PMID- 28275119
OWN - NLM
STAT- MEDLINE
DCOM- 20180214
LR  - 20191210
IS  - 1549-490X (Electronic)
IS  - 1083-7159 (Print)
IS  - 1083-7159 (Linking)
VI  - 22
IP  - 4
DP  - 2017 Apr
TI  - Phase I Dose-Escalation Study of Pilaralisib (SAR245408, XL147) in Combination 
      with Paclitaxel and Carboplatin in Patients with Solid Tumors.
PG  - 377-e37
LID - 10.1634/theoncologist.2016-0257 [doi]
AB  - LESSONS LEARNED: Despite involvement of PI3K pathway activation in tumorigenesis 
      of solid tumors, single-agent PI3K inhibitors have shown modest clinical 
      activity.Preclinical evidence suggests that combining PI3K pathway inhibitors and 
      chemotherapy can enhance antitumor effects.In patients with solid tumors, the 
      PI3K inhibitor pilaralisib had a favorable safety profile but did not enhance the 
      antitumor activity of paclitaxel plus carboplatin.Further clinical evaluation is 
      warranted to identify effective combination strategies with PI3K pathway 
      inhibitors. BACKGROUND: Pilaralisib (SAR245408) is an oral, pan-class I 
      phosphoinositide 3-kinase (PI3K) inhibitor. This phase I dose-escalation study 
      evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and 
      pharmacodynamics of pilaralisib in capsule and tablet formulations, administered 
      in combination with paclitaxel and carboplatin in patients with advanced solid 
      tumors. METHODS: A 3 + 3 design was used. Pilaralisib was administered once daily 
      (QD); paclitaxel (up to 175 mg/m(2)) and carboplatin (up to area under the curve 
      [AUC] of 6) were administered on day 1 of 21-day cycles. An MTD expansion cohort 
      of patients with endometrial carcinoma was included. RESULTS: Fifty-eight 
      patients were enrolled. Six patients (10.3%) had dose-limiting toxicities, of 
      which only rash (two patients, 3.4%) occurred in more than one patient. The MTD 
      of pilaralisib tablets in combination with paclitaxel and carboplatin was 
      determined to be 200 mg QD. The most frequently reported adverse events (AEs) of 
      any grade were neutropenia (67.2%) and thrombocytopenia (67.2%). PK data showed 
      no interaction between pilaralisib and paclitaxel/carboplatin. Tumor tissue 
      showed moderate inhibition of PI3K and mitogen-activated protein kinase (MAPK) 
      pathways. Seven of 52 evaluable patients had a partial response (PR; 13.5%). 
      CONCLUSION: Pilaralisib had a favorable safety profile but did not enhance the 
      antitumor activity of paclitaxel plus carboplatin in solid tumors. The Oncologist 
      2017;22:377-378.
CI  - (c) AlphaMed Press; the data published online to support this summary is the 
      property of the authors.
FAU - Wheler, Jennifer
AU  - Wheler J
AD  - The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 
      jwheler@gmail.com.
FAU - Mutch, David
AU  - Mutch D
AD  - Washington University, Washington School of Medicine, St Louis, Missouri, USA.
FAU - Lager, Joanne
AU  - Lager J
AD  - Sanofi, Cambridge, Massachusetts, USA.
FAU - Castell, Christelle
AU  - Castell C
AD  - Sanofi, Vitry-sur-Seine, France.
FAU - Liu, Li
AU  - Liu L
AD  - Sanofi, Bridgewater, New Jersey, USA.
FAU - Jiang, Jason
AU  - Jiang J
AD  - Sanofi, Bridgewater, New Jersey, USA.
FAU - Traynor, Anne M
AU  - Traynor AM
AD  - University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT00756847
PT  - Clinical Trial, Phase I
PT  - Journal Article
DEP - 20170308
PL  - England
TA  - Oncologist
JT  - The oncologist
JID - 9607837
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinoxalines)
RN  - 0 (Sulfonamides)
RN  - 0 (XL147)
RN  - BG3F62OND5 (Carboplatin)
RN  - P88XT4IS4D (Paclitaxel)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage
MH  - Carboplatin/administration & dosage
MH  - Drug-Related Side Effects and Adverse Reactions/pathology
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/*drug therapy/pathology
MH  - Paclitaxel/administration & dosage
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Kinase Inhibitors/*administration & dosage/adverse effects
MH  - Quinoxalines/*administration & dosage/adverse effects
MH  - Sulfonamides/*administration & dosage/adverse effects
PMC - PMC5388374
EDAT- 2017/03/10 06:00
MHDA- 2018/02/15 06:00
PMCR- 2017/03/08
CRDT- 2017/03/10 06:00
PHST- 2016/09/19 00:00 [received]
PHST- 2016/11/29 00:00 [accepted]
PHST- 2017/03/10 06:00 [pubmed]
PHST- 2018/02/15 06:00 [medline]
PHST- 2017/03/10 06:00 [entrez]
PHST- 2017/03/08 00:00 [pmc-release]
AID - theoncologist.2016-0257 [pii]
AID - ONCO12065 [pii]
AID - 10.1634/theoncologist.2016-0257 [doi]
PST - ppublish
SO  - Oncologist. 2017 Apr;22(4):377-e37. doi: 10.1634/theoncologist.2016-0257. Epub 
      2017 Mar 8.