PMID- 25500057
OWN - NLM
STAT- MEDLINE
DCOM- 20151209
LR  - 20220316
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Linking)
VI  - 21
IP  - 4
DP  - 2015 Feb 15
TI  - A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib 
      (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in 
      patients with selected advanced solid tumors.
PG  - 730-8
LID - 10.1158/1078-0432.CCR-14-1814 [doi]
AB  - PURPOSE: MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In 
      this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan 
      class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated. EXPERIMENTAL 
      DESIGN: This open-label, dose-finding, phase Ib study comprised dose escalation, 
      followed by expansion part in patients with RAS- or BRAF-mutant non-small cell 
      lung, ovarian, or pancreatic cancer. RESULTS: Of note, 113 patients were 
      enrolled, 66 and 47 in dose-escalation and -expansion parts, respectively. MTD 
      was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients 
      with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) 
      buparlisib 60 mg + trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs 
      included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) 
      increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) 
      occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate 
      aminotransferase/alanine aminotransferase) increase, and rash. For all (21) 
      patients with ovarian cancer, overall response rate was 29% [1 complete response, 
      5 partial responses (PR)], disease control rate 76%, and median progression-free 
      survival was 7 months. Minimal activity was observed in patients with non-small 
      cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). 
      Relative to historical data, buparlisib exposure increased and trametinib 
      exposure slightly increased with the combination. CONCLUSIONS: At RP2D, 
      buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for 
      patients with KRAS-mutant ovarian cancer. Long-term tolerability of the 
      combination at RP2D is challenging, due to frequent dose interruptions and 
      reductions for toxicity.
CI  - (c)2014 American Association for Cancer Research.
FAU - Bedard, Philippe L
AU  - Bedard PL
AD  - Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
FAU - Tabernero, Josep
AU  - Tabernero J
AD  - Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), 
      Universitat Autonoma de Barcelona, Barcelona, Spain.
FAU - Janku, Filip
AU  - Janku F
AD  - The University of Texas MD Anderson Cancer Center, Houston, Texas.
FAU - Wainberg, Zev A
AU  - Wainberg ZA
AD  - UCLA-University of California, Los Angeles, California.
FAU - Paz-Ares, Luis
AU  - Paz-Ares L
AD  - Hospital Universitario Virgen del Rocio, Seville, Spain.
FAU - Vansteenkiste, Johan
AU  - Vansteenkiste J
AD  - Respiratory Oncology, University Hospital KU Leuven, Leuven, Belgium.
FAU - Van Cutsem, Eric
AU  - Van Cutsem E
AD  - Digestive Oncology, University Hospital KU Leuven, Leuven, Belgium.
FAU - Perez-Garcia, Jose
AU  - Perez-Garcia J
AD  - Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), 
      Universitat Autonoma de Barcelona, Barcelona, Spain.
FAU - Stathis, Anastasios
AU  - Stathis A
AD  - Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
FAU - Britten, Carolyn D
AU  - Britten CD
AD  - UCLA-University of California, Los Angeles, California.
FAU - Le, Ngocdiep
AU  - Le N
AD  - GlaxoSmithKline Oncology R&D, Collegeville, Pennsylvania.
FAU - Carter, Kirsten
AU  - Carter K
AD  - Novartis Pharma AG, Basel, Switzerland.
FAU - Demanse, David
AU  - Demanse D
AD  - Novartis Pharma AG, Basel, Switzerland.
FAU - Csonka, Denes
AU  - Csonka D
AD  - Novartis Pharma AG, Basel, Switzerland.
FAU - Peters, Malte
AU  - Peters M
AD  - Novartis Pharma AG, Basel, Switzerland.
FAU - Zubel, Angela
AU  - Zubel A
AD  - Novartis Pharma AG, Basel, Switzerland.
FAU - Nauwelaerts, Heidi
AU  - Nauwelaerts H
AD  - Novartis Pharma AG, Basel, Switzerland.
FAU - Sessa, Cristiana
AU  - Sessa C
AD  - Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. 
      Cristiana.Sessa@eoc.ch.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141210
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Aminopyridines)
RN  - 0 (Morpholines)
RN  - 0 (NVP-BKM120)
RN  - 0 (Pyridones)
RN  - 0 (Pyrimidinones)
RN  - 33E86K87QN (trametinib)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Aminopyridines/*administration & dosage/adverse effects
MH  - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse 
      effects
MH  - Disease-Free Survival
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/mortality
MH  - Pyridones/*administration & dosage/adverse effects
MH  - Pyrimidinones/*administration & dosage/adverse effects
EDAT- 2014/12/17 06:00
MHDA- 2015/12/15 06:00
CRDT- 2014/12/16 06:00
PHST- 2014/12/16 06:00 [entrez]
PHST- 2014/12/17 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
AID - 1078-0432.CCR-14-1814 [pii]
AID - 10.1158/1078-0432.CCR-14-1814 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2015 Feb 15;21(4):730-8. doi: 10.1158/1078-0432.CCR-14-1814. 
      Epub 2014 Dec 10.