title: Vandetanib plus sirolimus in adults with recurrent glioblastoma: results of a phase I and dose expansion cohort study.
abstract: Targeting specific molecular alterations in glioblastoma (GBM) might more effectively kill tumor cells and increase survival. Vandetanib inhibits epidermal growth factor receptor and vascular endothelial growth factor receptor 2. Sirolimus inhibits mammalian target of rapamycin (mTOR), a member the phosphoinositide 3-Kinase signaling pathway. We sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of vandetanib combined with sirolimus. Twenty-two patients (14 men; 8 women) with recurrent GBM enrolled. Median age and KPS were 52.5 years and 90 %, respectively. Patients were naive to anti-VEGF and anti-EGF therapy and mTOR inhibitors, and not on CYP3A4-inducing drugs. Vandetanib and sirolimus were orally administered on a continuous daily dosing schedule in escalating dose cohorts. Ten patients enrolled in the dose escalation phase. Twelve more enrolled at the MTD to explore progression-free survival at 6 months (PFS6) in a single arm, single stage phase II-type design. In total, 19 patients received at least one dose at the MTD, and 15 completed at least 1 cycle at MTD. MTD was 200 mg vandetanib plus 2 mg sirolimus. The DLT was elevated AST/SGOT. The most common toxicities were lymphopenia, fatigue, rash, and hypophosphatemia. For 19 patients who received at least one dose at the MTD, including seven from the phase I group, two had a partial response [10.5 %; 95 % CI (1, 33 %)] and PFS6 was 15.8 % [95 % CI (3.9, 34.9 %)]. Vandetanib and sirolimus can be safely co-administered on a continuous, daily dosing schedule.
authors.affiliation: Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Yawkey 9 East, 55 Fruit Street, Boston, MA, 02114, USA, chhedam@mskcc.org.
authors.forename: Milan G
authors.initials: MG
authors.lastname: Chheda
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.forename: Fred H
authors.initials: FH
authors.lastname: Hochberg
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Chi
authors.forename: Jan
authors.initials: J
authors.lastname: Drappatz
authors.forename: April F
authors.initials: AF
authors.lastname: Eichler
authors.forename: Daniel
authors.initials: D
authors.lastname: Yang
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Norden
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Gerstner
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Betensky
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D010880:Piperidines; D011799:Quinazolines; D020123:Sirolimus; C452423:vandetanib