title: Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02.
abstract: The activity of single-agent targeted molecular therapies in glioblastoma has been limited to date. The North American Brain Tumor Consortium examined the safety, pharmacokinetics, and efficacy of combination therapy with sorafenib, a small molecule inhibitor of Raf, vascular endothelial growth factor receptor 2, and platelet-derived growth factor receptor-β, and temsirolimus (CCI-779), an inhibitor of mammalian target of rapamycin. This was a phase I/II study. The phase I component used a standard 3 × 3 dose escalation scheme to determine the safety and tolerability of this combination therapy. The phase II component used a 2-stage design; the primary endpoint was 6-month progression-free survival (PFS6) rate. Thirteen patients enrolled in the phase I component. The maximum tolerated dosage (MTD) for combination therapy was sorafenib 800 mg daily and temsirolimus 25 mg once weekly. At the MTD, grade 3 thrombocytopenia was the dose-limiting toxicity. Eighteen patients were treated in the phase II component. At interim analysis, the study was terminated and did not proceed to the second stage. No patients remained progression free at 6 months. Median PFS was 8 weeks. The toxicity of this combination therapy resulted in a maximum tolerated dose of temsirolimus that was only one-tenth of the single-agent dose. Minimal activity in recurrent glioblastoma multiforme was seen at the MTD of the 2 combined agents.
authors.affiliation: Center for Neuro-Oncology, Dana Farber/Brigham and Women’s Cancer Center, Boston, Massachusetts 02215, USA.
authors.forename: Eudocia Q
authors.initials: EQ
authors.lastname: Lee
authors.forename: John
authors.initials: J
authors.lastname: Kuhn
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Lamborn
authors.forename: Lauren
authors.initials: L
authors.lastname: Abrey
authors.forename: Lisa M
authors.initials: LM
authors.lastname: DeAngelis
authors.forename: Frank
authors.initials: F
authors.lastname: Lieberman
authors.forename: H Ian
authors.initials: HI
authors.lastname: Robins
authors.forename: Susan M
authors.initials: SM
authors.lastname: Chang
authors.forename: W K Alfred
authors.initials: WK
authors.lastname: Yung
authors.forename: Jan
authors.initials: J
authors.lastname: Drappatz
authors.forename: Minesh P
authors.initials: MP
authors.lastname: Mehta
authors.forename: Victor A
authors.initials: VA
authors.lastname: Levin
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
authors.forename: Janet E
authors.initials: JE
authors.lastname: Dancey
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.forename: Mark R
authors.initials: MR
authors.lastname: Gilbert
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000077157:Sorafenib; D055815:Young Adult
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; C401859:temsirolimus; D000077157:Sorafenib; D020123:Sirolimus