Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme.
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.
Chang
Susan M
SM
University of California, San Francisco, San Francisco, CA 94143, USA. changs@neurosurg.ucsf.edu
Wen
Patrick
P
Cloughesy
Timothy
T
Greenberg
Harry
H
Schiff
David
D
Conrad
Charles
C
Fink
Karen
K
Robins
H Ian
HI
De Angelis
Lisa
L
Raizer
Jeffrey
J
Hess
Kenneth
K
Aldape
Ken
K
Lamborn
Kathleen R
KR
Kuhn
John
J
Dancey
Janet
J
Prados
Michael D
MD
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
D000927:Anticonvulsants; D000970:Antineoplastic Agents; C401859:temsirolimus; D020123:Sirolimus