This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Van Ummersen, L. Articles by Wilding, G. Search for Related Content PubMed PubMed Citation Articles by Van Ummersen, L. Articles by Wilding, G.

A Phase I Trial of Perifosine (NSC 639966) on a Loading Dose/Maintenance Dose Schedule in Patients with Advanced Cancer

Department of Medicine, University of Wisconsin, University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin

Perifosine (NSC 639966) is a synthetic, substituted heterocyclic alkylphosphocholine that acts primarily at the cell membrane targeting signal transduction pathways. Early clinical trials were limited because of dose-limiting gastrointestinal toxicity, and parenteral dosing of this class of agents is not possible because of their hemolytic properties; therefore, related compounds with an improved therapeutic index were developed. Toxicity was minimized and efficacy improved by using a loading dose/maintenance dose schedule, and therefore, this schedule was carried into clinical trials. This phase I trial enrolled 42 patients with incurable solid malignancies. The starting doses were 100 mg p.o. x four doses (every 6 hours) load followed by a 50 mg p.o. once daily maintenance dose with escalation of either component in successive dose levels. No treatment related deaths occurred. The maximum-tolerated dose was determined to be 150 mg p.o. x four doses load and 100 mg p.o. once daily maintenance. Dose-limiting toxicities such as nausea, diarrhea, dehydration, and fatigue were seen early during the loading phase and were surmountable with the use of prophylactic 5-HT₃ receptor antagonists, dexamethasone, and loperamide. Toxicities during the chronic phase were difficult to manage and, given that pharmacokinetic data showed biologically active serum concentrations (based on preclinical data), raised the question of less frequent maintenance dosing. Pharmacokinetic data confirmed the maintenance of stable drug levels with chronic dosing and the long half-life. One partial response was seen, as were multiple patients with stable disease beyond course 2. These results suggest perifosine activity in sarcoma and perhaps renal cell carcinoma (stable disease in two patients who continued for 6 and 14 courses), thus justifying additional investigation of this agent in a phase II sarcoma trial.

This article has been cited by other articles:

				P. A Dennis Targeting Akt in Cancer: Promise, Progress, and Potential Pitfalls Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 25 - 35. [Abstract] [Full Text] [PDF]

				R. L. Vinall, K. Hwa, P. Ghosh, C.-X. Pan, P. N. Lara Jr., and R. W. de Vere White Combination Treatment of Prostate Cancer Cell Lines with Bioactive Soy Isoflavones and Perifosine Causes Increased Growth Arrest and/or Apoptosis Clin. Cancer Res., October 15, 2007; 13(20): 6204 - 6216. [Abstract] [Full Text] [PDF]

				C. J. Ong, A. Ming-Lum, M. Nodwell, A. Ghanipour, L. Yang, D. E. Williams, J. Kim, L. Demirjian, P. Qasimi, J. Ruschmann, et al. Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells Blood, September 15, 2007; 110(6): 1942 - 1949. [Abstract] [Full Text] [PDF]

				H. A. Elrod, Y.-D. Lin, P. Yue, X. Wang, S. Lonial, F. R. Khuri, and S.-Y. Sun The alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of Akt and activation of the extrinsic apoptotic pathway Mol. Cancer Ther., July 1, 2007; 6(7): 2029 - 2038. [Abstract] [Full Text] [PDF]

				L. de la Pena, W. E. Burgan, D. J. Carter, M. G. Hollingshead, M. Satyamitra, K. Camphausen, and P. J. Tofilon Inhibition of Akt by the alkylphospholipid perifosine does not enhance the radiosensitivity of human glioma cells. Mol. Cancer Ther., June 1, 2006; 5(6): 1504 - 1510. [Abstract] [Full Text] [PDF]

				M. Nyakern, A. Cappellini, I. Mantovani, and A. M. Martelli Synergistic induction of apoptosis in human leukemia T cells by the Akt inhibitor perifosine and etoposide through activation of intrinsic and Fas-mediated extrinsic cell death pathways. Mol. Cancer Ther., June 1, 2006; 5(6): 1559 - 1570. [Abstract] [Full Text] [PDF]

				T. Hideshima, L. Catley, H. Yasui, K. Ishitsuka, N. Raje, C. Mitsiades, K. Podar, N. C. Munshi, D. Chauhan, P. G. Richardson, et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells Blood, May 15, 2006; 107(10): 4053 - 4062. [Abstract] [Full Text] [PDF]

				S. R. Vink, S. Lagerwerf, E. Mesman, J. H.M. Schellens, A. C. Begg, W. J. van Blitterswijk, and M. Verheij Radiosensitization of Squamous Cell Carcinoma by the Alkylphospholipid Perifosine in Cell Culture and Xenografts Clin. Cancer Res., March 1, 2006; 12(5): 1615 - 1622. [Abstract] [Full Text] [PDF]

				C. A. Granville, R. M. Memmott, J. J. Gills, and P. A. Dennis Handicapping the Race to Develop Inhibitors of the Phosphoinositide 3-Kinase/Akt/Mammalian Target of Rapamycin Pathway Clin. Cancer Res., February 1, 2006; 12(3): 679 - 689. [Abstract] [Full Text] [PDF]

				C Festuccia, P Muzi, D Millimaggi, L Biordi, G L Gravina, S Speca, A Angelucci, V Dolo, C Vicentini, and M Bologna Molecular aspects of gefitinib antiproliferative and pro-apoptotic effects in PTEN-positive and PTEN-negative prostate cancer cell lines Endocr. Relat. Cancer, December 1, 2005; 12(4): 983 - 998. [Abstract] [Full Text] [PDF]

				H. Momota, E. Nerio, and E. C. Holland Perifosine Inhibits Multiple Signaling Pathways in Glial Progenitors and Cooperates With Temozolomide to Arrest Cell Proliferation in Gliomas In vivo Cancer Res., August 15, 2005; 65(16): 7429 - 7435. [Abstract] [Full Text] [PDF]

				S. J. Cohen, R. B. Cohen, and N. J. Meropol Targeting Signal Transduction Pathways in Colorectal Cancer--More Than Skin Deep J. Clin. Oncol., August 10, 2005; 23(23): 5374 - 5385. [Abstract] [Full Text] [PDF]