A Phase I, Dose Escalation Study of Oral ASP8273 in Patients with Non–small Cell Lung Cancers with Epidermal Growth Factor Receptor Mutations

Yu, Helena A.; Spira, Alexander I.; Horn, Leora; Weiss, Jared; West, Howard; Giaccone, Giuseppe; Evans, Tracey L.; Kelly, Ronan J.; Desai, Bhardwai B; Krivoshik, Andrew; Moran, Diarmuid M.; Poondru, Srinivasu; Fei, Jie; Aoyama, Kouji; Keating, Anne; Oxnard, Geoffrey R.

doi:10.1158/1078-0432.ccr-17-1447

Cited by 27 publications

(19 citation statements)

References 24 publications

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“…In the US-based, open-label phase I study (NCT02113813) of ASP8273 in 110 NSCLC patients with EGFR T790M who had progressed on a prior EGFR-TKI, clinical antitumor activity of ASP8273 was supported by decreased circulating EGFR T790M cell-free DNA to below the level of detection, confirming successful on-target inhibition. 13 Together, these results reveal that ASP8273 has antitumor activity and was tolerated well by patients with advanced disease. Generally, these ASP8273 clinical data provide further insight into achieving the optimal antitumor effects of third-generation EGFR-TKIs when used as first-line treatment for patients with EGFR activating mutations L858R and ex19del.…”

Section: Discussionmentioning

confidence: 76%

ASP8273 tolerability and antitumor activity in tyrosine kinase inhibitor‐naïve Japanese patients with EGFR mutation‐positive non‐small‐cell lung cancer

et al. 2018

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Epidermal growth factor receptor (EGFR) activating mutations occur in approximately 50% of East Asian patients with non‐small‐cell lung cancer (NSCLC) and confer sensitivity to tyrosine kinase inhibitors (TKIs). ASP8273 is an irreversible EGFR‐TKI, given orally, that inhibits EGFR activating mutations and has shown clinical activity in patients with EGFR mutation‐positive NSCLC. Epidermal growth factor receptor‐TKI‐naïve Japanese adult patients (≥20 years) with NSCLC harboring EGFR mutations were enrolled in this open‐label, single‐arm, phase II study (ClinicalTrials.gov identifier NCT02500927). Patients received ASP8273 300 mg once daily until discontinuation criteria were met. The primary end‐point was to determine the safety of ASP8273 300 mg; the secondary end‐point was antitumor activity defined by RECIST version 1.1. Thirty‐one patients (12 men and 19 women; median age, 64 years [range, 31‐82 years]) with EGFR mutation‐positive NSCLC were enrolled; as of 23 February 2016, 25 patients (81%) were still on study. Of the 31 patients, 27 (87%) had an exon 19 deletion (n = 13, 42%) or an L858R (n = 14, 45%) EGFR activating mutation, and two (7%) had an L861Q mutation. Five patients (16%) had other EGFR activating mutations, two had an activating mutation and the T790M resistance mutation. The most commonly reported treatment‐emergent adverse event was diarrhea (n = 24, 77%). All patients had at least one post‐baseline scan; one patient (3%) achieved a confirmed complete response, 13 (42%) had a confirmed partial response, and 15 (48%) had confirmed stable disease (disease control rate, 94% [n = 29/31]) per investigator assessment. Once‐daily ASP8273 at 300 mg was generally well tolerated and showed antitumor activity in TKI‐naïve Japanese patients with EGFR mutation‐positive NSCLC.

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Section: Discussionmentioning

confidence: 76%

ASP8273 tolerability and antitumor activity in tyrosine kinase inhibitor‐naïve Japanese patients with EGFR mutation‐positive non‐small‐cell lung cancer

et al. 2018

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“…We also identified the EGFR inhibitor ASP-8273 (naquotinib) [21][22][23] as an inhibitor of T. cruzi with good potency (EC 50 of 2.7 nM) and a SI of 191. Several studies have successfully explored kinase inhibitors of trypanosomatids as therapeutic agents [24][25][26], and this compound may represent yet another possible candidate for repurposing or further chemical derivatization.…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Screening of the ReFRAME Library Identifies Potential Drug Repurposing Candidates for Trypanosoma cruzi

et al. 2020

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Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, affects between 6 and 7 million people worldwide, with an estimated 300,000 to 1 million of these cases in the United States. In the chronic phase of infection, T. cruzi can cause severe gastrointestinal and cardiac disease, which can be fatal. Currently, only benznidazole is clinically approved by the FDA for pediatric use to treat this infection in the USA. Toxicity associated with this compound has driven the search for new anti-Chagas agents. Drug repurposing is a particularly attractive strategy for neglected diseases, as pharmacological parameters and toxicity are already known for these compounds, reducing costs and saving time in the drug development pipeline. Here, we screened 7680 compounds from the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library, a collection of drugs or compounds with confirmed clinical safety, against T. cruzi. We identified seven compounds of interest with potent in vitro activity against the parasite with a therapeutic index of 10 or greater, including the previously unreported activity of the antiherpetic compound 348U87. These results provide the framework for further development of new T. cruzi leads that can potentially move quickly to the clinic.

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“…which have previously been reported as having anti-Chagas activity, namely farnesyltransferase inhibitors(12)(13)(14)(15)(16)) (Prenyl-IN-1, incadronate disodium) and DNA topoisomerase inhibitors(17)(18)(19)(20) (NSC-706744, XR 5944).We also identified the EGFR inhibitor ASP-8273 (naquotinib)(21)(22)(23) as an inhibitor of T. cruzi with good potency (EC50 of 2.7 nM) and a SI of 191. Several studies have successfully explored kinase inhibitors of trypanosomatids as therapeutic agents(24)(25)(26), and this compound may represent yet another possible candidate for repurposing or further chemical derivatization.Interestingly, we identified two compounds with intriguing primary indications that may target T. cruzi by novel mechanisms.…”

mentioning

confidence: 85%

High-throughput screening of the ReFRAME library identifies potential drug repurposing candidates forTrypanosoma cruzi

Bernatchez

Chen

Hull

et al. 2019

Preprint

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Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, affects between 6 and 7 million people worldwide, with an estimated 300,000 to 1 million of these cases in the United States. In the chronic phase of infection, T. cruzi can cause severe gastrointestinal and cardiac disease, which can be fatal. Currently, only benznidazole is clinically-approved by the FDA for pediatric use to treat this infection in the USA. Toxicity associated with this compound has driven the search for new anti-Chagas agents. Drug repurposing is a particularly attractive strategy for neglected diseases, as pharmacological parameters and toxicity are already known for these compounds, reducing costs and saving time in the drug development pipeline. Here, we screened ~ 12,000 compounds from the ReFRAME library, a collection of drugs or compounds with confirmed clinical safety, against T. cruzi. We identified 7 compounds of interest with potent in vitro activity against the parasite with a therapeutic index of 10 or greater, including the previously-unreported activity of the antiherpetic compound 348U87. These results provide the framework for further development of new T. cruzi leads that can potentially move quickly to the clinic.

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A Phase I, Dose Escalation Study of Oral ASP8273 in Patients with Non–small Cell Lung Cancers with Epidermal Growth Factor Receptor Mutations

Cited by 27 publications

References 24 publications

ASP8273 tolerability and antitumor activity in tyrosine kinase inhibitor‐naïve Japanese patients with EGFR mutation‐positive non‐small‐cell lung cancer

ASP8273 tolerability and antitumor activity in tyrosine kinase inhibitor‐naïve Japanese patients with EGFR mutation‐positive non‐small‐cell lung cancer

High-Throughput Screening of the ReFRAME Library Identifies Potential Drug Repurposing Candidates for Trypanosoma cruzi

High-throughput screening of the ReFRAME library identifies potential drug repurposing candidates forTrypanosoma cruzi

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