A Phase I Multicenter Study of Continuous Oral Administration of Lonafarnib (SCH 66336) and Intravenous Gemcitabine in Patients With Advanced Cancer

REFERENCES

• Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature 1990;343:425–430.
   PubMed Web of Science ®Google Scholar
• Lobell RB. Prenylation of Ras GTPase superfamily proteins and their function in immunobiology. Adv Immunol 1998;68:145–189.
   PubMed Web of Science ®Google Scholar
• Schafer WR, Trueblood CE, Yang CC, Mayer MP, Rosenberg S, Poulter CD, Kim SH, Rine J. Enzymatic coupling of cholesterol intermediates to a mating pheromone precursor and to the ras protein. Science 1990;249:1133–1139.
   PubMed Web of Science ®Google Scholar
• Sebti SM. Protein farnesylation: implications for normal physiology, malignant transformation, and cancer therapy. Cancer Cell 2005;7:297–300.
   PubMed Web of Science ®Google Scholar
• Casey PJ, Solski PA, Der CJ, Buss JE. p21ras is modified by a farnesyl isoprenoid. Proc Natl Acad Sci U S A 1989;86:8323–8327.
   PubMed Web of Science ®Google Scholar
• Takai Y, Sasaki T, Matozaki T. Small GTP-binding proteins. Physiol Rev 2001;81:153–208.
   PubMed Web of Science ®Google Scholar
• Bos JL. Ras oncogenes in human cancer: a review. Cancer Res 1989;49:4682–4689.
   PubMed Web of Science ®Google Scholar
• Adjei AA. Blocking oncogenic Ras signaling for cancer therapy. J Natl Cancer Inst 2001;93:1062–1074.
   PubMed Web of Science ®Google Scholar
• Willumsen BM, Christensen A, Hubbert NL, Papageorge AG, Lowy DR. The p21 ras C-terminus is required for transformation and membrane association. Nature 1984;310:583–586.
   PubMed Web of Science ®Google Scholar
• Willumsen BM, Norris K, Papageorge AG, Hubbert NL, Lowy DR. Harvey murine sarcoma virus p21 ras protein: biological and biochemical significance of the cysteine nearest the carboxy terminus. EMBO J 1984;3:2581–2585.
   PubMed Web of Science ®Google Scholar
• Jackson JH, Cochrane CG, Bourne JR, Solski PA, Buss JE, Der CJ. Farnesol modification of Kirsten-ras exon 4B protein is essential for transformation. Proc Natl Acad Sci U S A 1990;87:3042–3046.
   PubMed Web of Science ®Google Scholar
• Peters DG, Hoover RR, Gerlach MJ, Koh EY, Zhang H, Choe K, Kirschmeier P, Bishop WR, Daley GQ. Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia. Blood 2001;97:1404–1412.
   PubMed Web of Science ®Google Scholar
• Petit T, Izbicka E, Lawrence RA, Bishop, WR, Weitman S, Von Hoff DD. Activity of SCH 66336, a tricyclic farnesyltransferase inhibitor, against human tumor colony-forming units. Ann Oncol 1999;10:449–453.
   PubMed Web of Science ®Google Scholar
• Liu M, Bryant MS, Chen J, Lee S, Yaremko B, Lipari P, Malkowski M, Ferrari E, Nielsen L, Prioli N, Dell J, Sinha D, Syed J, Korfmacher WA, Nomeir AA, Lin CC, Wang L, Taveras AG, Doll RJ, Njoroge FG, Mallams AK, Remiszewski S, Catino JJ, Girijavallabhan VM, Bishop WR, Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice. Cancer Res 1998;58:4947–4956.
   PubMed Web of Science ®Google Scholar
• Reichert A, Heisterkamp N, Daley GQ, Groffen J. Treatment of Bcr/Abl-positive acute lymphoblastic leukemia in P190 transgenic mice with the farnesyl transferase inhibitor SCH66336. Blood 2001;97:1399–1403.
   PubMed Web of Science ®Google Scholar
• Adjei AA, Erlichman C, Davis JN, Cutler DL, Sloan JA, Marks RS, Hanson LJ, Svingen PA, Atherton P, Bishop WR, Kirschmeier P, Kaufmann SH. A phase I trial of the farnesyl transferase inhibitor SCH66336: evidence for biological and clinical activity. Cancer Res 2000;60:1871–1877.
   PubMed Web of Science ®Google Scholar
• Eskens FA, Awada A, Cutler DL, de Jonge MJ, Luyten GP, Faber MN, Statkevich P, Sparreboom A, Verweij J, Hanauske AR, Piccart M. Phase I and pharmacokinetic study of the oral farnesyl transferase inhibitor SCH 66336 given twice daily to patients with advanced solid tumors. J Clin Oncol 2001;19:1167–1175.
   PubMed Web of Science ®Google Scholar
• Castaneda C, Meadows KL, Truax R, Morse MA, Kaufmann SH, Petros WP, Zhu Y, Statkevich P, Cutler DL, Hurwitz HI. Phase I and pharmacokinetic study of lonafarnib, SCH 66336, using a 2-week on, 2-week off schedule in patients with advanced solid tumors. Cancer Chemother Pharmacol 2011;67:455–463.
   PubMed Web of Science ®Google Scholar
• Awada A, Eskens FA, Piccart M, Cutler DL, van der Gaast A, Bleiberg H, Wanders J, Faber MN, Statkevich P, Fumoleau P, Verweij J. Phase I and pharmacological study of the oral farnesyltransferase inhibitor SCH 66336 given once daily to patients with advanced solid tumours. Eur J Cancer 2002;38:2272–2278.
   PubMed Web of Science ®Google Scholar
• Sun J, Blaskovich MA, Knowles D, QianY, Ohkanda J, Bailey RD, Hamilton AD, Sebti SM. Antitumor efficacy of a novel class of non-thiol-containing peptidomimetic inhibitors of farnesyltransferase and geranylgeranyltransferase I: combination therapy with the cytotoxic agents cisplatin, Taxol, and gemcitabine. Cancer Res 1999;59:4919–4926.
   PubMed Web of Science ®Google Scholar
• Eskens FA, Awada A, Cutler DL, de Jonge MJ, Luyten GP, Faber MN, Statkevich P, Sparreboom A, Verweij J, Hanauske AR, Piccart M. Phase I and pharmacokinetic study of the oral farnesyl transferase inhibitor SCH 66336 given twice daily to patients with advanced solid tumors. J Clin Oncol 2001;19:1167–1175.
   PubMed Web of Science ®Google Scholar
• Le Tourneau C, Lee JJ, Siu LL. Dose escalation methods in phase I cancer clinical trials. J Natl Cancer Inst 2009;101:708–720.
   PubMed Web of Science ®Google Scholar
• A Phase I Study of Cyclic Two-Week Oral Administration of SCH 66336 in Patients With Advanced Cancer (Schering-Plough Clinical document no. 1715018). Kenilworth, NJ: Schering-Plough Research Institute, 2001.
   Google Scholar
• Phase I Study to Determine the Safety of SCH 66336 in Patients With a Solid Tumor on Twice Daily Oral Schedule for 28 days (Clinical document no. 1760976). Kenilworth, NJ: Schering-Plough Research Institute, 2001.
   Google Scholar
• Theodore C, Geoffrois L, Vermorken JB, Caponigro F, Fiedler W, Chollet P, Ravaud A, Peters GJ, de Balincourt C, Lacombe D, Fumoleau P. Multicentre EORTC study 16997: feasibility and phase II trial of farnesyl transferase inhibitor & gemcitabine combination in salvage treatment of advanced urothelial tract cancers. Eur J Cancer 2005;41:1150–1157.
   PubMed Web of Science ®Google Scholar
• Adjei AA, Mauer A, Bruzek L, Marks RS, Hillman S, Geyer S, Hanson LJ, Wright JJ, Erlichman C, Kaufmann SH, Vokes EE. Phase II study of the farnesyl transferase inhibitor R115777 in patients with advanced non-small-cell lung cancer. J Clin Oncol 2003;21:1760–1766.
   PubMed Web of Science ®Google Scholar
• Hanrahan EO, Kies MS, Glisson BS, Khuri FR, Feng L, Tran HT, Ginsberg LE, Truong MT, Hong WK, Kim ES. A phase II study of lonafarnib (SCH66336) in patients with chemorefractory, advanced squamous cell carcinoma of the head and neck. Am J Clin Oncol 2009;3:274–279.
   Google Scholar
• Heymach JV, Johnson DH, Khuri FR, Safran H, Schlabach LL, Yunus F, DeVore RF III, De Porre PM, Richards HM, Jia X, Zhang S, Johnson BE. Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer. Ann Oncol 2004;15:1187–1193.
   PubMed Web of Science ®Google Scholar
• Johnston SR, Hickish T, Ellis P, Houston S, Kelland L, Dowsett M, Salter J, Michiels B, Perez-Ruixo JJ, Palmer P, Howes A. Phase II study of the efficacy and tolerability of two dosing regimens of the farnesyl transferase inhibitor, R115777, in advanced breast cancer. J Clin Oncol 2003;21:2492–2499.
   PubMed Web of Science ®Google Scholar
• Macdonald JS, McCoy S, Whitehead RP, Iqbal S, Wade JL III, Giguere JK, Abbruzzese JL. A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a Southwest oncology group (SWOG 9924) study. Invest New Drugs 2005;23:485–487.
   PubMed Web of Science ®Google Scholar
• Rosenberg JE, von der Maase H, Seigne JD, Mardiak J, Vaughn DJ, Moore M, Sahasrabudhe D, Palmer PA, Perez-Ruixo JJ, Small EJ. A phase II trial of R115777, an oral farnesyl transferase inhibitor, in patients with advanced urothelial tract transitional cell carcinoma. Cancer 2005;103:2035–2041.
   PubMed Web of Science ®Google Scholar
• Sharma S, Kemeny N, Kelsen DP, Ilson D, O'Reilly E, Zaknoen S, Baum C, Statkevich P, Hollywood E, Zhu Y, Saltz LB. A phase II trial of farnesyl protein transferase inhibitor SCH 66336, given by twice-daily oral administration, in patients with metastatic colorectal cancer refractory to 5-fluorouracil and irinotecan. Ann Oncol 2002;13:1067–1071.
   PubMed Web of Science ®Google Scholar
• Whitehead RP, McCoy S, Macdonald JS, Rivkin SE, Neubauer MA, Dakhil SR, Lenz HJ, Tanaka MS, Abbruzzese JL. Phase II trial of R115777 (NSC #70818) in patients with advanced colorectal cancer: a Southwest Oncology Group study. Invest New Drugs 2006;24:335–341.
   PubMed Web of Science ®Google Scholar
• Winquist E, Moore MJ, Chi KN, Ernst DS, Hirte H, North S, Powers J, Walsh W, Boucher T, Patton R, Seymour L. A multinomial phase II study of lonafarnib (SCH 66336) in patients with refractory urothelial cancer. Urol Oncol 2005;23:143–149.
   PubMed Web of Science ®Google Scholar
• Rao S, Cunningham D, de Gramont A, Scheithauer W, Smakal M, Humblet Y, Kourteva G, Iveson T, Andre T, Dostalova J, Illes A, Belly R, Perez-Ruixo JJ, Park YC, Palmer PA. Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer. J Clin Oncol 2004;22:3950–3957.
   PubMed Web of Science ®Google Scholar
• Adjei AA, Croghan GA, Erlichman C, Marks RS, Reid JM, Sloan JA, Pitot HC, Alberts SR, Goldberg RM, Hanson LJ, Bruzek LM, Atherton P, Thibault A, Palmer PA, Kaufmann SH. A phase I trial of the farnesyl protein transferase inhibitor R115777 in combination with gemcitabine and cisplatin in patients with advanced cancer. Clin Cancer Res 2003;9:2520–2526.
   PubMed Web of Science ®Google Scholar
• 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;23:991–1003.
   PubMed Web of Science ®Google Scholar
• 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;17:1709–1717.
   PubMed Web of Science ®Google Scholar
• Khuri FR, Glisson BS, Kim ES, Statkevich P, Thall PF, Meyers ML, Herbst RS, Munden RF, Tendler C, Zhu Y, Bangert S, Thompson E, Lu C, Wang XM, Shin DM, Kies MS, Papadimitrakopoulou V, Fossella FV, Kirschmeier P, Bishop WR, Hong WK. Phase I study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in solid tumors. Clin Cancer Res 2004;10:2968–2976.
   PubMed Web of Science ®Google Scholar
• Kim ES, Kies MS, Fossella FV, Glisson BS, Zaknoen S, Statkevich P, Munden RF, Summey C, Pisters KM, Papadimitrakopoulou V, Tighiouart M, Rogatko A, Khuri FR. Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma. Cancer 2005;104:561–569.
   PubMed Web of Science ®Google Scholar
• Ready NE, Lipton A, Zhu Y, Statkevich P, Frank E, Curtis D, Bukowski RM. Phase I study of the farnesyltransferase inhibitor lonafarnib with weekly paclitaxel in patients with solid tumors. Clin Cancer Res 2007;13:576–583.
   PubMed Web of Science ®Google Scholar
• Siegel-Lakhai WS, Crul M, Zhang S, Sparidans RW, Pluim D, Howes A, Solanki B, Beijnen JH, Schellens JH. Phase I and pharmacological study of the farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777) in combination with gemcitabine and cisplatin in patients with advanced solid tumours. Br J Cancer 2005;93:1222–1229.
   PubMed Web of Science ®Google Scholar
• Sparano JA, Moulder S, Kazi A, Coppola D, Negassa A, Vahdat L, Li T, Pellegrino C, Fineberg S, Munster P, MalafaM, 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;15:2942–2948.
   PubMed Web of Science ®Google Scholar
• Sparreboom A, Kehrer DF, Mathijssen RH, Xie R, de Jonge MJ, de Bruijn P, Planting AS, Eskens FA, Verheij C, de Heus G, Klaren A, Zhang S, Verhaeghe T, Palmer PA, Verweij J. Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor. Br J Cancer 2004;90:1508–1515.
   PubMed Web of Science ®Google Scholar
• Chow LQ, Eckhardt SG, O'Bryant CL, Schultz MK, Morrow M, Grolnic S, Basche M, Gore L. A phase I safety, pharmacological, and biological study of the farnesyl protein transferase inhibitor, lonafarnib (SCH 663366), in combination with cisplatin and gemcitabine in patients with advanced solid tumors. Cancer Chemother Pharmacol 2008;62:631–646.
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, van de Velde H, Karasek P, Oettle H, Vervenne WL, Szawlowski A, Schoffski P, Post S, Verslype C, Neumann H, Safran H, Humblet Y, Perez Ruixo J, Ma Y, Von Hoff D. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 2004;22:1430–1438.
   PubMed Web of Science ®Google Scholar
• ClinicalTrials.gov Identifier: NCT00050336.
   Google Scholar
• Borthakur G, Kantarjian H, Daley G, Talpaz M, O'Brien S, Garcia-Manero G, Giles F, Faderl S, Sugrue M, Cortes J. Pilot study of lonafarnib, a farnesyl transferase inhibitor, in patients with chronic myeloid leukemia in the chronic or accelerated phase that is resistant or refractory to imatinib therapy. Cancer 2006;106:346–352.
   PubMed Web of Science ®Google Scholar
• Feldman EJ, Cortes J, DeAngelo DJ, Holyoake T, Simonsson B, O'Brien SG, Reiffers J, Turner AR, Roboz GJ, Lipton JH, Maloisel F, Colombat P, Martinelli G, Nielsen JL, Petersdorf S, Guilhot F, Barker J, Kirschmeier P, Frank E, Statkevich P, Zhu Y, Loechner S, List A. On the use of lonafarnib in myelodysplastic syndrome and chronic myelomonocytic leukemia. Leukemia 2008;22:1707–1711.
   PubMed Web of Science ®Google Scholar
• Harousseau JL, Lancet JE, Reiffers J, Lowenberg B, Thomas X, Huguet F, Fenaux P, Zhang S, Rackoff W, De Porre P, Stone R. A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib in patients with refractory or relapsed acute myeloid leukemia. Blood 2007;109:5151–5156.
   PubMed Web of Science ®Google Scholar
• 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;14:3077–3082.
   PubMed Web of Science ®Google Scholar
• 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;109:1387–1394.
   PubMed Web of Science ®Google Scholar
• Ravoet C, Mineur P, Robin V, Debusscher L, Bosly A, Andre M, El Housni H, Soree A, Bron D, MartiatP. Farnesyl transferase inhibitor (lonafarnib) in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia: a phase II study. Ann Hematol 2008;87:881–885.
   PubMed Web of Science ®Google Scholar
• James GL, Goldstein JL, Brown MS. Polylysine and CVIM sequences of K-RasB dictate specificity of prenylation and confer resistance to benzodiazepine peptidomimetic in vitro. J Biol Chem 1995;270:6221–6226.
   PubMed Web of Science ®Google Scholar
• Lerner EC, Zhang TT, Knowles DB, Qian Y, Hamilton AD, Sebti SM. Inhibition of the prenylation of K-Ras, but not H- or N-Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase I inhibitor in human tumor cell lines. Oncogene 1997;15:1283–1288.
   PubMed Web of Science ®Google Scholar
• Rowell CA, Kowalczyk JJ, Lewis MD, Garcia AM. Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras in vivo. J Biol Chem 1997;272:14093–14097.
   PubMed Web of Science ®Google Scholar
• Whyte DB, Kirschmeier P, Hockenberry TN, Nunez-Oliva I, James L, Catino JJ, Bishop WR, Pai JK. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J Biol Chem 1997;272:14459–14464.
   PubMed Web of Science ®Google Scholar
• Ashar HR, James L, Gray K, Carr D, Black S, Armstrong L, Bishop WR, Kirschmeier P. Farnesyl transferase inhibitors block the farnesylation of CENP-E and CENP-F and alter the association of CENP-E with the microtubules. J Biol Chem 2000;275:30451–30457.
   PubMed Web of Science ®Google Scholar
• Basso AD, Mirza A, Liu G, Long BJ, Bishop WR, Kirschmeier P. The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity. J Biol Chem 2005;280:31101–31108.
   PubMed Web of Science ®Google Scholar
• Lebowitz PF, Casey PJ, Prendergast GC, Thissen JA. Farnesyltransferase inhibitors alter the prenylation and growth-stimulating function of RhoB. J Biol Chem 1997;272: 15591–15594.
   PubMed Web of Science ®Google Scholar
• Liu A, Du W, Liu JP, Jessell TM, Prendergast GC. RhoB alteration is necessary for apoptotic and antineoplastic responses to farnesyltransferase inhibitors. Mol Cell Biol 2000;20:6105–6113.
   PubMed Web of Science ®Google Scholar
• Feldkamp MM, Lau N, Roncari L, Guha A. Isotype-specific Ras.GTP-levels predict the efficacy of farnesyl transferase inhibitors against human astrocytomas regardless of Ras mutational status. Cancer Res 2001;61:4425–4431.
   PubMed Web of Science ®Google Scholar