title: Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme.
abstract: OBJECTIVE
  Loss of PTEN, which is common in glioblastoma multiforme (GBM), results in activation of the mammalian target of rapapmycin (mTOR), thereby increasing mRNA translation of a number of key proteins required for cell-cycle progression. CCI-779 is an inhibitor of mTOR. The primary objectives of this study were to determine the efficacy of CCI-779 in patients with recurrent GBM and to further assess the toxicity of the drug.
  
  
  METHODS
  CCI-779 was administered weekly at a dose of 250 mg intravenously for patients on enzyme-inducing anti-epileptic drugs (EIAEDs). Patients not on EIAEDs were initially treated at 250 mg; however, the dose was reduced to 170 mg because of intolerable side effects. Treatment was continued until unacceptable toxicity, tumor progression, or patient withdrawal. The primary endpoint was 6-month progression-free survival.
  
  
  RESULTS
  Forty-three patients were enrolled; 29 were not on EIAEDs. The expected toxicity profile of increased lipids, lymphopenia, and stomatitis was seen. There were no grade IV hematological toxicities and no toxic deaths. One patient was progression free at 6 months. Of the patients assessable for response, there were 2 partial responses and 20 with stabilization of disease. The median time to progression was 9 weeks.
  
  
  CONCLUSIONS
  CCI-779 was well tolerated at this dose schedule; however, there was no evidence of efficacy in patients with recurrent GBM. Despite initial disease stabilization in approximately 50% of patients, the durability of response was short. Because of the low toxicity profile, CCI-779 may merit exploration in combination with other modalities.
authors: University of California, San Francisco, San Francisco, CA 94143, USA. changs@neurosurg.ucsf.edu
authors: Susan M
authors: SM
authors: Chang
authors: Patrick
authors: P
authors: Wen
authors: Timothy
authors: T
authors: Cloughesy
authors: Harry
authors: H
authors: Greenberg
authors: David
authors: D
authors: Schiff
authors: Charles
authors: C
authors: Conrad
authors: Karen
authors: K
authors: Fink
authors: H Ian
authors: HI
authors: Robins
authors: Lisa
authors: L
authors: De Angelis
authors: Jeffrey
authors: J
authors: Raizer
authors: Kenneth
authors: K
authors: Hess
authors: Ken
authors: K
authors: Aldape
authors: Kathleen R
authors: KR
authors: Lamborn
authors: John
authors: J
authors: Kuhn
authors: Janet
authors: J
authors: Dancey
authors: Michael D
authors: MD
authors: Prados
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000927:Anticonvulsants / Q000008:administration & dosage / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D018572:Disease-Free Survival; D004347:Drug Interactions; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D006937:Hypercholesterolemia / Q000139:chemically induced; D007262:Infusions, Intravenous; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D000970:Antineoplastic Agents; C401859:temsirolimus; D020123:Sirolimus