A Phase 1 Study of LY2874455, an Oral Selective pan-FGFR Inhibitor, in Patients with Advanced Cancer

Michael, Michael; Bang, Yung Jue; Park, Young Suk; Kang, Yoon Koo; Kim, Tae Min; Hamid, Oday; Thornton, Donald E.; Tate, Sonya C.; Raddad, Eyas; Tie, Jeanne

doi:10.1007/s11523-017-0502-9

Cited by 65 publications

(52 citation statements)

References 31 publications

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“…BGJ398, another selective FGFR1‐3 inhibitor, showed antitumor activity in several tumor types and had a tolerable safety profile in a phase I study in patients with advanced solid tumors, whereas JNJ‐42756493, a pan‐FGFR inhibitor recently approved by the FDA for urothelial carcinoma, showed a clinical response with acceptable safety in a similar patient population . Similar findings have been reported for the pan‐FGFR inhibitors LY2874455 and ARQ 087 . Clinical trials are ongoing for other highly selective FGFR inhibitors in development, such as TAS‐120 and INCB054828, in which patients are screened for FGFR abnormalities using next‐generation sequencing or FISH techniques.…”

Section: Introductionsupporting

confidence: 56%

First‐in‐human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors

et al. 2020

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Fibroblast growth factor receptors (FGFR) are a family of transmembrane receptor tyrosine kinases involved in regulating cellular processes. FGFR mutations are implicated in oncogenesis, representing therapeutic potential in the form of FGFR inhibitors. This phase I, first-in-human study in Japan evaluated safety and tolerability of E7090, a potent selective FGFR1-3 inhibitor, in patients with advanced solid tumors.Dose escalation (daily oral dose of 1-180 mg) was carried out to assess dose-limiting toxicity (DLT), maximum tolerated dose, and pharmacokinetics. Pharmacodynamic markers (serum phosphate, fibroblast growth factor 23, and 1,25-(OH) 2 -vitamin D)were also evaluated. A total of 24 patients refractory to standard therapy or for whom no appropriate treatment was available were enrolled. No DLT were observed up to the 140-mg dose; one patient in the 180-mg cohort experienced a DLT (increased aspartate aminotransferase/alanine aminotransferase, grade 3). The maximum tolerated dose was not reached. Dose-dependent increases in the maximum concentration and area under the curve from time 0 to the last measurable concentration were observed up to 180 mg. Dose-dependent increases were observed in all pharmacodynamic markers and plateaued at 100-140 mg, indicating sufficient FGFR pathway inhibition at doses ≥100 mg. In conclusion, E7090 showed a manageable safety profile with no DLT at doses ≤140 mg. Maximum tolerated dose was not determined.The recommended dose for the follow-up expansion part, restricted to patients with tumors harboring FGFR alterations, was determined as 140 mg, once daily.

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Section: Introductionsupporting

confidence: 56%

First‐in‐human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors

et al. 2020

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“…On the basis of recently published phase I data on other selective FGFR antagonists (20,21,28), the observed toxicity profile, predominated by dose-dependent asymptomatic hyperphosphatemia, appears to be typical for this new class of drug, despite varying dosing schedules, with BGJ398 (20) and JNJ-42756493 (21) given intermittently and LY2874455 given twice daily (28). The observed pharmacokinetic profile of Debio 1347 with steady state rapidly being achieved and only limited plasma accumulation in this study supports continuous once daily dosing.…”

Section: Discussionmentioning

confidence: 99%

“…In 23 patients with FGFR alterations receiving JNJ-42756493, there were 5 PRs (1 unconfirmed) after 6-8 weeks of treatment and 8 patients had stable disease for >3 months (21). With LY2874455, the majority of patients had stable disease, except 1 PR in a patient with gastric cancer (28).…”

Section: Discussionmentioning

confidence: 99%

A Phase I, Open-Label, Multicenter, Dose-escalation Study of the Oral Selective FGFR Inhibitor Debio 1347 in Patients with Advanced Solid Tumors Harboring FGFR Gene Alterations

Voss

Hierro

Heist

et al. 2019

Clinical Cancer Research

104

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Purpose: To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor.Patients and Methods: This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring FGFR1-3 gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose-limiting toxicities (DLT) were evaluated during the first 4 weeks on treatment, pharmacokinetics/pharmacodynamics postfirst dose and after 4 weeks.Results: A total of 71 patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were FGFR1 amplifications (40%) and mutations in FGFR2 (12%) and FGFR3 (17%); 12 patients (21%) showed FGFR fusions. Five patients at three dose levels had six DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis). The maximum tolerated dose was not reached, but dermatologic toxicity became sometimes dose limiting beyond the DLT period at !80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, 3 with FGFR fusions, demonstrated partial responses, 10 additional patients' tumor size regressions of 30%. Plasma half-life was 11.5 hours. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses !60 mg/day.Conclusions: Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study.

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“…Therefore, identification of potent and selective FGFRs inhibitors is an unmet medical need, although severalF GFR-selective inhibitors have progressed into clinicalt rials, such as NVP-BGJ398, AZD4547, CH5183284, LY2874455, and JNJ-42756493. [29][30][31][32][33] Aw ide range of small molecules bearing an indazole nucleus wered ocumented to have FGFR inhibitory activity. Turner et al described the use of ad enovo-based design approach to identify initial hits andf ound an indazole-based pharmacophore that showed encouraging levels of inhibition toward FGFRs.…”

Section: Blockade Of Fgfrsmentioning

confidence: 99%

Recent Advances in the Development of Indazole‐based Anticancer Agents

et al. 2018

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Cancer is one of the leading causes of human mortality globally; therefore, intensive efforts have been made to seek new active drugs with improved anticancer efficacy. Indazole-containing derivatives are endowed with a broad range of biological properties, including anti-inflammatory, antimicrobial, anti-HIV, antihypertensive, and anticancer activities. In recent years, the development of anticancer drugs has given rise to a wide range of indazole derivatives, some of which exhibit outstanding activity against various tumor types. The aim of this review is to outline recent developments concerning the anticancer activity of indazole derivatives, as well as to summarize the design strategies and structure-activity relationships of these compounds.

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A Phase 1 Study of LY2874455, an Oral Selective pan-FGFR Inhibitor, in Patients with Advanced Cancer

Abstract: LY2874455 has an RP2D of 16 mg BID and demonstrated good tolerability and activity in solid-organ cancer patients. The role of FGFR inhibition on tumor growth in patients requires further study. (NCT01212107).

Cited by 65 publications

References 31 publications

First‐in‐human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors

First‐in‐human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors

A Phase I, Open-Label, Multicenter, Dose-escalation Study of the Oral Selective FGFR Inhibitor Debio 1347 in Patients with Advanced Solid Tumors Harboring FGFR Gene Alterations

Recent Advances in the Development of Indazole‐based Anticancer Agents

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