%0 Journal Article
%A van Brummelen, Emilie M J
%A Levchenko, Evgeny
%A Dómine, Manuel
%A Fennell, Dean A
%A Kindler, Hedy L
%A Viteri, Santiago
%A Gadgeel, Shirish
%A López, Pilar Garrido
%A Kostorov, Vladimir
%A Morgensztern, Daniel
%A Orlov, Sergey
%A Zauderer, Marjorie G
%A Vansteenkiste, Johan F
%A Baker-Neblett, Katherine
%A Vasquez, James
%A Wang, Xiaowei
%A Bellovin, David I
%A Schellens, Jan H M
%A Yan, Li
%A Mitrica, Ionel
%A DeYoung, M Phillip
%A Trigo, Jose
%T A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma.
%D 2019
%U http://hdl.handle.net/10668/13925
%X Background Fibroblast growth factors (FGFs) have a fundamental role in cancer. Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Methods A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed/cisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma. Doses were escalated according to a 3 + 3 design, followed by cohort expansion at the maximum tolerated dose (MTD). Endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics. Results 36 patients were dosed at 10, 15, and 20 mg/kg doses of GSK3052230. Three dose-limiting toxicities were observed at 20 mg/kg and one at 15 mg/kg. The MTD was defined as 15 mg/kg and used for cohort expansion. The most common treatment-related adverse events (AEs) were nausea (56%), decreased appetite (36%), infusion reactions (36%), decreased neutrophil counts (36%), and fatigue (33%). The confirmed ORR was 39% (95% CI: 23.1-56.5) (14/36 PRs) and 47% had stable disease (17/36), giving a disease control rate of 86%. At 15 mg/kg GSK3052230 (n = 25), the ORR was 44% (95% CI: 24.4-65.1), and the median PFS was 7.4 months (95% CI: 6.7-13.4). Four patients had disease control for over 1 year, and three were still ongoing. Conclusion At 15 mg/kg weekly, GSK3052230 was well tolerated in combination with pemetrexed/cisplatin and durable responses were observed. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug.
%K Combination therapy
%K FGF
%K Ligand trap
%K Mesothelioma
%K Phase 1
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