Vol. 9, 4761–4771, October 15, 2003 Clinical Cancer Research 4761 A Phase I, Pharmacokinetic, and Biological Study of the Farnesyltransferase Inhibitor Tipifarnib in Combination with Gemcitabine in Patients with Advanced Malignancies Amita Patnaik,1 S. Gail Eckhardt, the pharmacokinetic behavior of each agent administered Elzbieta Izbicka, Anthony A. Tolcher, alone and together. The proportions of unfarnesylated and Lisa A. Hammond, Chris H. Takimoto, farnesylated HDJ2, a chaperone protein that undergoes far- nesylation, were measured in peripheral blood mononuclear Garry Schwartz, Heather McCreery, cells. Andrew Goetz, Masataka Mori, Kazutoyo Terada, Results: Nineteen evaluable patients were treated with Lou Gentner, Mary-Ellen Rybak, 74 courses of tipifarnib/gemcitabine (mg/mg/m2). Myelosup- Henry Richards, Steven Zhang, and pression was the principal toxicity. Dose-limiting myelosup- Eric K. Rowinsky pression occurred in 2 of 5 patients at the 300/1000 dose level, whereas 2 of 11 evaluable patients at the 200/1000 dose Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas 78229 [A. P., S. G. E., E. I., A. A. T., level experienced dose-limiting toxicity. There was no evi- L. A. H., C. H. T., H. M., A. G., E. K. R.]; Brooke Army Medical dence of clinically relevant pharmacokinetic interactions Center, San Antonio, Texas 78234-6200 [G. S.]; Kumamoto between tipifarnib and gemcitabine. Inhibition of farnesyla- University School of Medicine, Kumamoto, Japan 860-8556 [M. M., tion of HDJ2, a potential surrogate for Ras and/or other K. T.]; and Johnson and Johnson Pharmaceutical Research and potentially relevant farnesylated proteins, was demon- Development, Titusville, New Jersey 08560 [L. G., M-E. R., H. R., S. Z.] strated in peripheral blood mononuclear cells at all dose levels. Partial responses were noted in patients with ad- vanced pancreatic and nasopharyngeal carcinomas. ABSTRACT Conclusions: On the basis of the results of this study, Purpose: To assess the feasibility of administering tipi- the tipifarnib/gemcitabine dose level of 200/1000 is recom- farnib, an oral nonpeptidomimetic competitive inhibitor of mended for disease-directed studies. At this dose level, bio- farnesyltransferase, in combination with gemcitabine and logically relevant plasma concentrations of tipifarnib that recommend doses for disease-directed clinical trials. The consistently inhibit protein farnesylation in vitro are study also sought to identify drug-drug pharmacokinetic achieved and drug-induced inhibition of protein farnesyla- interactions, evaluate effects on protein farnesylation, and tion is measured in most patients. seek preliminary evidence for clinical activity. Experimental Design: Patients with advanced solid ma- INTRODUCTION lignancies were treated with tipifarnib at doses of 100, 200, Ras proteins are activated downstream of receptor tyrosine 2 and 300 mg twice daily continuously and 1000 mg/m gem- kinases and trigger a cascade of phosphorylation events through citabine i.v. on days 1, 8, and 15 every 4 weeks. To identify sequential activation of multiple effector pathways, including pharmacokinetic interactions, the treatment and plasma the mitogen-activated protein kinase, and phosphoinositide- sampling schemes were designed to permit comparisons of 3-OH kinase pathways, which are critical for cell proliferation, differentiation, and survival (1–5). After synthesis as cytosolic precursors, Ras proteins undergo a series of posttranslational modifications, the first and most important being the addition of Received 3/27/03; revised 7/7/03; accepted 7/7/03. a 15-carbon farnesyl isoprenoid group catalyzed by FTase,2 The costs of publication of this article were defrayed in part by the enabling association with the cell membrane (1, 5, 6). When Ras payment of page charges. This article must therefore be hereby marked is stimulated by receptor activation to bind GTP, it activates advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. several downstream effectors, thereby promoting cell prolifera- Some patients were treated at the Frederic C. Barter Clinical Research tion. The intrinsic GTPase activity of Ras then serves to revert Unit of the Audie Murphy Veterans Administration Hospital (San An- the molecule back to its inactive state. Mutations in the ras tonio, TX), supported in part by NIH Grant MO1-RR01346. Presented genes that are most commonly found in human malignancies in part at the 36th Annual Meeting of the American Society of Clinical Oncology, 11th Annual Meeting of National Cancer Institute–American Association for Cancer Research, Inc./European Organization for Re- search and Treatment of Cancer, and 92nd Annual Meeting of the American Association for Cancer Research, Inc. 2 The abbreviations used are: FTase, farnesyltransferase; FTI, FTase 1 To whom requests for reprints should be addressed, at Institute for inhibitor; GGTase I, geranylgeranyltransferase type I; MTD, maximum Drug Development, Cancer Therapy and Research Center, 7979 Wurz- tolerated dose; BID, twice daily; ANC, absolute neutrophil count; DLT, bach, Suite Z400, San Antonio, TX 78229. Phone: (210) 949-5069; Fax: dose-limiting toxicity; PBMC, peripheral blood mononuclear cell; (210) 692-7502; E-mail: [email protected]. HPLC, high-performance liquid chromatography. Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2003 American Association for Cancer Research. 4762 Phase I Trial of Tipifarnib and Gemcitabine ical and pharmacological foundation for disease-directed trials, including a Phase III study in advanced pancreas cancer (22). The objectives of this study were to: (a) characterize the prin- cipal toxicities of tipifarnib administered BID in combination with gemcitabine on a conventional dose schedule (1000 mg/m2 i.v. on days 1, 8, and 15 every 4 weeks) in patients with advanced solid malignancies; (b) determine the MTD of tipi- farnib in combination with gemcitabine on this dose schedule and recommend doses for subsequent disease-directed trials; (c) describe the pharmacokinetics and pharmacodynamics of tipi- farnib and gemcitabine in combination and determine whether there are major effects of each agent on the clearance of the other; (d) seek preliminary evidence of antitumor activity in Fig. 1 Structure of tipifarnib. patients with advanced malignancies; and (e) determine whether farnesylation of HDJ2, a chaperone protein and potential surro- gate for Ras and/or other critical farnesylated proteins, is inhib- ited at clinically relevant doses of tipifarnib and gemcitabine. favor Ras in its GTP-bound active state, in which it constitu- tively enables transmission of proliferative and survival signals (1, 2, 4, 7). Abnormal expression and conformation changes in MATERIALS AND METHODS Ras, conferred by ras gene mutations, have been demonstrated Patients with histologically confirmed advanced solid ma- in ϳ30% of all human malignancies including ϳ50% of colo- lignancies refractory to standard therapy or for whom no effec- rectal, 70–90% of pancreatic, and 30% of non-small cell lung tive therapy existed were candidates for this study. Eligibility cancers (7). criteria included: (a) age of Ն18 years; (b) Eastern Cooperative FTIs were developed on the premise that FTase inhibition Oncology Group performance status Յ2 (ambulatory and capa- would prevent Ras processing and, hence, transduction of crit- ble of self-care); (c) no chemotherapy, radiotherapy, or investi- ical proliferative and survival signals (8). The coupling of Ras to gational therapy within the previous 4 weeks (6 weeks for protein tyrosine kinases also raises the possibility that malig- nitrosoureas or mitomycin C); (d) adequate hematopoietic nancies driven by overactivity upstream of Ras might be inhib- (ANC, Ն1,500/␮l; platelets, Ն100,000/␮l; hemoglobin, Ն9 ited by therapeutics against this target (1, 9). Additionally, a g/dl), hepatic (total bilirubin within the institutional normal large number of multifunctional proteins, as well as Ras, un- limits; aspartate aminotransferase and alanine aminotransferase dergo farnesylation, and several of these proteins, including Յ2.0 times the institutional upper normal limits, unless caused RhoB, Akt2, and the centromere-associated protein-E and cen- by hepatic metastases, in which case elevations of Յ5.0 times tromere-associated protein-F centromeric proteins, seem to be the upper normal limits were permitted), and renal (serum affected critically by FTIs (10–13). creatinine within institutional normal limits) functions; (e)no Tipifarnib (R115777, Zarnestra; Johnson & Johnson Phar- prior extensive myelotoxic therapy [defined as more than six maceutical Research and Development, Titusville, NJ; Fig. 1), courses of alkylating agent-containing chemotherapy (except an oral quinolone analogue of imidazole-containing heterocyclic low-dose cisplatin); more than four courses of carboplatin; two compounds, is a nonpeptidomimetic competitive inhibitor of or more courses of mitomycin C or a nitrosourea; irradiation to FTase (14, 15). Tipifarnib is highly specific for FTase and does Ն25% of hematopoietic reserves; high-dose chemotherapy, fol- not inhibit GGTase I, which can alternatively prenylate both lowed by hematopoietic stem cell rescue]; (f) no concurrent K-Ras and RhoB (6, 14). Tipifarnib inhibits the growth of a radiation therapy (except palliative radiation therapy), chemo- broad spectrum of human malignancies in vitro and in human therapy, hormonal therapy,