PMID- 32147671
OWN - NLM
STAT- MEDLINE
DCOM- 20201230
LR  - 20210310
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Print)
IS  - 0007-0920 (Linking)
VI  - 122
IP  - 8
DP  - 2020 Apr
TI  - Imatinib in combination with phosphoinositol kinase inhibitor buparlisib in 
      patients with gastrointestinal stromal tumour who failed prior therapy with 
      imatinib and sunitinib: a Phase 1b, multicentre study.
PG  - 1158-1165
LID - 10.1038/s41416-020-0769-y [doi]
AB  - BACKGROUND: The majority of patients with advanced gastrointestinal stromal 
      tumours (GISTs) develop resistance to imatinib and sunitinib, the standard of 
      care for these patients. This study evaluated the combination of buparlisib, an 
      oral phosphoinositide 3-kinase (PI3K) inhibitor, with imatinib in patients with 
      advanced GIST, who have failed prior therapy with imatinib and sunitinib. 
      METHODS: This Phase 1b, multicentre, open-label study aimed to determine the 
      maximum tolerated dose (MTD) and/or a recommended Phase 2 dose of buparlisib in 
      combination with 400 mg of imatinib through a dose-escalation part and a 
      dose-expansion part, and also evaluated the clinical profile of the combination. 
      RESULTS: Sixty patients were enrolled, including 25 in the dose-escalation part 
      and 35 in the dose-expansion part. In the combination, MTD of buparlisib was 
      established as 80 mg. No partial or complete responses were observed. The 
      estimated median progression-free survival was 3.5 months in the expansion phase. 
      Overall, 98.3% of patients had treatment-related adverse events (AEs), including 
      45% with grade 3 or 4 AEs. CONCLUSIONS: Buparlisib in combination with imatinib 
      provided no additional benefit compared with currently available therapies. Due 
      to the lack of objective responses, further development of this combination was 
      not pursued for third-line/fourth-line advanced/metastatic GIST. TRIAL 
      REGISTRATION NUMBER: NCT01468688.
FAU - Gelderblom, Hans
AU  - Gelderblom H
AD  - Leiden University Medical Center, Leiden, The Netherlands. 
      a.j.gelderblom@lumc.nl.
FAU - Jones, Robin L
AU  - Jones RL
AD  - The Royal Marsden Hospital and Institute of Cancer Research, London, UK.
FAU - George, Suzanne
AU  - George S
AD  - Dana-Farber Cancer Institute Boston, Boston, MA, USA.
FAU - Valverde Morales, Claudia
AU  - Valverde Morales C
AD  - Vall D'Hebron University Hospital, Barcelona, Spain.
FAU - Benson, Charlotte
AU  - Benson C
AD  - The Royal Marsden Hospital, London, UK.
FAU - Jean-Yves Blay
AU  - Jean-Yves Blay
AD  - Centre Leon Berard, Lyon, France.
AD  - Unicancer, Paris, France.
FAU - Renouf, Daniel J
AU  - Renouf DJ
AD  - BC Cancer - Vancouver Centre, Vancouver, Canada.
FAU - Doi, Toshihiko
AU  - Doi T
AD  - National Cancer Center Hospital East, Kashiwa, Japan.
FAU - Le Cesne, Axel
AU  - Le Cesne A
AD  - Institut Gustave Roussy, Villejuif Cedex, France.
FAU - Leahy, Michael
AU  - Leahy M
AD  - The Christie Hospital, Manchester, UK.
FAU - Hertle, Sabine
AU  - Hertle S
AD  - Novartis Pharma AG, Basel, Switzerland.
FAU - Aimone, Paola
AU  - Aimone P
AD  - Novartis Pharma AG, Basel, Switzerland.
FAU - Brandt, Ulrike
AU  - Brandt U
AD  - Novartis Pharma AG, Basel, Switzerland.
FAU - Schӧffski, Patrick
AU  - Schӧffski P
AD  - University Hospitals Leuven, Department of General Medical Oncology, Leuven 
      Cancer Institute, KU Leuven, Leuven, Belgium.
LA  - eng
SI  - ClinicalTrials.gov/NCT01468688
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20200309
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (Aminopyridines)
RN  - 0 (Morpholines)
RN  - 0 (NVP-BKM120)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 8A1O1M485B (Imatinib Mesylate)
RN  - V99T50803M (Sunitinib)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aminopyridines/*administration & dosage/adverse effects
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Female
MH  - Gastrointestinal Neoplasms/*drug therapy/mortality
MH  - Gastrointestinal Stromal Tumors/*drug therapy/mortality
MH  - Humans
MH  - Imatinib Mesylate/*administration & dosage/adverse effects
MH  - Male
MH  - Mental Disorders/chemically induced
MH  - Middle Aged
MH  - Morpholines/*administration & dosage/adverse effects
MH  - Phosphoinositide-3 Kinase Inhibitors/*administration & dosage
MH  - Sunitinib/*administration & dosage
PMC - PMC7156686
COIS- All the investigators received a research grant to conduct the trial discussed in 
      the publication. In addition, H.G. reports grants to his institute. R.L.J. 
      received honoraria and consultation fees from Adaptimmune, Blueprint, Clinigen, 
      Eisai, Epizyme, Daichii Sankyo, Deciphera Pharmacuticals, Immunedesign, Johnson 
      and Johnson, Eli Lilly, Merck, Pfizer and Pharmamar. S.G. reports being a 
      consultant and on the advisory board of ARIAD, Pfizer, Bayer, Blueprint 
      Medicines, Deciphera Pharmaceuticals, Exelixis, Eli Lilly, AstraZeneca, Research 
      to Practice, MORE Health and Huron Consulting; reports receiving research funds 
      to her institution from ARIAD, Pfizer, Bayer, Blueprint Medicines, Deciphera 
      Pharmaceuticals and Novartis; royalties from Wolters Kluwer Health 
      (https://www.uptodate.com/home); equity from AbbVie (none currently), Abbott Labs 
      and Allergan; reports holding leadership positions as Vice-Chair Alliance for 
      Clinical Trials in Oncology and Vice-President of Alliance Foundation. CVM 
      reports receiving fees for the advisory board from Novartis, Pfizer and Bayer. 
      J.Y.B. reports receiving grant, personal fees and nonfinancial support from 
      Novartis. D.J.R., M.L. and P.S. received institutional funding from Novartis for 
      clinical and translational research in GIST and other sarcomas. T.D. reports 
      research grant and personal fees from Lilly, Chugai Pharma, Kyowa Hakko Kirin, 
      MSD, Daichi Sankyo, Sumitomo Group and Taiho, research grant from Novartis, Merck 
      Serono, Astellas Pharma, Janssen, Boehringer Ingelheim, Takeda, Pfizer, Celgene, 
      Bristol Myers Squibb, AbbVie and Quintiles and personal fees from Amgen outside 
      the submitted work. A.L.C. reports receiving personal fees from Pfizer, 
      Pharmamar, Novartis, Amgen and Lilly. C.B. has no conflicts to disclose. S.H., 
      P.A. and U.B. are employees of Novartis Pharma AG, Basel, Switzerland.
EDAT- 2020/03/10 06:00
MHDA- 2020/12/31 06:00
PMCR- 2021/03/09
CRDT- 2020/03/10 06:00
PHST- 2019/09/04 00:00 [received]
PHST- 2020/02/12 00:00 [accepted]
PHST- 2020/03/10 06:00 [pubmed]
PHST- 2020/12/31 06:00 [medline]
PHST- 2020/03/10 06:00 [entrez]
PHST- 2021/03/09 00:00 [pmc-release]
AID - 10.1038/s41416-020-0769-y [pii]
AID - 769 [pii]
AID - 10.1038/s41416-020-0769-y [doi]
PST - ppublish
SO  - Br J Cancer. 2020 Apr;122(8):1158-1165. doi: 10.1038/s41416-020-0769-y. Epub 2020 
      Mar 9.