Abstract
Purpose: 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. Experimental Design: 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.
Similar content being viewed by others
References
Knobbe CB, Merlo A, Reifenberger G: Pten signaling in gliomas. Neuro-oncol 4: 196–211, 2002
Sasaki H, Zlatescu MC, Betensky RA, Ino Y, Cairncross JG, Louis DN: PTEN is a target of chromosome 10q loss in anaplastic oligodendrogliomas and PTEN alterations are associated with poor prognosis. Am J Pathol 159: 359–367, 2001
Sano T, Lin H, Chen X, Langford LA, Koul D, Bondy ML, Hess KR, Myers JN, Hong YK, Yung WK, Steck PA: Differential expression of MMAC/PTEN in glioblastoma multiforme: Relationship to localization and prognosis. Cancer Res 59: 1820–1824, 1999
Smith JS, Tachibana I, Passe SM, Huntley BK, Borell TJ, Iturria N, O’Fallon JR, Schaefer PL, Scheithauer BW, James CD, Buckner JC, Jenkins RB: PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J Natl Cancer Inst 93: 1246–1256, 2001
Hidalgo M, Rowinsky EK: The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 19: 6680–6686, 2000
Chen J, Fang Y: A novel pathway regulating the mammalian target of rapamycin (mTOR) signaling. Biochem Pharmacol 64: 1071–1077, 2002
Schmelzle T, Hall MN: TOR, a central controller of cell growth. Cell 103: 253–262, 2000
Geoerger B, Kerr K, Tang CB, Fung KM, Powell B, Sutton LN, Phillips PC, Janss AJ: Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy. Cancer Res 61: 1527–1532, 2001
Chang SM, Kuhn J, Wen P, Greenberg H, Schiff D, Conrad C, Fink K, Robins HI, Cloughesy T, De Angelis L, Razier J, Hess K, Dancey J, Prados MD, North American Brain Tumor Consortium and the National Cancer Institute: Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs. Invest New Drugs (in press) 22: 427–435, 2004
Macdonald DR, Cascino TL, Schold SC, Jr, Cairncross JG: Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8: 1277–1280, 1990
Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR, Park Y, Liou SH, Marshall B, Boni JP, Dukart G, Sherman ML: Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22: 909–918, 2004
Lang FF, Gilbert MR, Puduvalli VK, Weinberg J, Levin VA, Yung WK, Sawaya R, Fuller GN, Conrad CA: Toward better early-phase brain tumor clinical trials: A reappraisal of current methods and proposals for future strategies. Neuro-oncol 4: 268–277, 2002
Gera JF, Mellinghoff IK, Shi Y, Rettig MB, Tran C, Hsu JH, Sawyers CL, Lichtenstein AK: AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression. J Biol Chem 279: 2737–2746, 2004
Choe G, Horvath S, Cloughesy TF, Crosby K, Seligson D, Palotie A, Inge L, Smith BL, Sawyers CL, Mischel PS: Analysis of the phosphatidylinositol 3’-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res 63: 2742–2746, 2003
Klingler-Hoffmann M, Bukczynska P, Tiganis T: Inhibition of phosphatidylinositol 3-kinase signaling negates the growth advantage imparted by a mutant epidermal growth factor receptor on human glioblastoma cells. Int J Cancer 105: 331–339, 2003
Schober R, Bilzer T, Waha A, Reifenberger G, Wechsler W, von Deimling A, Wiestler OD, Westphal M, Kemshead JT, Vega F, Delattre JY, Stasiecki-Steinfeld P: The epidermal growth factor receptor in glioblastoma: Genomic amplification, protein expression, and patient survival data in a therapeutic trial. Clin Neuropathol 14: 169–174, 1995
Huang S, Houghton PJ: Mechanisms of resistance to rapamycins. Drug Resist Updat 4: 378–391, 2001
Hosoi H, Dilling MB, Liu LN, Danks MK, Shikata T, Sekulic A, Abraham RT, Lawrence JC, Jr., Houghton PJ: Studies on the mechanism of resistance to rapamycin in human cancer cells. Mol Pharmacol 54: 815–824, 1998
Eshleman JS, Carlson BL, Mladek AC, Kastner BD, Shide KL, Sarkaria JN: Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. Cancer Res 62: 7291–7297, 2002
Grunwald V, DeGraffenried L, Russel D, Friedrichs WE, Ray RB, Hidalgo M: Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells. Cancer Res 62: 6141–6145, 2002
Tanaka M, Koul D, Davies MA, Liebert M, Steck PA, Grossman HB: MMAC1/PTEN inhibits cell growth and induces chemosensitivity to doxorubicin in human bladder cancer cells. Oncogene 19: 5406–5412, 2000
Author information
Authors and Affiliations
Consortia
Rights and permissions
About this article
Cite this article
Chang, S.M., Wen, P., Cloughesy, T. et al. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 23, 357–361 (2005). https://doi.org/10.1007/s10637-005-1444-0
Issue Date:
DOI: https://doi.org/10.1007/s10637-005-1444-0