PMID- 31065954
OWN - NLM
STAT- MEDLINE
DCOM- 20210303
LR  - 20211204
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Print)
IS  - 0167-6997 (Linking)
VI  - 38
IP  - 2
DP  - 2020 Apr
TI  - A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed 
      and cisplatin in patients with malignant pleural mesothelioma.
PG  - 457-467
LID - 10.1007/s10637-019-00783-7 [doi]
AB  - 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.
FAU - van Brummelen, Emilie M J
AU  - van Brummelen EMJ
AD  - Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The 
      Netherlands.
FAU - Levchenko, Evgeny
AU  - Levchenko E
AD  - Petrov Research Institute of Oncology, St. Petersburg, Russian Federation.
FAU - Domine, Manuel
AU  - Domine M
AD  - Instituto de Investigacion Sanitaria Fundacion Jimenez Diaz, Madrid, Spain.
FAU - Fennell, Dean A
AU  - Fennell DA
AD  - University of Leicester & University Hospitals of Leicester NHS Trust, Leicester, 
      UK.
FAU - Kindler, Hedy L
AU  - Kindler HL
AD  - University of Chicago Medical Center, Chicago, IL, USA.
FAU - Viteri, Santiago
AU  - Viteri S
AD  - Instituto Oncologico Rosell, Hospital Universitario Dexeus, Grupo Quironsalud, 
      Barcelona, Spain.
FAU - Gadgeel, Shirish
AU  - Gadgeel S
AD  - Karmanos Cancer Institute, Detroit, MI, USA.
FAU - Lopez, Pilar Garrido
AU  - Lopez PG
AD  - Hospital Universitario Ramon y Cajal, Madrid, Spain.
FAU - Kostorov, Vladimir
AU  - Kostorov V
AD  - Leningrad Regional Oncology Dispensary, St. Petersburg, Russian Federation.
FAU - Morgensztern, Daniel
AU  - Morgensztern D
AD  - Washington University School of Medicine, St. Louis, MO, USA.
FAU - Orlov, Sergey
AU  - Orlov S
AD  - First Pavlov State Medical University, St. Petersburg, Russian Federation.
FAU - Zauderer, Marjorie G
AU  - Zauderer MG
AD  - Memorial Sloan Kettering Cancer Center, New York, NY, USA.
FAU - Vansteenkiste, Johan F
AU  - Vansteenkiste JF
AD  - Respiratory Oncology Unit, Department of Pneumology, University Hospitals KU 
      Leuven, Leuven, Belgium.
FAU - Baker-Neblett, Katherine
AU  - Baker-Neblett K
AD  - GlaxoSmithKline, Inc., 1250 South Collegeville Road, Collegeville, PA, USA.
FAU - Vasquez, James
AU  - Vasquez J
AD  - GlaxoSmithKline, Inc., 1250 South Collegeville Road, Collegeville, PA, USA.
FAU - Wang, Xiaowei
AU  - Wang X
AD  - GlaxoSmithKline, Inc., 1250 South Collegeville Road, Collegeville, PA, USA.
FAU - Bellovin, David I
AU  - Bellovin DI
AD  - Five Prime Therapeutics, Inc., South San Francisco, CA, USA.
FAU - Schellens, Jan H M
AU  - Schellens JHM
AD  - Utrecht University, Utrecht, The Netherlands.
FAU - Yan, Li
AU  - Yan L
AD  - GlaxoSmithKline, Inc., 1250 South Collegeville Road, Collegeville, PA, USA.
FAU - Mitrica, Ionel
AU  - Mitrica I
AD  - GlaxoSmithKline, Inc., 1250 South Collegeville Road, Collegeville, PA, USA.
FAU - DeYoung, M Phillip
AU  - DeYoung MP
AD  - GlaxoSmithKline, Inc., 1250 South Collegeville Road, Collegeville, PA, USA. 
      maurice.p.deyoung@gsk.com.
FAU - Trigo, Jose
AU  - Trigo J
AUID- ORCID: 0000-0002-4489-2683
AD  - Phase I Trials Unit, Medical Oncology Department, Hospital Universitario Virgen 
      de la Victoria, IBIMA, Campus Universitario Teatinos, s/n 29010, Malaga, Spain. 
      jmtrigo@seom.org.
LA  - eng
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - P30 CA022453/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190507
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Ligands)
RN  - 0 (Oncogene Proteins, Fusion)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 04Q9AIZ7NO (Pemetrexed)
RN  - 103107-01-3 (Fibroblast Growth Factor 2)
RN  - CTG26PRE5S (FP-1039)
RN  - EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 1)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents/*administration & dosage/adverse effects/pharmacokinetics
MH  - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse 
      effects
MH  - Cisplatin/*administration & dosage/adverse effects
MH  - Female
MH  - Fibroblast Growth Factor 2/metabolism
MH  - Humans
MH  - Immunoglobulin G/*administration & dosage/adverse effects
MH  - Ligands
MH  - Male
MH  - Mesothelioma, Malignant/*drug therapy/metabolism
MH  - Middle Aged
MH  - Oncogene Proteins, Fusion/*administration & dosage/adverse 
      effects/pharmacokinetics
MH  - Pemetrexed/*administration & dosage/adverse effects
MH  - Receptor, Fibroblast Growth Factor, Type 1/*administration & dosage
MH  - Recombinant Fusion Proteins
MH  - Treatment Outcome
PMC - PMC6898757
MID - NIHMS1060523
OTO - NOTNLM
OT  - Combination therapy
OT  - FGF
OT  - Ligand trap
OT  - Mesothelioma
OT  - Phase 1
COIS- Conflict of interest M. Domine reports receiving speakers' bureau honoraria and 
      is a consultant/advisory board member for AstraZeneca (AZ), Bristol-Myers Squibb 
      (BMS), Boehringer Ingelheim (BI), Celgene, MSD, Roche-Genentech, and AbbVie. D.A. 
      Fennell reports receiving commercial research grants from Astex, Bayer, and BI, 
      speakers' bureau honoraria from BI and BMS and is a consultant/advisory board 
      member for Roche, Bayer, Aldeyra Therapeutics, AbbVie, and BMS. H.L. Kindler 
      reports receiving commercial research grants from Aduro Biotech, AZ, Bayer, 
      GlaxoSmithKline (GSK), Merck, MedImmune, Verastem, BMS, Eli Lilly, Polaris, and 
      Deciphera and is a consultant/advisory board member for Aduro Biotech, MedImmune, 
      Bayer, Celgene, GSK, AZ, Merck, BMS, BI, Ipsen, Erytech Pharma, Five Prime 
      Therapeutics, and Paredox Therapeutics. S. Gadgeel is a consultant/advisory board 
      member for AZ, Roche-Genentech, Takeda, BMS, and AbbVie. P. Garrido Lopez reports 
      receiving commercial research grants from GSK, Celgene, Sanofi, PharmaMar, 
      Theradex, Roche, BMS, Lilly, Guardant, Sysmex, Takeda, AZ, BI, and Novartis and 
      is a consultant/advisory board member for Roche, MSD, BMS, BI, Pfizer, Abbvie, 
      Guardant, Novartis, Lilly, AZ, Janssen, Sysmex, Blueprint Medicine, and Takeda. 
      D. Morgensztern is a consultant/advisory board member for Takeda, AbbVie, BMS, 
      and PharmaMar. M.G. Zauderer is an employee of MSKCC and MSKCC has an 
      institutional collaboration agreement with IBM for Watson for Oncology and 
      receives royalties from IBM, is the Chair of the Board of Directors of the 
      Mesothelioma Applied Research Foundation, reports receiving commercial research 
      grants from MedImmune, Epizyme, Polaris, Sellas Life Sciences, BMS, and 
      Millenium, and is a consultant/advisory board member for Epizyme and Aldeyra 
      Therapeutics. J.F. Vansteenkiste reports receiving research funding/honoraria 
      from MSD, AZ, BMS, BI, and Roche and is a consultant/advisory board member for 
      AZ, BMS, BI, MSD, and Roche. K. Baker-Neblett, X. Wang, L. Yan, I. Mitrica, and 
      M.P. DeYoung are employees of and hold ownership interest in GlaxoSmithKline. J. 
      Vasquez is an employee of GlaxoSmithKline. D.I. Bellovin is an employee of and 
      holds ownership interest in Five Prime Therapeutics. J.H.M. Schellens is an 
      employee of and holds ownership interest in Modra Pharmaceuticals and is a 
      consultant/advisory board member for Debiopharm. J.M. Trigo reports receiving 
      speakers' bureau honoraria from BMS and BI and is a consultant/advisory board 
      member for BMS, BI, Merck, and Takeda. No potential conflicts of interest were 
      disclosed by the other authors.
EDAT- 2019/05/09 06:00
MHDA- 2021/03/04 06:00
PMCR- 2021/04/01
CRDT- 2019/05/09 06:00
PHST- 2019/03/10 00:00 [received]
PHST- 2019/04/12 00:00 [accepted]
PHST- 2019/05/09 06:00 [pubmed]
PHST- 2021/03/04 06:00 [medline]
PHST- 2019/05/09 06:00 [entrez]
PHST- 2021/04/01 00:00 [pmc-release]
AID - 10.1007/s10637-019-00783-7 [pii]
AID - 10.1007/s10637-019-00783-7 [doi]
PST - ppublish
SO  - Invest New Drugs. 2020 Apr;38(2):457-467. doi: 10.1007/s10637-019-00783-7. Epub 
      2019 May 7.