TY - JOUR
T1 - Phase I dose-escalation study of pilaralisib (SAR245408, XL147), a pan-class I PI3K inhibitor, in combination with erlotinib in patients with solid tumors
AU - Soria, Jean Charles
AU - Lorusso, Patricia
AU - Bahleda, Ratislav
AU - Lager, Oanne
AU - Liu D, Li
AU - Jiang, Jason
AU - Martini, Jean François
AU - Mace, Sandrine
AU - Burri, Howard
N1 - Publisher Copyright:
© AlphaMed Press 2015.
PY - 2015/3/1
Y1 - 2015/3/1
N2 - Background. This phase I study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of pilaralisib (SAR245408), an oral pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, in combination with erlotinib, an epidermal growth factor receptor (EGFR) inhibitor. Methods. In a 3 + 3 dose-escalation study, patients with advanced solid tumors received pilaralisib capsules once daily (21 days per 28-day cycle; 50-600 mg) plus erlotinib tablets once daily (28 days per 28-day cycle; 100 or 150 mg). An MTD expansion cohort of patients with non-small cell lung cancer who had previously received treatment with an EGFR inhibitor was included. Results. Thirty-five patients were enrolled. Only one patient had an EGFR activating mutation. One dose-limiting toxicity was reported (grade4 drug reaction or rash with eosinophilia and systemic symptoms). MTD was pilaralisib 400 mg plus erlotinib 150 mg.The most commonly reported treatment-related adverse events were rash (62.9%), diarrhea (42.9%), and fatigue (40.0%). Pilaralisib PK findings were consistent with previous studies, suggesting erlotinib had no effect on pilaralisib pharmacokinetics. Pharmacodynamic analyses indicated moderate inhibition of PI3K, mitogen-activated protein kinase, and EGFR pathways. Of 27 evaluable patients, one had a partial response (3.7%) and 14 (51.9%) had stable disease. There was no association between molecular alterations of PI3K pathway components and clinical activity. Conclusion. Pilaralisib plus erlotinib had limited antitumor activity. Safety findings were similar to recent studies of single-agent pilaralisib or other PI3K inhibitors.
AB - Background. This phase I study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of pilaralisib (SAR245408), an oral pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, in combination with erlotinib, an epidermal growth factor receptor (EGFR) inhibitor. Methods. In a 3 + 3 dose-escalation study, patients with advanced solid tumors received pilaralisib capsules once daily (21 days per 28-day cycle; 50-600 mg) plus erlotinib tablets once daily (28 days per 28-day cycle; 100 or 150 mg). An MTD expansion cohort of patients with non-small cell lung cancer who had previously received treatment with an EGFR inhibitor was included. Results. Thirty-five patients were enrolled. Only one patient had an EGFR activating mutation. One dose-limiting toxicity was reported (grade4 drug reaction or rash with eosinophilia and systemic symptoms). MTD was pilaralisib 400 mg plus erlotinib 150 mg.The most commonly reported treatment-related adverse events were rash (62.9%), diarrhea (42.9%), and fatigue (40.0%). Pilaralisib PK findings were consistent with previous studies, suggesting erlotinib had no effect on pilaralisib pharmacokinetics. Pharmacodynamic analyses indicated moderate inhibition of PI3K, mitogen-activated protein kinase, and EGFR pathways. Of 27 evaluable patients, one had a partial response (3.7%) and 14 (51.9%) had stable disease. There was no association between molecular alterations of PI3K pathway components and clinical activity. Conclusion. Pilaralisib plus erlotinib had limited antitumor activity. Safety findings were similar to recent studies of single-agent pilaralisib or other PI3K inhibitors.
UR - http://www.scopus.com/inward/record.url?scp=84925409338&partnerID=8YFLogxK
U2 - 10.1634/theoncologist.2014-0449
DO - 10.1634/theoncologist.2014-0449
M3 - Article
C2 - 25669662
AN - SCOPUS:84925409338
SN - 1083-7159
VL - 20
SP - 245
EP - 246
JO - Oncologist
JF - Oncologist
IS - 3
ER -