Funded Grants

Phase II Clinical Trial of Perifosine + Temsirolimus for Recurrent Glioblastoma with Tissue and Imaging Correlates of Response


Glioblastoma (GBM) is the most common and most aggressive brain tumor in adults with an average survival of 15-18 months. Patients who respond well to initial therapy almost always suffer a recurrence. The past 25 years have seen only modest advances in the treatment and outcomes, and the search for more effective treatment is a priority.


While treatment options have not accelerated as rapidly as any of us would like, great strides have been made in understanding the molecular mechanisms contributing to GBM growth. This has led to development of new treatments. No single agent discovered yet impedes the progression of these aggressive tumors in a durable manner, but preliminary results suggest that combinations of drugs may slow (or reverse) GBM growth. We hope with your support to expand upon these initial findings, and to develop a new protocol for the treatment of GBM that will prolong survival.


The Columbia faculty is uniquely well suited to make progress in this area of investigation. Our outstanding clinicians and investigators bring a wealth of experience and knowledge to the challenges posed by GBM. They will be supported by the infrastructure and administration of Columbia University. As medicine grows increasingly collaborative, academic medical centers have the unique capacity to forge and foster investigative work between and across disciplines. Our proposal originates in the Department of Neurology, while drawing on resources from Neurosurgery, Pathology, Radiology, and the Herbert Irving Comprehensive Cancer Center.

Temsirolimus and mTOR; Perifosine and AKT

Approximately 70% of GBMs exhibit abnormally activated AKT signaling. AKT activates several targets including the mammalian target of rapamycin (mTOR), stimulating multiple oncogenic processes (Fig. 1). AKT and mTOR are crucial actors in the etiology and growth of brain tumors, and this signaling axis has emerged as a compelling molecular target in GBM.

Figure 1

Temsirolimus is a commercially available agent that is approved for use in kidney cancer. This agent inhibits mTOR, crosses the blood-brain barrier, and achieves therapeutic concentrations in brain tumor tissue.[1] However, it has only modest antitumor activity as a single agent in recurrent GBMs.[2, 3] One of the reasons temsirolimus alone is ineffective in treatment of GBMs is that inhibition of mTOR activates AKT through a feedback loop, which also drives GBM growth. [4-6] Our goal, then, is to allow temsirolimus to impede mTOR, while avoiding a simultaneous increase in AKT activation.

Perifosine is a recently developed drug designed to function as an AKT inhibitor.[7] It is being studied as a treatment for sarcoma, melanoma, and other cancers as well as brain tumors.[8-13] As is the case with inhibiting mTOR, impeding AKT alone with perifosine alone is insufficient in treating GBM.[14]

Our working hypothesis is that a combination of temsirolimus and perifosine will prove more effective against GBMs than either drug alone. Moreover, working together these agents will provide a more promising course of treatment than anything currently available pharmaceutically for patients with recurrent GBMs. A phase I trial of the combination, developed by the Principal Investigator of this grant (Andrew B. Lassman, MD) and conducted at Memorial Sloan-Kettering Cancer Center (MSKCC), is reaching its conclusion. Among 26 patients accrued to date, there was one dose limiting toxicity (thrombocytopenia) in a patient who was heavily pre-treated with myelosuppressive chemotherapy. There were no grade 4 (or 5) toxicities.[15] The maximum tolerated dose (MTD) of the combination therapy far exceeds the dose of temsirolimus that can be combined with other small molecule inhibitors such as sorafinib (25 mg weekly temsirolimus)[16] or erlotinib (15 mg weekly temsirolimus)[17]; the inability to give higher doses may have contributed to poor blood-brain-barrier penetration and lack of efficacy with these other combinations. Therefore, by the start of proposed funding through this grant, the recommended phase II dose for combination therapy will be defined. We are seeking funding for a phase II trial of this protocol.

  1. Kuhn, J.G., et al., Pharmacokinetic and tumor distribution characteristics of temsirolimus in patients with recurrent malignant glioma. Clin Cancer Res, 2007. 13 (24): p. 7401-6.
  2. Chang, S.M., et al., Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs, 2005. 23 (4): p. 357-61.
  3. Galanis, E., et al., Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol, 2005. 23 (23): p. 5294-304.
  4. Sun, S.Y., et al., Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res, 2005. 65 (16): p. 7052-8.
  5. O'Reilly, K.E., et al., mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res, 2006. 66 (3): p. 1500-8.
  6. Cloughesy, T.F., et al., Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med, 2008. 5 (1): p. e8.
  7. Kondapaka, S.B., et al., Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther, 2003. 2 (11): p. 1093-103.
  8. Bailey, H.H., et al., Phase II study of daily oral perifosine in patients with advanced soft tissue sarcoma. Cancer, 2006. 107 (10): p. 2462-7.
  9. Argiris, A., et al., A phase II trial of perifosine, an oral alkylphospholipid, in recurrent or metastatic head and neck cancer. Cancer Biol Ther, 2006. 5 (7): p. 766-70.
  10. Knowling, M., et al., A phase II study of perifosine (D-21226) in patients with previously untreated metastatic or locally advanced soft tissue sarcoma: A National Cancer Institute of Canada Clinical Trials Group trial. Invest New Drugs, 2006. 24 (5): p. 435-9.
  11. Posadas, E.M., et al., A phase II study of perifosine in androgen independent prostate cancer. Cancer Biol Ther, 2005. 4 (10): p. 1133-7.
  12. Ernst, D.S., et al., Phase II study of perifosine in previously untreated patients with metastatic melanoma. Invest New Drugs, 2005. 23 (6): p. 569-75.
  13. Van Ummersen, L., et al., A phase I trial of perifosine (NSC 639966) on a loading dose/maintenance dose schedule in patients with advanced cancer. Clin Cancer Res, 2004. 10 (22): p. 7450-6.
  14. Lassman, A.B., et al., Clinical and molecular-metabolic phase II trial of perifosine for recurrent/progressive malignant glioma [abstract MA-15] . Neuro Oncol, 2007. 9 (4): p. 518-519.
  15. Lassman, A.B., et al., Phase I trial of temsirolimus and perifosine for recurrent or progressive malignant glioma. Neuro Oncol, 2011. 13 (suppl 3): p. iii85-iii91.
  16. Wen, P.Y., et al., Phase I/II study of sorafenib and temsirolimus for patients with recurrent glioblastoma (GBM) (NABTC 05-02) [Abstract] . J Clin Oncol, 2009. 27 (15s): p. Supplement; Abstract 2006.
  17. Chang, S.M., et al., Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas (MG) (NABTC 04-02) [Abstract] . J Clin Oncol, 2009. 27 (15s; Abstract 2004).