PMID- 24652201
OWN - NLM
STAT- MEDLINE
DCOM- 20150302
LR  - 20211021
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Linking)
VI  - 32
IP  - 4
DP  - 2014 Aug
TI  - Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral 
      pan-Class I PI3K inhibitor, in patients with advanced solid tumors.
PG  - 670-81
LID - 10.1007/s10637-014-0082-9 [doi]
AB  - PURPOSE: The pan-Class I PI3K inhibitor buparlisib (BKM120) has shown activity in 
      a range of preclinical cancer models. This first-in-man study was initiated to 
      identify the maximum tolerated dose (MTD) of buparlisib (100 mg/day) and to 
      assess safety and preliminary efficacy. METHODS: Patients with advanced solid 
      tumors (N = 83) enrolled in a Phase I dose-escalation and -expansion study of 
      single-agent buparlisib. Patients in the dose-expansion arm (n = 43) had tumor 
      samples with PIK3CA and/or PTEN alterations. RESULTS: The most common cancers 
      were colorectal (n = 31) and breast cancer (n = 21). Median number of prior 
      antineoplastic regimens was four (range: 1-12). Grade 3/4 adverse events (AEs) 
      included asthenia (12.0 %) and performance status decrease (9.6 %). 
      Treatment-related AEs (all grades) included decreased appetite, diarrhea, nausea 
      (each in 33 % of patients), hyperglycemia (31 %) and rash (29 %). One confirmed 
      partial response (PR; triple-negative breast cancer) and three unconfirmed PRs 
      (parotid gland carcinoma, epithelioid hemangiothelioma, ER + breast cancer) were 
      reported. Tumor molecular status did not predict clinical benefit in the full 
      study cohort, or among the colorectal or breast cancer subpopulations. 
      Pharmacodynamic biomarkers ((18)F-FDG-PET, C-peptide, pS6) demonstrated 
      dose-dependent changes; however, tumor heterogeneity precluded a clear 
      correlation with clinical benefit. CONCLUSION: Buparlisib was well tolerated up 
      to the 100 mg/day dose and showed preliminary activity in patients with advanced 
      cancers. Future studies in more homogeneous patient populations will evaluate 
      buparlisib in combination with other agents and further investigate the use of 
      predictive biomarkers.
FAU - Rodon, Jordi
AU  - Rodon J
AD  - Vall d'Hebron University Hospital, Barcelona, Spain, jrodon@vhio.net.
FAU - Brana, Irene
AU  - Brana I
FAU - Siu, Lillian L
AU  - Siu LL
FAU - De Jonge, Maja J
AU  - De Jonge MJ
FAU - Homji, Natasha
AU  - Homji N
FAU - Mills, David
AU  - Mills D
FAU - Di Tomaso, Emmanuelle
AU  - Di Tomaso E
FAU - Sarr, Celine
AU  - Sarr C
FAU - Trandafir, Lucia
AU  - Trandafir L
FAU - Massacesi, Cristian
AU  - Massacesi C
FAU - Eskens, Ferry
AU  - Eskens F
FAU - Bendell, Johanna C
AU  - Bendell JC
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20140321
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Aminopyridines)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Morpholines)
RN  - 0 (NVP-BKM120)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (PIK3CA protein, human)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
SB  - IM
MH  - Administration, Oral
MH  - Adult
MH  - Aged
MH  - Aminopyridines/*administration & dosage/adverse effects
MH  - Biomarkers, Tumor/metabolism
MH  - Class I Phosphatidylinositol 3-Kinases
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Morpholines/*administration & dosage/adverse effects
MH  - Neoplasms/*drug therapy/metabolism
MH  - PTEN Phosphohydrolase/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Kinase Inhibitors/administration & dosage/adverse effects
EDAT- 2014/03/22 06:00
MHDA- 2015/03/03 06:00
CRDT- 2014/03/22 06:00
PHST- 2013/12/17 00:00 [received]
PHST- 2014/02/28 00:00 [accepted]
PHST- 2014/03/22 06:00 [entrez]
PHST- 2014/03/22 06:00 [pubmed]
PHST- 2015/03/03 06:00 [medline]
AID - 10.1007/s10637-014-0082-9 [doi]
PST - ppublish
SO  - Invest New Drugs. 2014 Aug;32(4):670-81. doi: 10.1007/s10637-014-0082-9. Epub 
      2014 Mar 21.