Reference Detail

Ref Type

Journal Article

PMID

(30745300)

Authors

Voss MH, Hierro C, Heist RS, Cleary JM, Meric-Bernstam F, Tabernero J, Janku F, Gandhi L, Iafrate AJ, Borger DR, Ishii N, Hu Y, Kirpicheva Y, Nicolas-Metral V, Pokorska-Bocci A, Vaslin Chessex A, Zanna C, Flaherty KT, Baselga J

Title

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	25	9	2019 May 01	2699-2707	Clin Cancer Res

URL

Abstract Text

To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor.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.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.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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Zoligratinib	Zoligratinib	58	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Zoligratinib		CH5183284\|FF284\|debiopharm 1347\|Debio 1347\|Debio1347\|Debio-1347\|FF284	FGFR1 Inhibitor 28 FGFR2 Inhibitor 23 FGFR3 Inhibitor 19	Zoligratinib inhibits FGFR-1, -2, and -3, resulting in decreased downstream signaling, and potentially leading to reduced tumor cell proliferation and angiogenesis, and increased cell death in FGFR-overexpressing tumor cells (PMID: 30745300).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR1 amp	lung squamous cell carcinoma	predicted - sensitive	Zoligratinib	Case Reports/Case Series	Actionable	In a Phase I trial, Debio 1347 treatment resulted in a stable disease with 26.7% reduction of tumor size and 100% decrease of DUSP6 score in a patient with lung squamous cell carcinoma harboring FGFR1 amplification (PMID: 30745300; NCT01948297).	30745300
FGFR2 fusion FGFR1 amp	colon cancer	predicted - sensitive	Zoligratinib	Case Reports/Case Series	Actionable	In a Phase I trial, Debio 1347 treatment resulted in a partial response with 49.5% reduction of tumor size and 66% decrease of DUSP6 score in a patient with colon cancer harboring FGFR1 amplification and FGFR2 fusion (PMID: 30745300; NCT01948297).	30745300
FGFR2 fusion	Advanced Solid Tumor	no benefit	Zoligratinib	Phase I	Actionable	In a Phase I trial, Debio 1347 treatment resulted in partial response in 10.5% (6/57) and stable disease in 28.1% (16/57) of patients with advanced solid tumors harboring genomic alterations of FGFR1/2/3, including amplifications, fusions, and mutations (PMID: 30745300; NCT01948297).	30745300
FGFR1 amp	Advanced Solid Tumor	predicted - sensitive	Zoligratinib	Phase I	Actionable	In a Phase I trial, Debio 1347 treatment resulted in partial response in 10.5% (6/57) and stable disease in 28.1% (16/57) of patients with advanced solid tumors harboring genomic alterations of FGFR1/2/3, including amplifications, fusions, and mutations (PMID: 30745300; NCT01948297).	30745300
FGFR1 fusion	Advanced Solid Tumor	no benefit	Zoligratinib	Phase I	Actionable	In a Phase I trial, Debio 1347 treatment resulted in partial response in 10.5% (6/57) and stable disease in 28.1% (16/57) of patients with advanced solid tumors harboring genomic alterations of FGFR1/2/3, including amplifications, fusions, and mutations (PMID: 30745300; NCT01948297).	30745300
FGFR3 fusion	Advanced Solid Tumor	no benefit	Zoligratinib	Phase I	Actionable	In a Phase I trial, Debio 1347 treatment resulted in partial response in 10.5% (6/57) and stable disease in 28.1% (16/57) of patients with advanced solid tumors harboring genomic alterations of FGFR1/2/3, including amplifications, fusions, and mutations (PMID: 30745300; NCT01948297).	30745300
FGFR2 amp	Advanced Solid Tumor	predicted - sensitive	Zoligratinib	Phase I	Actionable	In a Phase I trial, Debio 1347 treatment resulted in partial response in 10.5% (6/57) and stable disease in 28.1% (16/57) of patients with advanced solid tumors harboring genomic alterations of FGFR1/2/3, including amplifications, fusions, and mutations (PMID: 30745300; NCT01948297).	30745300
FGFR1 mutant	Advanced Solid Tumor	predicted - sensitive	Zoligratinib	Phase I	Actionable	In a Phase I trial, Debio 1347 treatment resulted in partial response in 10.5% (6/57) and stable disease in 28.1% (16/57) of patients with advanced solid tumors harboring genomic alterations of FGFR1/2/3, including amplifications, fusions, and mutations (PMID: 30745300; NCT01948297).	30745300
FGFR2 amp FGFR2 mut	cervical adenocarcinoma	predicted - sensitive	Zoligratinib	Case Reports/Case Series	Actionable	In a Phase I trial, Debio 1347 treatment resulted in a partial response with 50% reduction of tumor size and 56% decrease of DUSP6 score in a patient with cervical adenocarcinoma harboring FGFR2 amplification and FGFR2 mutation (PMID: 30745300; NCT01948297).	30745300
FGFR2 amp	uterine cancer	predicted - sensitive	Zoligratinib	Case Reports/Case Series	Actionable	In a Phase I trial, Debio 1347 treatment resulted in a stable disease with 3.9% change of tumor size and 60% decrease of DUSP6 score in a patient with uterine cancer harboring FGFR2 amplification (PMID: 30745300; NCT01948297).	30745300
FGFR3 amp	Advanced Solid Tumor	predicted - sensitive	Zoligratinib	Phase I	Actionable	In a Phase I trial, Debio 1347 treatment resulted in partial response in 10.5% (6/57) and stable disease in 28.1% (16/57) of patients with advanced solid tumors harboring genomic alterations of FGFR1/2/3, including amplifications, fusions, and mutations (PMID: 30745300; NCT01948297).	30745300
FGFR2 amp	breast cancer	sensitive	Zoligratinib	Case Reports/Case Series	Actionable	In a Phase I trial, Debio 1347 treatment resulted in a stable disease with 19.4% reduction of tumor size and 41% decrease of DUSP6 score in a patient with lung squamous cell carcinoma harboring FGFR2 amplification (PMID: 30745300; NCT01948297).	30745300
FGFR3 mutant	Advanced Solid Tumor	predicted - sensitive	Zoligratinib	Phase I	Actionable	In a Phase I trial, Debio 1347 treatment resulted in partial response in 10.5% (6/57) and stable disease in 28.1% (16/57) of patients with advanced solid tumors harboring genomic alterations of FGFR1/2/3, including amplifications, fusions, and mutations (PMID: 30745300; NCT01948297).	30745300
FGFR2 mutant	Advanced Solid Tumor	predicted - sensitive	Zoligratinib	Phase I	Actionable	In a Phase I trial, Debio 1347 treatment resulted in partial response in 10.5% (6/57) and stable disease in 28.1% (16/57) of patients with advanced solid tumors harboring genomic alterations of FGFR1/2/3, including amplifications, fusions, and mutations (PMID: 30745300; NCT01948297).	30745300