Phase I dose-escalation study of pilaralisib (SAR245408, XL147), a pan-class I PI3K inhibitor, in combination with erlotinib in patients with solid tumors.

Abstract

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 (grade 4 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.

• Authors: Jean-Charles Soria, Patricia LoRusso, Ratislav Bahleda, Joanne Lager, Li Liu, Jason Jiang, Jean-François Martini, Sandrine Macé, Howard Burris
• Journal: The oncologist (Oncologist) Vol. 20 Issue 3 Pg. 245-6 (Mar 2015) ISSN: 1549-490X [Electronic] England
• PMID: 25669662 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: ©AlphaMed Press; the data published online to support this summary is the property of the authors.

Chemical References

• Phosphoinositide-3 Kinase Inhibitors
• Quinazolines
• Quinoxalines
• Sulfonamides
• XL147
• Erlotinib Hydrochloride

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy)
• Dose-Response Relationship, Drug
• Erlotinib Hydrochloride
• Female
• Humans
• Lung Neoplasms (drug therapy)
• Male
• Phosphoinositide-3 Kinase Inhibitors
• Quinazolines (administration & dosage, pharmacokinetics)
• Quinoxalines (administration & dosage, pharmacokinetics)
• Sulfonamides (administration & dosage, pharmacokinetics)
• Treatment Outcome