Phase I safety and pharmacokinetic study of the PI3K/mTOR inhibitor SAR245409 (XL765) in combination with erlotinib in patients with advanced solid tumors.
BACKGROUND
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.


CONCLUSIONS
MTDs of SAR245409 and erlotinib were below the single-agent doses of either agent, despite the lack of major pharmacokinetic interaction.
*Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts; †Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania; ‡Translational Medicine, Exelixis, Inc., South San Francisco, San Francisco, California; §Translational and Experimental Medicine, Sanofi, Vitry-sur-Seine, France; ‖Center for Thoracic Centers, Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts; ¶Clinical Development Oncology, Sanofi, Cambridge, Massachusetts; #Pharmacokinetic Modeling and Simulation, Sanofi, Cambridge, Massachusetts; **Biostatistics and Programming, Sanofi, Cambridge, Massachusetts; ††Early Drug Development Center, Dana-Farber Cancer Institute, Boston, Massachusetts; ‡‡Department of Medical Oncology, Vall d'ebron University Hospital, Barcelona, Spain.
Pasi A
PA
Jänne
Roger B
RB
Cohen
A Douglas
AD
Laird
Sandrine
S
Macé
Jeffrey A
JA
Engelman
Rodrigo
R
Ruiz-Soto
Kevin
K
Rockich
Jianbo
J
Xu
Geoffrey I
GI
Shapiro
Pablo
P
Martinez
Enriqueta
E
Felip
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D015331:Cohort Studies; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D011799:Quinazolines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011810:Quinoxalines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012449:Safety; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution
D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011810:Quinoxalines; D013449:Sulfonamides; C576808:XL765; D000069347:Erlotinib Hydrochloride; C546842:MTOR protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases