In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 2500-2500
Abstract:
2500 Background: Oncogenic alterations in fibroblast growth factor receptors (FGFR) are seen across multiple solid tumor malignancies. Debio 1347 is an orally available, highly selective panFGFR inhibitor with potent antitumor effect in preclinical models bearing FGFR1-3 genetic alterations. Methods: Patients harboring defined FGFR 1, 2 or 3 alterations received escalating doses of Debio 1347 starting from 10 mg once daily. Dose escalation followed a 3+3+3 algorithm based on a modified Fibonacci sequence. The MTD was defined as the level where ≥ 3/9 patients suffer a DLT. Pharmacokinetics (PK) and pharmacodynamic were serially evaluated in blood, skin and/or tumor tissue. Results: Fifty-six patients were enrolled, including patients with mutations (n = 17), amplifications (n = 28) and fusions (n = 11). The dose was escalated up to 150 mg over 8 cohorts. DLTs were experienced by 4/56 patients, including G2 intolerable dry mouth + eyes at 60 mg, G3 hypercalcemia + hyperamylasemia at 80 mg, and G3 bilirubin increase at 110 mg. At data cut-off, the most common treatment-emergent adverse events (TEAE) were hyperphosphatemia (73%), fatigue (41%), diarrhea (39%), nausea (37%), and inappetence (32%). Fifteen patients (27%) experienced a grade ≥ 3 related TEAE. Twenty-five patients (47%) required dose modification, primarily due to hyperphosphatemia and cutaneous toxicity. An MTD has not been reached. PK appeared overall linear, with a half-life of 14 hours; hyperphosphatemia was dose-dependent. Among the 54 response-evaluable patients, 4 confirmed and 1 unconfirmed partial responses were observed in patients with cholangiocarcinoma (FGFR2 mutant), uterine (FGFR2 and FGFR1 amplified), colon (FGFR2 fusion), and urothelial cancer (FGFR3 fusion); an additional 10 patients had target regression 〈 30%. Conclusions: Debio 1347 had a tolerable and manageable safety profile. Encouraging antitumor activity was seen in several tumor types, mainly in patients with FGFR2 or 3 gene alterations, including fusion events, treated at 80 mg and 110 mg daily. Efficacy will be further explored in disease-specific and molecularly defined expansion cohorts. Clinical trial information: NCT1948297.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2017.35.15_suppl.2500
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2017
detail.hit.zdb_id:
2005181-5
