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Tipifarnib

Deacription of Tipifarnib: Tipifarnib is a nonpeptidomimetic quinolinone with potential antineoplastic activity. Tipifarnib binds to and inhibits the enzyme farnesyl protein transferase, an enzyme involved in protein processing (farnesylation) for signal transduction. By inhibiting the farnesylation of proteins, this agent prevents the activation of Ras oncogenes, inhibits cell growth, induces apoptosis, and inhibits angiogenesis. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

Development status of Tipifarnib:  Tipifarnib was submitted to the FDA by Johnson & Johnson for the treatment of AML in patients aged 65 and over with a New Drug Application (NDA) to the Food and Drug Administration (FDA) on January 24, 2005. In June 2005, the FDA issued a "not approvable" letter for tipifarnib. However, research and clinical trials have been actively  continued. 

Current developer:  Johnson & Johnson Pharmaceutical Research & Development, L.L.C

Tipifarnib (Zarnestra) is a farnesyltransferase inhibitor that is being investigated in patients 65 years of age and older with newly diagnosed acute myeloid leukemia (AML). It is also being tested in clinical trials in patients in certain stages of breast cancer. According to http://en.wikipedia.org/wiki/Tipifarnib, Tipifarnib was submitted to the FDA by Johnson & Johnson for the treatment of AML in patients aged 65 and over with a New Drug Application (NDA) to the Food and Drug Administration (FDA) on January 24, 2005. In June 2005, the FDA issued a "not approvable" letter for tipifarnib. However, Research and clinical trials have been actively continued.

New Phase II trials using tipifarnib plus etoposide:  Tipifarnib (T) exhibits modest activity in elderly adults with newly diagnosed acute myelogenous leukemia (AML). Based on preclinical synergy, a phase 1 trial of T plus etoposide (E) yielded 25% complete remission (CR). We selected 2 comparable dose levels for a randomized phase 2 trial in 84 adults (age range, 70-90 years; median, 76 years) who were not candidates for conventional chemotherapy. Arm A (T 600 mg twice a day × 14 days, E 100 mg days 1-3 and 8-10) and arm B (T 400 mg twice a day × 14 days, E 200 mg days 1-3 and 8-10) yielded similar CR, but arm B had greater toxicity. Total CR was 25%, day 30 death rate 7%. A 2-gene signature of high RASGRP1 and low aprataxin (APTX) expression previously predicted for T response. Assays using blasts from a subset of 40 patients treated with T plus E on this study showed that AMLs with a RASGRP1/APTX ratio of more than 5.2 had a 78% CR rate and negative predictive value 87%. This ratio did not correlate with outcome in 41 patients treated with conventional chemotherapies. The next T-based clinical trials will test the ability of the 2-gene signature to enrich for T responders prospectively. This study is registered at www.clinicaltrials.gov as #NCT00602771. (source: Blood. 2012 Jan 5;119(1):55-63).

 1: Margolin KA, Moon J, Flaherty LE, Lao CD, Akerley WL 3rd, Othus M, Sosman JA, Kirkwood JM, Sondak VK. Randomized Phase II Trial of Sorafenib with Temsirolimus or Tipifarnib in Untreated Metastatic Melanoma (S0438). Clin Cancer Res. 2012 Feb 7. [Epub ahead of print] PubMed PMID: 22228638.

2: Ruchlemer R. Two genes, tipifarnib, and AML. Blood. 2012 Jan 5;119(1):2-3. PubMed PMID: 22223817.

3: Krzykowska-Petitjean K, Małecki J, Bentke A, Ostrowska B, Laidler P. Tipifarnib and tanespimycin show synergic proapoptotic activity in U937 cells. J Cancer Res Clin Oncol. 2011 Dec 31. [Epub ahead of print] PubMed PMID: 22209975.

4: Karp JE, Vener TI, Raponi M, Ritchie EK, Smith BD, Gore SD, Morris LE, Feldman EJ, Greer JM, Malek S, Carraway HE, Ironside V, Galkin S, Levis MJ, McDevitt MA, Roboz GR, Gocke CD, Derecho C, Palma J, Wang Y, Kaufmann SH, Wright JJ, Garret-Mayer E. Multi-institutional phase 2 clinical and pharmacogenomic trial of tipifarnib plus etoposide for elderly adults with newly diagnosed acute myelogenous leukemia. Blood. 2012 Jan 5;119(1):55-63. Epub 2011 Oct 14. PubMed PMID: 22001391.

5: Bai F, Villagra AV, Zou J, Painter JS, Connolly K, Blaskovich MA, Sokol L, Sebti S, Djeu JY, Loughran TP, Wei S, Sotomayor E, Epling-Burnette P. Tipifarnib-mediated suppression of T-bet-dependent signaling pathways. Cancer Immunol Immunother. 2011 Oct 9. [Epub ahead of print] PubMed PMID: 21983879.

6: Witzig TE, Tang H, Micallef IN, Ansell SM, Link BK, Inwards DJ, Porrata LF, Johnston PB, Colgan JP, Markovic SN, Nowakowski GS, Thompson CA, Allmer C, Maurer MJ, Gupta M, Weiner G, Hohl R, Kurtin PJ, Ding H, Loegering D, Schneider P, Peterson K, Habermann TM, Kaufmann SH. Multi-institutional phase 2 study of the farnesyltransferase inhibitor tipifarnib (R115777) in patients with relapsed and refractory lymphomas. Blood. 2011 Nov 3;118(18):4882-9. Epub 2011 Jul 1. PubMed PMID: 21725056; PubMed Central PMCID: PMC3208296.

7: Kirschbaum MH, Synold T, Stein AS, Tuscano J, Zain JM, Popplewell L, Karanes C, O'Donnell MR, Pulone B, Rincon A, Wright J, Frankel P, Forman SJ, Newman EM. A phase 1 trial dose-escalation study of tipifarnib on a week-on, week-off schedule in relapsed, refractory or high-risk myeloid leukemia. Leukemia. 2011 Oct;25(10):1543-7. doi: 10.1038/leu.2011.124. Epub 2011 May 31. PubMed PMID: 21625235; PubMed Central PMCID: PMC3165084.

8: Marcuzzi A, De Leo L, Decorti G, Crovella S, Tommasini A, Pontillo A. The farnesyltransferase inhibitors tipifarnib and lonafarnib inhibit cytokines secretion in a cellular model of mevalonate kinase deficiency. Pediatr Res. 2011 Jul;70(1):78-82. PubMed PMID: 21430599.

9: Yanamandra N, Buzzeo RW, Gabriel M, Hazlehurst LA, Mari Y, Beaupre DM, Cuevas J. Tipifarnib-induced apoptosis in acute myeloid leukemia and multiple myeloma cells depends on Ca2+ influx through plasma membrane Ca2+ channels. J Pharmacol Exp Ther. 2011 Jun;337(3):636-43. Epub 2011 Mar 4. PubMed PMID: 21378206; PubMed Central PMCID: PMC3101005.

10: Haas-Kogan DA, Banerjee A, Poussaint TY, Kocak M, Prados MD, Geyer JR, Fouladi M, Broniscer A, Minturn JE, Pollack IF, Packer RJ, Boyett JM, Kun LE. Phase II trial of tipifarnib and radiation in children with newly diagnosed diffuse intrinsic pontine gliomas. Neuro Oncol. 2011 Mar;13(3):298-306. PubMed PMID: 21339191; PubMed Central PMCID: PMC3064607.

11: Hong DS, Cabanillas ME, Wheler J, Naing A, Tsimberidou AM, Ye L, Waguespack SG, Hernandez M, El Naggar AK, Bidyasar S, Wright J, Sherman SI, Kurzrock R, Busaidy NL. Inhibition of the Ras/Raf/MEK/ERK and RET kinase pathways with the combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in medullary and differentiated thyroid malignancies. J Clin Endocrinol Metab. 2011 Apr;96(4):997-1005. Epub 2011 Feb 2. Erratum in: J Clin Endocrinol Metab. 2011 Jul;96(7):2286. Busaidy, Naifa L [added]; El Naggar, Alder K [corrected to El Naggar, Adel K]. PubMed PMID: 21289252; PubMed Central PMCID: PMC3070247.

12: Lancet JE, Duong VH, Winton EF, Stuart RK, Burton M, Zhang S, Cubitt C, Blaskovich MA, Wright JJ, Sebti S, Sullivan DM. A phase I clinical-pharmacodynamic study of the farnesyltransferase inhibitor tipifarnib in combination with the proteasome inhibitor bortezomib in advanced acute leukemias. Clin Cancer Res. 2011 Mar 1;17(5):1140-6. Epub 2011 Jan 13. PubMed PMID: 21233404; PubMed Central PMCID: PMC3049960.

13: Jabbour E, Kantarjian H, Ravandi F, Garcia-Manero G, Estrov Z, Verstovsek S, O'Brien S, Faderl S, Thomas DA, Wright JJ, Cortes J. A phase 1-2 study of a farnesyltransferase inhibitor, tipifarnib, combined with idarubicin and cytarabine for patients with newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome. Cancer. 2011 Mar 15;117(6):1236-44. doi: 10.1002/cncr.25575. Epub 2010 Oct 19. PubMed PMID: 20960519.

14: Nghiemphu PL, Wen PY, Lamborn KR, Drappatz J, Robins HI, Fink K, Malkin MG, Lieberman FS, DeAngelis LM, Torres-Trejo A, Chang SM, Abrey L, Fine HA, Demopoulos A, Lassman AB, Kesari S, Mehta MP, Prados MD, Cloughesy TF; North American Brain Tumor Consortium. A phase I trial of tipifarnib with radiation therapy, with and without temozolomide, for patients with newly diagnosed glioblastoma. Int J Radiat Oncol Biol Phys. 2011 Dec 1;81(5):1422-7. Epub 2010 Oct 8. PubMed PMID: 20934264; PubMed Central PMCID: PMC3020272.

15: Widemann BC, Arceci RJ, Jayaprakash N, Fox E, Zannikos P, Goodspeed W, Goodwin A, Wright JJ, Blaney SM, Adamson PC, Balis FM. Phase 1 trial and pharmacokinetic study of the farnesyl transferase inhibitor tipifarnib in children and adolescents with refractory leukemias: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2011 Feb;56(2):226-33. doi: 10.1002/pbc.22775. Epub 2010 Sep 21. PubMed PMID: 20860038; PubMed Central PMCID: PMC3271115.

16: David E, Kaufman JL, Flowers CR, Schafer-Hales K, Torre C, Chen J, Marcus AI, Sun SY, Boise LH, Lonial S. Tipifarnib sensitizes cells to proteasome inhibition by blocking degradation of bortezomib-induced aggresomes. Blood. 2010 Dec 9;116(24):5285-8. Epub 2010 Sep 15. PubMed PMID: 20844234.

17: Kraus JM, Tatipaka HB, McGuffin SA, Chennamaneni NK, Karimi M, Arif J, Verlinde CL, Buckner FS, Gelb MH. Second generation analogues of the cancer drug clinical candidate tipifarnib for anti-Chagas disease drug discovery. J Med Chem. 2010 May 27;53(10):3887-98. PubMed PMID: 20429511; PubMed Central PMCID: PMC2877169.

18: Biagi C, Astolfi A, Masetti R, Serravalle S, Franzoni M, Chiarini F, Melchionda F, Pession A. Pediatric early T-cell precursor leukemia with NF1 deletion and high-sensitivity in vitro to tipifarnib. Leukemia. 2010 Jun;24(6):1230-3. Epub 2010 Apr 29. PubMed PMID: 20428205.

19: Epling-Burnette PK, Loughran TP Jr. Suppression of farnesyltransferase activity in acute myeloid leukemia and myelodysplastic syndrome: current understanding and recommended use of tipifarnib. Expert Opin Investig Drugs. 2010 May;19(5):689-98. Review. PubMed PMID: 20402600; PubMed Central PMCID: PMC3252817.

20: Dalenc F, Doisneau-Sixou SF, Allal BC, Marsili S, Lauwers-Cances V, Chaoui K, Schiltz O, Monsarrat B, Filleron T, Renée N, Malissein E, Meunier E, Favre G, Roché H. Tipifarnib plus tamoxifen in tamoxifen-resistant metastatic breast cancer: a negative phase II and screening of potential therapeutic markers by proteomic analysis. Clin Cancer Res. 2010 Feb 15;16(4):1264-71. Epub 2010 Feb 9. PubMed PMID: 20145184.

21: Nagai T, Ohmine K, Fujiwara S, Uesawa M, Sakurai C, Ozawa K. Combination of tipifarnib and rapamycin synergistically inhibits the growth of leukemia cells and overcomes resistance to tipifarnib via alteration of cellular signaling pathways. Leuk Res. 2010 Aug;34(8):1057-63. Epub 2010 Jan 13. PubMed PMID: 20071026.

22: Rolland D, Ribrag V, Haioun C, Ghesquieres H, Jardin F, Bouabdallah R, Franchi P, Briere J, De Kerviler E, Chassagne-Clement C, Raponi M, Houlgatte R, Jais JP, Thieblemont C. Phase II trial and prediction of response of single agent tipifarnib in patients with relapsed/refractory mantle cell lymphoma: a Groupe d'Etude des Lymphomes de l'Adulte trial. Cancer Chemother Pharmacol. 2010 Mar;65(4):781-90. Epub 2009 Dec 4. PubMed PMID: 19960345.

23: Hong DS, Sebti SM, Newman RA, Blaskovich MA, Ye L, Gagel RF, Moulder S, Wheler JJ, Naing A, Tannir NM, Ng CS, Sherman SI, El Naggar AK, Khan R, Trent J, Wright JJ, Kurzrock R. Phase I trial of a combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in advanced malignancies. Clin Cancer Res. 2009 Nov 15;15(22):7061-8. Epub 2009 Nov 10. PubMed PMID: 19903778; PubMed Central PMCID: PMC2784003.

24: Chennamaneni NK, Arif J, Buckner FS, Gelb MH. Isoquinoline-based analogs of the cancer drug clinical candidate tipifarnib as anti-Trypanosoma cruzi agents. Bioorg Med Chem Lett. 2009 Dec 1;19(23):6582-4. Epub 2009 Oct 13. PubMed PMID: 19875282; PubMed Central PMCID: PMC2783978.

25: Karp JE, Lancet JE. Tipifarnib in the treatment of newly diagnosed acute myelogenous leukemia. Biologics. 2008 Sep;2(3):491-500. PubMed PMID: 19707379; PubMed Central PMCID: PMC2721391.

26: Harousseau JL, Martinelli G, Jedrzejczak WW, Brandwein JM, Bordessoule D, Masszi T, Ossenkoppele GJ, Alexeeva JA, Beutel G, Maertens J, Vidriales MB, Dombret H, Thomas X, Burnett AK, Robak T, Khuageva NK, Golenkov AK, Tothova E, Mollgard L, Park YC, Bessems A, De Porre P, Howes AJ; FIGHT-AML-301 Investigators. A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older. Blood. 2009 Aug 6;114(6):1166-73. Epub 2009 May 21. PubMed PMID: 19470696.

27: Ferrara F. Tipifarnib and etoposide for older AML patients: from bench to bedside. Blood. 2009 May 14;113(20):4824-5. PubMed PMID: 19443668.

28: van der Weide K, de Jonge-Peeters SD, Kuipers F, de Vries EG, Vellenga E. Combining simvastatin with the farnesyltransferase inhibitor tipifarnib results in an enhanced cytotoxic effect in a subset of primary CD34+ acute myeloid leukemia samples. Clin Cancer Res. 2009 May 1;15(9):3076-83. Epub 2009 Apr 21. PubMed PMID: 19383813.

29: Sparano JA, Moulder S, Kazi A, Coppola D, Negassa A, Vahdat L, Li T, Pellegrino C, Fineberg S, Munster P, Malafa M, Lee D, Hoschander S, Hopkins U, Hershman D, Wright JJ, Kleer C, Merajver S, Sebti SM. Phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide in patients with clinical stage IIB-IIIC breast cancer. Clin Cancer Res. 2009 Apr 15;15(8):2942-8. Epub 2009 Apr 7. PubMed PMID: 19351752; PubMed Central PMCID: PMC2785076.

30: Möller I, Blum S, Gattermann N, Haas R, Habersang K, Germing U, Kuendgen A. Repeated responses of an elderly patient with high-risk myelodysplastic syndrome to sequential therapy with tipifarnib, 5-azacitidine, and decitabine. Ann Hematol. 2009 Nov;88(11):1141-4. Epub 2009 Mar 17. PubMed PMID: 19290525.

31: Li T, Christos PJ, Sparano JA, Hershman DL, Hoschander S, O'Brien K, Wright JJ, Vahdat LT. Phase II trial of the farnesyltransferase inhibitor tipifarnib plus fulvestrant in hormone receptor-positive metastatic breast cancer: New York Cancer Consortium Trial P6205. Ann Oncol. 2009 Apr;20(4):642-7. Epub 2009 Jan 19. PubMed PMID: 19153124; PubMed Central PMCID: PMC2660860.

32: Karp JE, Flatten K, Feldman EJ, Greer JM, Loegering DA, Ricklis RM, Morris LE, Ritchie E, Smith BD, Ironside V, Talbott T, Roboz G, Le SB, Meng XW, Schneider PA, Dai NT, Adjei AA, Gore SD, Levis MJ, Wright JJ, Garrett-Mayer E, Kaufmann SH. Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide. Blood. 2009 May 14;113(20):4841-52. Epub 2008 Dec 24. PubMed PMID: 19109557; PubMed Central PMCID: PMC2686135.

33: Brandwein JM, Leber BF, Howson-Jan K, Schimmer AD, Schuh AC, Gupta V, Yee KW, Wright J, Moore M, MacAlpine K, Minden MD; NCI CTEP Protocol 6670. A phase I study of tipifarnib combined with conventional induction and consolidation therapy for previously untreated patients with acute myeloid leukemia aged 60 years and over. Leukemia. 2009 Apr;23(4):631-4. Epub 2008 Dec 18. PubMed PMID: 19092853.

34: Kotsianidis I, Bazdiara I, Anastasiades A, Spanoudakis E, Pantelidou D, Margaritis D, Bourikas G, De Coster R, De Porre P, Tsatalas C. In vitro effects of the farnesyltransferase inhibitor tipifarnib on myelodysplastic syndrome progenitors. Acta Haematol. 2008;120(1):51-6. Epub 2008 Sep 30. PubMed PMID: 18824842.

35: Lustig R, Mikkelsen T, Lesser G, Grossman S, Ye X, Desideri S, Fisher J, Wright J; New Approaches to Brain Tumor Therapy CNS Consortium. Phase II preradiation R115777 (tipifarnib) in newly diagnosed GBM with residual enhancing disease. Neuro Oncol. 2008 Dec;10(6):1004-9. Epub 2008 Aug 25. PubMed PMID: 18725460; PubMed Central PMCID: PMC2718997.

36: Hong DS, Reddy SB, Prieto VG, Wright JJ, Tannir NM, Cohen PR, Diwan AH, Evans HL, Kurzrock R. Multiple squamous cell carcinomas of the skin after therapy with sorafenib combined with tipifarnib. Arch Dermatol. 2008 Jun;144(6):779-82. PubMed PMID: 18559769.

37: Martinelli G, Iacobucci I, Paolini S, Ottaviani E. Farnesyltransferase inhibition in hematologic malignancies: the clinical experience with tipifarnib. Clin Adv Hematol Oncol. 2008 Apr;6(4):303-10. Review. PubMed PMID: 18496498.

38: Karp JE, Smith BD, Gojo I, Lancet JE, Greer J, Klein M, Morris L, Levis MJ, Gore SD, Wright JJ, Garrett-Mayer E. Phase II trial of tipifarnib as maintenance therapy in first complete remission in adults with acute myelogenous leukemia and poor-risk features. Clin Cancer Res. 2008 May 15;14(10):3077-82. PubMed PMID: 18483374; PubMed Central PMCID: PMC3074480.

39: Hong D, Ye L, Gagel R, Chintala L, El Naggar AK, Wright J, Kurzrock R. Medullary thyroid cancer: targeting the RET kinase pathway with sorafenib/tipifarnib. Mol Cancer Ther. 2008 May;7(5):1001-6. Epub 2008 Apr 29. PubMed PMID: 18445656.

40: Haas-Kogan DA, Banerjee A, Kocak M, Prados MD, Geyer JR, Fouladi M, McKnight T, Poussaint TY, Broniscer A, Blaney SM, Boyett JM, Kun LE. Phase I trial of tipifarnib in children with newly diagnosed intrinsic diffuse brainstem glioma. Neuro Oncol. 2008 Jun;10(3):341-7. Epub 2008 Apr 16. PubMed PMID: 18417739; PubMed Central PMCID: PMC2563056.

41: Kurzrock R, Kantarjian HM, Blascovich MA, Bucher C, Verstovsek S, Wright JJ, Pilat SR, Cortes JE, Estey EH, Giles FJ, Beran M, Sebti SM. Phase I study of alternate-week administration of tipifarnib in patients with myelodysplastic syndrome. Clin Cancer Res. 2008 Jan 15;14(2):509-14. PubMed PMID: 18223226.

42: Burnett AK, Kell J. Tipifarnib in acute myeloid leukemia. Drugs Today (Barc). 2007 Nov;43(11):795-800. PubMed PMID: 18174965.

43: Raponi M, Lancet JE, Fan H, Dossey L, Lee G, Gojo I, Feldman EJ, Gotlib J, Morris LE, Greenberg PL, Wright JJ, Harousseau JL, Löwenberg B, Stone RM, De Porre P, Wang Y, Karp JE. A 2-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia. Blood. 2008 Mar 1;111(5):2589-96. Epub 2007 Dec 26. PubMed PMID: 18160667.

44: Thomas X, Elhamri M. Tipifarnib in the treatment of acute myeloid leukemia. Biologics. 2007 Dec;1(4):415-24. PubMed PMID: 19707311; PubMed Central PMCID: PMC2721284.

45: Fouladi M, Nicholson HS, Zhou T, Laningham F, Helton KJ, Holmes E, Cohen K, Speights RA, Wright J, Pollack IF; Children's Oncology Group. A phase II study of the farnesyl transferase inhibitor, tipifarnib, in children with recurrent or progressive high-grade glioma, medulloblastoma/primitive neuroectodermal tumor, or brainstem glioma: a Children's Oncology Group study. Cancer. 2007 Dec 1;110(11):2535-41. PubMed PMID: 17932894.

46: Martin LA, Head JE, Pancholi S, Salter J, Quinn E, Detre S, Kaye S, Howes A, Dowsett M, Johnston SR. The farnesyltransferase inhibitor R115777 (tipifarnib) in combination with tamoxifen acts synergistically to inhibit MCF-7 breast cancer cell proliferation and cell cycle progression in vitro and in vivo. Mol Cancer Ther. 2007 Sep;6(9):2458-67. PubMed PMID: 17876043.

47: Johnston SR, Semiglazov VF, Manikhas GM, Spaeth D, Romieu G, Dodwell DJ, Wardley AM, Neven P, Bessems A, Park YC, De Porre PM, Perez Ruixo JJ, Howes AJ. A phase II, randomized, blinded study of the farnesyltransferase inhibitor tipifarnib combined with letrozole in the treatment of advanced breast cancer after antiestrogen therapy. Breast Cancer Res Treat. 2008 Jul;110(2):327-35. Epub 2007 Sep 13. PubMed PMID: 17851757.

48: Cortes J, Quintás-Cardama A, Garcia-Manero G, O'Brien S, Jones D, Faderl S, Ebarb T, Giles F, Thomas D, Kantarjian H. Phase 1 study of tipifarnib in combination with imatinib for patients with chronic myelogenous leukemia in chronic phase after imatinib failure. Cancer. 2007 Nov 1;110(9):2000-6. PubMed PMID: 17849425.

49: Miyoshi T, Nagai T, Kikuchi S, Ohmine K, Nakamura M, Hanafusa T, Komatsu N, Ozawa K. Cloning and characterization of a human BCR/ABL-positive cell line, K562/RR, resistant to the farnesyltransferase inhibition by tipifarnib. Exp Hematol. 2007 Sep;35(9):1358-65. Epub 2007 Jul 25. PubMed PMID: 17656006.

50: Mesa RA, Camoriano JK, Geyer SM, Wu W, Kaufmann SH, Rivera CE, Erlichman C, Wright J, Pardanani A, Lasho T, Finke C, Li CY, Tefferi A. A phase II trial of tipifarnib in myelofibrosis: primary, post-polycythemia vera and post-essential thrombocythemia. Leukemia. 2007 Sep;21(9):1964-70. Epub 2007 Jun 21. PubMed PMID: 17581608.

51: Moyal EC, Laprie A, Delannes M, Poublanc M, Catalaa I, Dalenc F, Berchery D, Sabatier J, Bousquet P, De Porre P, Alaux B, Toulas C. Phase I trial of tipifarnib (R115777) concurrent with radiotherapy in patients with glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 2007 Aug 1;68(5):1396-401. Epub 2007 Jun 14. PubMed PMID: 17570606.

52: Awada A, Zhang S, Gil T, de Valeriola D, Lalami Y, De Porre P, Piccart-Gebhart MJ. A phase I clinical and pharmacokinetic study of tipifarnib in combination with docetaxel in patients with advanced solid malignancies. Curr Med Res Opin. 2007 May;23(5):991-1003. PubMed PMID: 17519066.

53: Armand JP, Burnett AK, Drach J, Harousseau JL, Löwenberg B, San Miguel J. The emerging role of targeted therapy for hematologic malignancies: update on bortezomib and tipifarnib. Oncologist. 2007 Mar;12(3):281-90. Review. PubMed PMID: 17405892.

54: Raponi M, Harousseau JL, Lancet JE, Löwenberg B, Stone R, Zhang Y, Rackoff W, Wang Y, Atkins D. Identification of molecular predictors of response in a study of tipifarnib treatment in relapsed and refractory acute myelogenous leukemia. Clin Cancer Res. 2007 Apr 1;13(7):2254-60. PubMed PMID: 17404110.

55: Perez-Ruixo JJ, Chen W, Zhang S, Hayes S, Chow A. Exposure-toxicity relationships for tipifarnib in cancer patients. Br J Clin Pharmacol. 2007 Aug;64(2):219-32. Epub 2007 Mar 22. PubMed PMID: 17378913; PubMed Central PMCID: PMC2000631.

56: Harousseau JL, Lancet JE, Reiffers J, Lowenberg B, Thomas X, Huguet F, Fenaux P, Zhang S, Rackoff W, De Porre P, Stone R; Farnesyltransferase Inhibition Global Human Trials (FIGHT) Acute Myeloid Leukemia Study Group. A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib in patients with refractory or relapsed acute myeloid leukemia. Blood. 2007 Jun 15;109(12):5151-6. Epub 2007 Mar 9. PubMed PMID: 17351110.

57: Jabbour E, Kantarjian H, Cortes J. Clinical activity of tipifarnib in hematologic malignancies. Expert Opin Investig Drugs. 2007 Mar;16(3):381-92. Review. PubMed PMID: 17302532.

58: Medeiros BC, Landau HJ, Morrow M, Lockerbie RO, Pitts T, Eckhardt SG. The farnesyl transferase inhibitor, tipifarnib, is a potent inhibitor of the MDR1 gene product, P-glycoprotein, and demonstrates significant cytotoxic synergism against human leukemia cell lines. Leukemia. 2007 Apr;21(4):739-46. Epub 2007 Feb 1. PubMed PMID: 17268526.

59: Fenaux P, Raza A, Mufti GJ, Aul C, Germing U, Kantarjian H, Cripe L, Kerstens R, De Porre P, Kurzrock R. A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome. Blood. 2007 May 15;109(10):4158-63. Epub 2007 Jan 30. PubMed PMID: 17264294.

60: Lancet JE, Gojo I, Gotlib J, Feldman EJ, Greer J, Liesveld JL, Bruzek LM, Morris L, Park Y, Adjei AA, Kaufmann SH, Garrett-Mayer E, Greenberg PL, Wright JJ, Karp JE. A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood. 2007 Feb 15;109(4):1387-94. Epub 2006 Nov 2. PubMed PMID: 17082323; PubMed Central PMCID: PMC1794070.

61: Siegel-Lakhai WS, Crul M, De Porre P, Zhang S, Chang I, Boot H, Beijnen JH, Schellens JH. Clinical and pharmacologic study of the farnesyltransferase inhibitor tipifarnib in cancer patients with normal or mildly or moderately impaired hepatic function. J Clin Oncol. 2006 Oct 1;24(28):4558-64. PubMed PMID: 17008695.

62: Zhang S, Zannikos P, Awada A, Piccart-Gebhart M, Dirix LY, Fumoleau P, Verhaeghe T, Francois M, De Porre P. Pharmacokinetics of tipifarnib after oral and intravenous administration in subjects with advanced cancer. J Clin Pharmacol. 2006 Oct;46(10):1116-27. PubMed PMID: 16988200.

63: Gore L, Holden SN, Cohen RB, Morrow M, Pierson AS, O'Bryant CL, Persky M, Gustafson D, Mikule C, Zhang S, Palmer PA, Eckhardt SG. A phase I safety, pharmacological and biological study of the farnesyl protein transferase inhibitor, tipifarnib and capecitabine in advanced solid tumors. Ann Oncol. 2006 Nov;17(11):1709-17. Epub 2006 Sep 15. PubMed PMID: 16980604.

64: Cloughesy TF, Wen PY, Robins HI, Chang SM, Groves MD, Fink KL, Junck L, Schiff D, Abrey L, Gilbert MR, Lieberman F, Kuhn J, DeAngelis LM, Mehta M, Raizer JJ, Yung WK, Aldape K, Wright J, Lamborn KR, Prados MD. Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study. J Clin Oncol. 2006 Aug 1;24(22):3651-6. PubMed PMID: 16877733.

65: Perez-Ruixo JJ, Piotrovskij V, Zhang S, Hayes S, De Porre P, Zannikos P. Population pharmacokinetics of tipifarnib in healthy subjects and adult cancer patients. Br J Clin Pharmacol. 2006 Jul;62(1):81-96. PubMed PMID: 16842381; PubMed Central PMCID: PMC1885079.

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