PMID- 25537644
OWN - NLM
STAT- MEDLINE
DCOM- 20150928
LR  - 20220331
IS  - 1573-7217 (Electronic)
IS  - 0167-6806 (Linking)
VI  - 149
IP  - 1
DP  - 2015 Jan
TI  - Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or 
      trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic 
      breast cancer.
PG  - 151-61
LID - 10.1007/s10549-014-3248-4 [doi]
AB  - This phase I/II dose-escalation study investigated the maximum tolerated dose 
      (MTD), safety, pharmacokinetics, and efficacy of the pan-class I phosphoinositide 
      3-kinase inhibitor pilaralisib in combination with trastuzumab (Arm 1) or 
      trastuzumab plus paclitaxel (Arm 2) in patients with HER2-positive metastatic 
      breast cancer. Patients had progressed on prior trastuzumab (Arms 1 and 2) and 
      received prior taxane (Arm 2). The MTD of pilaralisib was determined using a 3 + 
      3 dose-escalation design (starting dose 200 mg once daily). Forty-two patients 
      were enrolled (21 in each arm). Five patients had a dose-limiting toxicity (DLT; 
      three in Arm 1 and two in Arm 2). Dose-limiting toxicities were rash (three 
      patients) and neutropenia (two patients). The MTD of pilaralisib was determined 
      at 400 mg once daily in both arms. The most frequently reported treatment-related 
      adverse events (AEs) were diarrhea (23.8 % in Arm 1 vs. 66.7 % in Arm 2), fatigue 
      (14.3 vs. 42.9 %), and rash (33.3 vs. 38.1 %). The most frequently reported 
      treatment-related grade >/=3 AEs were erythematous rash (9.5 %) in Arm 1 and 
      diarrhea, peripheral neuropathy, and neutropenia (14.3 % each) in Arm 2. 
      Steady-state pilaralisib exposure was similar to previous studies with 
      pilaralisib monotherapy. No responses occurred in Arm 1; four of 20 evaluable 
      patients (20 %) in Arm 2 had a partial response. Observed PIK3CA mutations in 
      cell-free circulating DNA did not correlate with response. Pilaralisib in 
      combination with trastuzumab with or without paclitaxel had an acceptable safety 
      profile in metastatic HER2-positive breast cancer, with clinical activity in the 
      paclitaxel arm.
FAU - Tolaney, Sara
AU  - Tolaney S
AD  - Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA, 
      stolaney@partners.org.
FAU - Burris, Howard
AU  - Burris H
FAU - Gartner, Elaina
AU  - Gartner E
FAU - Mayer, Ingrid A
AU  - Mayer IA
FAU - Saura, Cristina
AU  - Saura C
FAU - Maurer, Matthew
AU  - Maurer M
FAU - Ciruelos, Eva
AU  - Ciruelos E
FAU - Garcia, Agustin A
AU  - Garcia AA
FAU - Campana, Frank
AU  - Campana F
FAU - Wu, Bin
AU  - Wu B
FAU - Xu, Yi
AU  - Xu Y
FAU - Jiang, Jason
AU  - Jiang J
FAU - Winer, Eric
AU  - Winer E
FAU - Krop, Ian
AU  - Krop I
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141224
PL  - Netherlands
TA  - Breast Cancer Res Treat
JT  - Breast cancer research and treatment
JID - 8111104
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Quinoxalines)
RN  - 0 (Sulfonamides)
RN  - 0 (XL147)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - P188ANX8CK (Trastuzumab)
RN  - P88XT4IS4D (Paclitaxel)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antibodies, Monoclonal, Humanized/*administration & dosage/adverse effects
MH  - Antineoplastic Combined Chemotherapy Protocols
MH  - Breast Neoplasms/*drug therapy/pathology
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Paclitaxel/*administration & dosage/adverse effects
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Quinoxalines/*administration & dosage
MH  - Receptor, ErbB-2/genetics
MH  - Sulfonamides/*administration & dosage
MH  - Trastuzumab
EDAT- 2014/12/30 06:00
MHDA- 2015/09/29 06:00
CRDT- 2014/12/25 06:00
PHST- 2014/12/15 00:00 [received]
PHST- 2014/12/15 00:00 [accepted]
PHST- 2014/12/25 06:00 [entrez]
PHST- 2014/12/30 06:00 [pubmed]
PHST- 2015/09/29 06:00 [medline]
AID - 10.1007/s10549-014-3248-4 [doi]
PST - ppublish
SO  - Breast Cancer Res Treat. 2015 Jan;149(1):151-61. doi: 10.1007/s10549-014-3248-4. 
      Epub 2014 Dec 24.