachdev, Jasgit C.; Infante, Jeffrey R.; Mita, Monica; Natale, Ronald B.; Arkenau, Hendrik‐Tobias; Wilcoxen, Keith; Kansra, Vikram; Laken, Haley; Hughes, Lorraine; Brooks, David G.; Martell, Robert E.; Anthony, Stephen P.

doi:10.1200/jco.2014.32.15_suppl.e19005

Cited by 13 publications

(12 citation statements)

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“…TSR-011 is an oral dual ALK (IC 50 , 0.7 nmol) and pan-TRK (IC 50 , <3 nmol) inhibitor that had been tested in a phase I/IIa clinical trial (NCT02048488) to determine its safety, tolerability, RP2D, and antitumor activity in patients with advanced tumors refractory to previous treatment with ALK inhibitors (44). TSR-011 was administered orally in dose escalation (30-480 mg 2 or 3 times a day) to 23 patients.…”

Section: Trk Fusion Protein Inhibitors In Clinical Trialsmentioning

confidence: 99%

Emerging Targeted Therapy for Tumors with NTRK Fusion Proteins

Kheder

Hong

2018

Clinical Cancer Research

137

114

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The oncogenesis-promoting role of chromosomal rearrangements for several hematologic and solid malignancies is well recognized. However, identifying targetable, actionable, and druggable chromosomal rearrangements remains a challenge. Targeting gene fusions and chromosomal rearrangements is an effective strategy in treating gene rearrangement-driven tumors. The (eurotrophic yrosineeceptor inase) gene family encodes three tropomyosin-related kinase (TRK) receptors that preserve central and peripheral nervous system development and function. genes, similar to other genes, are subject to alterations, including fusions. Preclinical studies have demonstrated that TRK fusion proteins promote oncogenesis by mediating constitutive cell proliferation and survival. Several clinical trials have estimated the safety and efficacy of TRK fusion kinase receptor inhibitors and have demonstrated encouraging antitumor activity in patients with -rearranged malignancies. Specifically, larotrectinib and entrectinib have emerged as potent, safe, and promising TRK inhibitors. Herein, we discuss the potential oncogenic characteristics of TRK fusion proteins in various malignancies and highlight ongoing clinical trials of kinase inhibitors targeting them.

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Section: Trk Fusion Protein Inhibitors In Clinical Trialsmentioning

confidence: 99%

Emerging Targeted Therapy for Tumors with NTRK Fusion Proteins

Kheder

Hong

2018

Clinical Cancer Research

137

114

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“…TSR-011 is a dual ALK/TRK inhibitor developed by Tesaro, Inc., Waltham, MA, USA. It is currently recruiting in a phase I/IIa trial (NCT02048488) [ 99 ]; Preliminary results showed a dose range of 30–480 mg, with the DLTs to be dysaesthesia and QTc prolongation. PK modeling has identified 60 mg to have minimal peak exposure with sustained trough concentrations above IC50 required for ALK inhibition.…”

Section: Alk Inhibitors In Clinical Usementioning

confidence: 99%

Novel ALK inhibitors in clinical use and development

et al. 2015

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Anaplastic lymphoma kinase 1 (ALK-1) is a member of the insulin receptor tyrosine kinase family. ALK-1 was initially found in anaplastic large cell lymphoma (ALCL). ALK mutations have also been implicated in the pathogenesis of non-small cell lung cancer (NSCLC) and other solid tumors. Multiple small molecule inhibitors with activity against ALK and related oncoproteins are under clinical development. Two of them, crizotinib and ceritinib, have been approved by FDA for treatment of locally advanced and metastatic NSCLC. More agents (alectinib, ASP3026, X396) with improved safety, selectivity, and potency are in the pipeline. Dual inhibitors targeting ALK and EGFRm (AP26113), TRK (TSR011), FAK (CEP-37440), or ROS1 (RXDX-101, PF-06463922) are under active clinical development.

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“…A phase I/II trial is ongoing (NCT01970865). TSR-011 is currently used in a phase I/IIa trial (NCT02048488): its preclinical data show a high affinity for the ALK domain and preliminary data show promising results (110).…”

Section: "Third Generation" Inhibitorsmentioning

confidence: 99%

ALK inhibitors for clinical use in cancer therapy

Farina

Gambacorti‐Passerini

2016

Front Biosci

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Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase protein implicated in a variety of tumors, both solid and hematological. Few years ago crizotinib, an inhibitor of the receptor tyrosine kinases c-Met and ALK, demonstrated its activity in ALK positive non-small-cell lung cancer and other tumors with excellent toxicity profile. Subsequently several ALK inhibitors have been developed, offering new personalized treatment options. This review addresses some clinical considerations on the use of ALK inhibitors in ALK positive tumors and on the development of resistance to them.

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Phase (Ph) 1/2 study of TSR-011, a potent inhibitor of ALK and TRK, including crizotinib-resistant ALK mutations.

Cited by 13 publications

References 0 publications

Emerging Targeted Therapy for Tumors with NTRK Fusion Proteins

Emerging Targeted Therapy for Tumors with NTRK Fusion Proteins

Novel ALK inhibitors in clinical use and development

ALK inhibitors for clinical use in cancer therapy

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