Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma.
We evaluated the anti-tumor activity and safety of erlotinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent glioblastoma (GBM) in a phase 2, open-label, single-arm trial. Thirty-two patients received daily erlotinib and sirolimus. The doses of erlotinib and sirolimus were 150 mg and 5 mg for patients not on concurrent CYP3A-inducing anti-epileptics (EIAEDS), and 450 mg and 10 mg for patients on EIAEDS. Evaluations were performed every two months. The primary endpoint was 6-month progression-free survival and secondary endpoints included safety and overall survival. Archival tumor samples were assessed for EGFR, EGFRvIII, PTEN, pAKT and pS6. Enrolled patients were heavily pre-treated including 53% who had received three or more prior chemotherapy agents and 28% who had received prior bevacizumab therapy. The most common grade > or = 2 adverse events were rash (59%), mucositis (34%) and diarrhea (31%). Grade 3 or higher events were rare. Best radiographic response included stable disease in 15 patients (47%); no patients achieved either a CR or PR. The estimated 6-month progression-free survival was 3.1% for all patients. Progression-free survival was better for patients not on EIAEDs (P = 0.03). Tumor markers failed to show an association with PFS except for increased pAKT expression which achieved borderline significance (P = 0.045). Although neither rash nor diarrhea had an association with outcome, hyperlipidemia was associated with longer PFS (P = 0.029). Erlotinib plus sirolimus was well tolerated but had negligible activity among unselected recurrent GBM patients. (ClinicalTrials.gov number: NCT0062243).
Reardon
David A
DA
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA. reard003@mc.duke.edu
Desjardins
Annick
A
Vredenburgh
James J
JJ
Gururangan
Sridharan
S
Friedman
Allan H
AH
Herndon
James E
JE
Marcello
Jennifer
J
Norfleet
Julie A
JA
McLendon
Roger E
RE
Sampson
John H
JH
Friedman
Henry S
HS
D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D000069347:Erlotinib Hydrochloride; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D020123:Sirolimus / Q000627:therapeutic use*; D016896:Treatment Outcome
D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D020123:Sirolimus