A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma Journal Article
| Authors: | van Brummelen, E. M. J.; Levchenko, E.; Dómine, M.; Fennell, D. A.; Kindler, H. L.; Viteri, S.; Gadgeel, S.; López, P. G.; Kostorov, V.; Morgensztern, D.; Orlov, S.; Zauderer, M. G.; Vansteenkiste, J. F.; Baker-Neblett, K.; Vasquez, J.; Wang, X.; Bellovin, D. I.; Schellens, J. H. M.; Yan, L.; Mitrica, I.; DeYoung, M. P.; Trigo, J. |
| Article Title: | A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma |
| Abstract: | 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. © 2019, Springer Science+Business Media, LLC, part of Springer Nature. |
| Keywords: | clinical article; protein expression; aged; unclassified drug; constipation; fatigue; paresthesia; cisplatin; diarrhea; drug safety; hypertension; antineoplastic agent; progression free survival; sensory neuropathy; anemia; leukopenia; mucosa inflammation; nausea; vomiting; tinnitus; asthenia; drug dose escalation; rash; fibroblast growth factor 2; multicenter study; immunogenicity; drug response; pleura mesothelioma; mesothelioma; open study; time to maximum plasma concentration; maximum tolerated dose; phase 1 clinical trial; combination therapy; disease control; hiccup; alopecia; pemetrexed; drug tolerance; phase 1; dysgeusia; hypesthesia; decreased appetite; fgf; upper abdominal pain; body weight disorder; lacrimation disorder; infusion related reaction; human; male; female; priority journal; article; gsk 3052230; ligand trap; maximum concentration |
| Journal Title: | Investigational New Drugs |
| Volume: | 38 |
| Issue: | 2 |
| ISSN: | 0167-6997 |
| Publisher: | Springer |
| Date Published: | 2020-04-01 |
| Start Page: | 457 |
| End Page: | 467 |
| Language: | English |
| DOI: | 10.1007/s10637-019-00783-7 |
| PUBMED: | 31065954 |
| PROVIDER: | scopus |
| PMCID: | PMC6898757 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
