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Oncologist. 2015 Mar;20(3):245-6. doi: 10.1634/theoncologist.2014-0449. Epub 2015 Feb 10.

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

Author information

1
Gustave Roussy, Drug Development Department (DITEP), Villejuif, France; jean-charles.soria@igr.fr.
2
Yale Smilow Cancer Center, New Haven, Connecticut, USA;
3
Gustave Roussy, Drug Development Department (DITEP), Villejuif, France;
4
Sanofi, Cambridge, Massachusetts, USA;
5
Sanofi, Bridgewater, New Jersey, USA;
6
Exelixis Inc., South San Francisco, California, USA;
7
Sanofi, Vitry sur Seine, France;
8
Sarah Cannon Research Institute, Nashville, Tennessee, USA.

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00692640.

PMID:
25669662
PMCID:
PMC4350809
DOI:
10.1634/theoncologist.2014-0449
[Indexed for MEDLINE]
Free PMC Article

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