PMID- 24496004
OWN - NLM
STAT- MEDLINE
DCOM- 20141021
LR  - 20211203
IS  - 1556-1380 (Electronic)
IS  - 1556-0864 (Linking)
VI  - 9
IP  - 3
DP  - 2014 Mar
TI  - Phase I safety and pharmacokinetic study of the PI3K/mTOR inhibitor SAR245409 
      (XL765) in combination with erlotinib in patients with advanced solid tumors.
PG  - 316-23
LID - 10.1097/JTO.0000000000000088 [doi]
AB  - INTRODUCTION: The primary objectives of this phase I study were to evaluate the 
      safety and maximum tolerated dose (MTD) of SAR245409, a pan-class I 
      phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin inhibitor, 
      combined with erlotinib in patients with advanced solid tumors. METHODS: 
      Forty-six patients with advanced solid tumors were enrolled. Patients with lung 
      cancer (n = 37) had received an epidermal growth factor receptor (EGFR) inhibitor 
      before study entry. SAR245409 30, 50, 70, or 90 mg once daily (QD) or 20 or 30 mg 
      twice daily (BID) was administered, in combination with erlotinib 100 mg QD, in 
      28-day cycles. Dose escalation of SAR245409 followed a standard 3 + 3 design. 
      Patients were evaluated for adverse events (AEs). Additional evaluations included 
      pharmacokinetics, pharmacodynamic effects on PI3K and EGFR/mitogen-activated 
      protein kinase signaling pathways in tumor and skin samples, and tumor response. 
      RESULTS: The MTDs of SAR245409, in combination with erlotinib 100 mg QD, were 70 
      mg QD and 20 mg BID. The most frequently reported treatment-related AEs (any 
      grade) were diarrhea (35%), rash (35%), and nausea (28%). No treatment-related AE 
      occurred at grade 3/4 in more than one patient (2.2%). No major pharmacokinetic 
      interaction between SAR245409 and erlotinib was noted. Suppression of PI3K and 
      EGFR/mitogen-activated protein kinase signaling pathway biomarkers was observed 
      in skin and tumor samples. Stable disease was the best overall response reported, 
      occurring in 12 of 32 (37.5%) evaluable patients. CONCLUSION: MTDs of SAR245409 
      and erlotinib were below the single-agent doses of either agent, despite the lack 
      of major pharmacokinetic interaction.
FAU - Janne, Pasi A
AU  - Janne PA
AD  - *Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer 
      Science, Dana Farber Cancer Institute, Boston, Massachusetts; daggerDepartment of 
      Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania; 
      double daggerTranslational Medicine, Exelixis, Inc., South San Francisco, San Francisco, 
      California;  section signTranslational and Experimental Medicine, Sanofi, Vitry-sur-Seine, 
      France;  ||Center for Thoracic Centers, Massachusetts General Hospital Cancer 
      Center, Charlestown, Massachusetts;  paragraph signClinical Development Oncology, Sanofi, 
      Cambridge, Massachusetts; #Pharmacokinetic Modeling and Simulation, Sanofi, 
      Cambridge, Massachusetts; **Biostatistics and Programming, Sanofi, Cambridge, 
      Massachusetts; daggerdaggerEarly Drug Development Center, Dana-Farber Cancer Institute, 
      Boston, Massachusetts; double daggerdouble daggerDepartment of Medical Oncology, Vall d'ebron University 
      Hospital, Barcelona, Spain.
FAU - Cohen, Roger B
AU  - Cohen RB
FAU - Laird, A Douglas
AU  - Laird AD
FAU - Mace, Sandrine
AU  - Mace S
FAU - Engelman, Jeffrey A
AU  - Engelman JA
FAU - Ruiz-Soto, Rodrigo
AU  - Ruiz-Soto R
FAU - Rockich, Kevin
AU  - Rockich K
FAU - Xu, Jianbo
AU  - Xu J
FAU - Shapiro, Geoffrey I
AU  - Shapiro GI
FAU - Martinez, Pablo
AU  - Martinez P
FAU - Felip, Enriqueta
AU  - Felip E
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Thorac Oncol
JT  - Journal of thoracic oncology : official publication of the International 
      Association for the Study of Lung Cancer
JID - 101274235
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 0 (Quinoxalines)
RN  - 0 (Sulfonamides)
RN  - 0 (XL765)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols
MH  - Cohort Studies
MH  - ErbB Receptors/antagonists & inhibitors
MH  - Erlotinib Hydrochloride
MH  - Female
MH  - Follow-Up Studies
MH  - Humans
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Neoplasm Staging
MH  - Neoplasms/*drug therapy/pathology
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Prognosis
MH  - Protein Kinase Inhibitors/pharmacokinetics/therapeutic use
MH  - Quinazolines/*pharmacokinetics/therapeutic use
MH  - Quinoxalines/*pharmacokinetics/therapeutic use
MH  - Safety
MH  - Sulfonamides/*pharmacokinetics/therapeutic use
MH  - Survival Rate
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Tissue Distribution
EDAT- 2014/02/06 06:00
MHDA- 2014/10/22 06:00
CRDT- 2014/02/06 06:00
PHST- 2014/02/06 06:00 [entrez]
PHST- 2014/02/06 06:00 [pubmed]
PHST- 2014/10/22 06:00 [medline]
AID - S1556-0864(15)30213-6 [pii]
AID - 10.1097/JTO.0000000000000088 [doi]
PST - ppublish
SO  - J Thorac Oncol. 2014 Mar;9(3):316-23. doi: 10.1097/JTO.0000000000000088.