Abstract A098: Preliminary results from a phase 1/2 study of INCB054828, a highly selective fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with advanced malignancies
Authors: Saleh Mansoor , Gutierrez Martin , Subbiah Vivek , Smith David C. , Féliz Luis , Zhen Huiling , Ji Tao , Nemunaitis John 
Published: August 2018

Abstract
Background: FGFR inhibitors are effective against malignancies with FGFR pathway activation. INCB054828 is a selective inhibitor of FGFR1, 2 and 3. This phase 1/2 study evaluated INCB054828 alone, and in combination with other agents, in pts with refractory advanced malignancies; we report preliminary safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of INCB054828. Methods: In this 3-part study (NCT02393248), eligible adults had advanced solid tumors (parts 1 and 3) or tumors with FGF/FGFR alteration (part 2), ECOG performance status ≤1 (part 1) or ≤2 (parts 2 and 3), had progressed after prior therapy, and had no further effective standard therapy available. Pts received oral INCB054828 QD on a 21-d cycle (2-wk on/1-wk off). In part 1 (dose escalation), the first 3 cohorts (1—4 mg QD) evaluated single pts each followed by a 3+3 design (6—20 mg QD). In part 2 (dose expansion), pts were started at INCB054828 9 mg QD and increased to 13.5 mg QD. In part 3, this regimen was used in combination with standard therapies (dose-finding and expansion). Results: At data cutoff (31 Mar’17), 24, 37 and 22 pts were enrolled in parts 1, 2, and 3, respectively. Maximum tolerated dose was not reached in part 1. Maximum safely administered dose was 20 mg: 1 DLT (grade [G] 3 mucositis) was observed at 20 mg. Recommended phase 2 dose was 13.5 mg QD based on PD and clinical effect. Among all 61 pts in parts 1 and 2 (median age, 57 y [range, 21—77]; men, 43%), 48 (79%) discontinued therapy, mainly due to disease progression (52%). In these parts, most frequent all-cause, all-G treatment-emergent adverse events (TEAEs) were hyperphosphatemia (61%; all at doses ≥6 mg), fatigue (39%), dry mouth (31%), alopecia (28%), constipation (23%), and stomatitis (21%); most frequent G ≥3 TEAEs were fatigue (10%), pneumonia (8%), and hyponatremia (7%). Among all 22 pts in part 3 (median age, 62 y [range, 37—73]; men, 59%), 16 (73%) discontinued therapy, mainly due to disease progression (50%). Most frequent all-cause, all-G TEAEs were hyperphosphatemia (73%; all at doses ≥9 mg), anemia (64%), diarrhea (59%), fatigue (45%), dehydration (41%), and constipation, nausea and vomiting (each 36%); most frequent G ≥3 TEAEs were neutropenia (27%), anemia (23%), and diarrhea, hypokalemia, hypotension, neutrophil count decreased, platelet count decreased, white blood cell count decreased and thrombocytopenia (9% each). Hyperphosphatemia was managed with phosphate binders, diet, and/or dose interruption. In part 1, no pts had a complete response (CR) or partial response (PR); 9 and 8 pts had stable disease (SD) and progressive disease (PD), respectively. In part 2, most common tumors were cholangiocarcinoma (CCA; n=9), breast (n=8), and esophageal, ovarian, and head and neck (each n=3); 3 pts (with CCA) had a PR (9 mg QD, n=1; 13.5 mg QD, n=2); 9 and 14 pts had SD and PD, respectively. Terminal half-life was ~15 h; pFGFR2 was inhibited by 64% and 82% from baseline at steady-state trough after 9 and 13.5 mg QD, respectively. Conclusions: INCB054828 was generally well tolerated; hyperphosphatemia was the most common TEAE. PK/PD data support once-daily dosing (2-wk on/1-wk off) and sustained inhibition of FGFR signaling at doses &gt;9 mg. Preliminary efficacy in pts with FGFR pathway activation was observed. Updated data in all enrolled cohorts will be presented.
Citation Format: Mansoor Saleh, Martin Gutierrez, Vivek Subbiah, David C. Smith, Luis Féliz, Huiling Zhen, Tao Ji, John Nemunaitis. Preliminary results from a phase 1/2 study of INCB054828, a highly selective fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with advanced malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A098.