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Clinical Cancer Research Vol. 11, 1247-1252, February 2005
© 2005 American Association for Cancer Research

Cancer Therapy: Clinical

A Phase I Trial and Pharmacokinetic Study of Tipifarnib, a Farnesyltransferase Inhibitor, and Tamoxifen in Metastatic Breast Cancer

Peter F. Lebowitz1, Jennifer Eng-Wong1, Brigitte C. Widemann2, Frank M. Balis2, Nalini Jayaprakash2, Catherine Chow4, Geoff Clark3, Susan B. Gantz1, David Venzon5 and JoAnne Zujewski

1 Medical Oncology Clinical Research Unit, 2 Pediatric Oncology Branch, and 3 Cell and Cancer Biology Branch, National Cancer Institute and 4 Diagnostic Radiology Department and 5 Biostatistics, NIH, Bethesda, Maryland

Requests for reprints: Peter F. Lebowitz, Medical Oncology Clinical Research Unit, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892. Phone: 301-496-7665; Fax: 301-402-0172; E-mail: peter.lebowitz{at}nih.gov.


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: Farnesyltransferase (FTase) inhibitors, which were designed to inhibit oncogenic Ras, act synergistically with tamoxifen in preclinical breast cancer models. We studied the safety and toxicity of tipifarnib in combination with tamoxifen in metastatic breast cancer. The pharmacokinetics and pharmacodynamics of tipifarnib were also assessed.

Patients and Methods: Patients with metastatic, hormone receptor–positive breast cancer were enrolled. Two cohorts of patients were treated with tipifarnib at either 200 or 300 mg p.o. twice daily for 21 of 28 days. Tamoxifen (20 mg once daily) was started after 1 week of tipifarnib monotherapy to perform pharmacokinetics and FTase inhibition levels in peripheral blood mononuclear cells with tipifarnib alone and with tipifarnib and tamoxifen.

Results: A total of 12 heavily pretreated patients with prior progression on hormonal therapy were enrolled. Minimal toxicity was observed at the 200-mg dose level of tipifarnib. At the 300-mg dose, all six patients required dose reduction of tipifarnib due to toxicities that included grade 2 nausea, rash, and fatigue and grade 3 diarrhea and neutropenia. Tipifarnib pharmacokinetic and pharmacodynamic variables were similar in the presence and absence of tamoxifen. Average FTase inhibition was 42% at 200 mg and 54% at 300 mg in peripheral blood mononuclear cells. Of the 12 patients treated, there were two partial responses and one stable disease for >6 months.

Conclusions: Tipifarnib (200 mg twice daily for 21 of 28 days) and tamoxifen (20 mg once daily) can be given safely with minimal toxicity. Tamoxifen does not have a significant effect on tipifarnib pharmacokinetics.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The use of hormonal therapy for the treatment and prevention of breast cancer over the past century provides a glimpse of the potential impact and limitations of targeted anticancer therapies. In the metastatic setting, hormonal therapy achieves response rates between 30% and 70% with minimal side effects (1); however, all patients eventually develop hormone-refractory disease. The molecular basis of this resistance to hormonal treatment has been studied in some detail and multiple mechanisms have been identified. One well-described mode of hormone resistance is crosstalk between growth factor receptor pathways, such as epidermal growth factor receptor, HER2-neu, and insulin-like growth factor receptor-I, and the estrogen receptor (ER) signaling pathway (2). Activation of these growth factor receptor pathways leads to downstream kinase activity resulting in phosphorylation of ER and its coactivators. This phosphorylation facilitates ER-mediated gene transcription in an estrogen-independent fashion. Interestingly, in a reciprocal fashion, membrane-associated ER can also lead to activation of growth factor receptors and downstream kinases (3). This bidirectional crosstalk results in redundancy of the growth signal.

Signal transduction inhibitors, such as farnesyltransferase (FTase) inhibitors, that inhibit these mitogenic pathways, provide a potential strategy to combat hormonal resistance due to activation of alternative growth factor pathways (4). FTase inhibitors were initially designed to inhibit the proto-oncoprotein Ras, which acts as a critical signaling node in many growth factor signaling pathways (5). Whereas the precise mechanism of antitumor activity of these drugs may involve proteins other than Ras, including RhoB, CENP-E, and CENP-F, there is good evidence that FTIs block pathways leading to mitogen-activated protein kinase activation and may therefore combat hormonal resistance (6–8). In cell culture experiments, 4-hydroxytamoxifen and FTI-277 were found to inhibit breast cancer cell lines in a synergistic manner suggesting that concomitant pathway blockage may negate resistance due to pathway crosstalk (9).

Tipifarnib (Zarnestra, R115777 Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium) is an orally bioavailable quinolone analogue of imidazole that acts as a potent and selective inhibitor of FTase (10). This drug inhibits the growth of several human breast tumor cell lines in cell culture and xenograft models (10, 11). In addition, a phase II trial was recently reported showing modest single-agent clinical activity in advanced breast cancer with an objective response rate of 14% and a clinical benefit rate of 23% at a dose [300 mg twice daily (BID) for 21 of 28 days] that was well tolerated (12). Given the preclinical synergy of FTIs and tamoxifen, combining these two targeted therapies is a promising approach.

We conducted a phase I study of tipifarnib and tamoxifen to determine the toxicities, safety, and recommended dose of the regimen. Pharmacokinetic and pharmacodynamic studies were also done to determine effects of tamoxifen on tipifarnib levels and biological activity.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Eligibility. Women who were referred to the National Cancer Institute with hormone receptor–positive (defined as estrogen receptor >1% staining; ref. 13) metastatic breast cancer were eligible for the study. Other eligibility criteria included an absolute neutrophil count ≥1,500/mm3, platelet count ≥100,000/mm3, creatinine ≤1.5 mg/dL, total bilirubin ≤2.0 (unless evidence of Gilbert's disease), aspartate/alanine aminotransferase ≤3.0 x upper limit of normal, and Zubrod performance status 0-1. Life expectancy had to be at least 3 months. Patients had to have received at least one prior hormonal treatment; there were no limitations regarding prior chemotherapy regimens. Patients were excluded if they were pregnant, taking warfarin, or on cytochrome P450–inducing anticonvulsants.

The study protocol was approved by the Institutional Review Board of the National Cancer Institute. Informed written consent was provided by all patients before commencing the study.

Study Design and Treatment Regimen. A study schema is shown in Fig. 1. The trial was a dose escalation design with two dose levels of tipifarnib; the tamoxifen dose (20 mg p.o. four times daily) was the same at both levels. The first cohort of patients was treated at 200 mg of tipifarnib p.o. BID for 21 days of a 28-day cycle. The second cohort was treated at 300 mg of tipifarnib p.o. BID on the same schedule. Tamoxifen was started on cycle 1 day 8, after 1 week of single agent tipifarnib, and continued throughout the study. This design allowed pharmacokinetic and pharmacodynamic studies to be done with single-agent tipifarnib and with the combination regimen. Dose escalation from 200 mg BID to 300 mg BID was planned if 0 of 3 or 0 to 1 of six patients in the first cohort developed dose-limiting toxicity during the first two cycles, as described below. Patients were continued on treatment until disease progression or the development of prohibitive toxicity. Concomitant treatment with bisphosphonates and erythropoietin or erythropoietin analogues was allowed.



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  		Fig. 1 Treatment schema. Schedule was designed to collect pharmacokinetic (PK) and pharmacodynamic (PD) studies with tipifarnib alone and with the combined regimen.

 
Tamoxifen was obtained from commercial sources. Tipifarnib was obtained through the Cancer Therapeutics Evaluation Program under IND 58359.

Patient Evaluation. Initial assessment of patients included medical history, physical examination, CBC with differential, liver function tests, metabolic panel, urinalysis, pregnancy test and imaging of disease sites with tumor measurements (if appropriate) within 4 weeks of starting therapy. Patients were considered postmenopausal if they had not menstruated in >12 months or if their follicle-stimulating hormone level was in the postmenopausal range. ER and/or PR were considered positive if there was >1% staining. Her2-neu was considered positive if it was positive by fluorescent in situ hybridization. Patients were reassessed every 4 weeks with toxicity assessment, physical exam, and metabolic panel. During the first 12 weeks of therapy, CBC with differential was done weekly. Once hematologic counts were stable, monitoring was reduced to a minimum of every 4 weeks. Restaging imaging studies were done at least every 8 weeks. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria version 2.0. In patients with measurable disease, Response Evaluation Criteria in Solid Tumor were used to determine response (14).

Dose Modification. Dose modification guidelines were designed for chronic dosing of tipifarnib. Dose reductions of tipifarnib were done for toxicities considered at least possibly related to tipifarnib as described below; dose levels are shown in Table 1. If patients were taking 100 mg once daily (dose level, –2) and experienced toxicity requiring further dose reduction, treatment was stopped.


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  		Table 1 Tipifarnib dose levels

 
For an ANC <1,200/mm3 or platelets <75,000/mm3 during cycle 1 or 2, tipifarnib was held until recovery and then resumed with reduction by one dose level. For grade 3 or 4 neutropenia or thrombocytopenia during any cycle, tipifarnib was held until recovery to ANC ≥1,200/mm3 and platelets ≥75,000/mm3 and reduced by one dose level. Grade 2 neurotoxicity and grade 2 or 3 nonhematologic toxicities (excluding serum chemistry abnormalities) required holding drug until recovery to grade ≤1 and restarting with dose reduction if recovery occurred by 21 days. If recovery took longer than 21 days, treatment was discontinued. With grade 4 nonhematologic toxicity (excluding serum chemistry abnormalities) or reoccurrence of grade 2 neurotoxicity, therapy was discontinued. Serum chemistry and hepatic function laboratory toxicities greater than grade 3 required holding tipifarnib until recovery to grade ≤1 with resumption of therapy at one lower dose level. If recovery took longer than 21 days, therapy was discontinued. There was no planned dose modification of tamoxifen.

For purposes of dose escalation, dose-limiting toxicity was defined as grade ≥3 nonhematologic toxicity, grade 2 nonhematologic toxicity persisting for >3 weeks after onset, grade 4 neutropenia, or grade 4 thrombocytopenia.

Pharmacokinetic and Pharmacodynamic Studies. Blood samples for pharmacokinetic analysis were obtained at three time points: before first dose of drug, at steady state during cycle 1 between days 5 and 7 on single-agent tipifarnib, and at steady state during cycle 2 between days 7 and 15 on combination therapy. Venous blood samples were collected in heparinized tubes at 0, 0.5, 1, 2, 4, 8, and 12 hours after the morning dose of tipifarnib. Samples were centrifuged and the separated plasma was stored at –70°C before shipment to Johnson & Johnson Pharmaceutical Research and Development for determination of plasma tipifarnib concentration by a validated high-pressure liquid chromatography method as previously described (15), but using an API 3000 (Applied Biosystems, Foster City, CA) LC-MS/MS with TurboIonSpray interface operated in the positive-ion mode instead of UV detection.

The peak plasma concentration (Cmax) was the highest measured plasma concentration over the 12-hour monitoring period, and the Tmax was the time after the dose that the Cmax was achieved. The area under the plasma tipifarnib concentration-time curve for the dosing interval (AUC0-12h) was calculated using the trapezoidal method. Under steady-state conditions, the AUC for the dosing interval is equivalent to the AUC0-8 after a single dose. The average plasma concentration at steady state (Cave) was derived from AUC0-12h divided by the dosing interval (12 hours). The terminal slope of the plasma concentration-time curve was derived by linear regression after log transformation of the plasma concentrations, and this slope was used to estimate the terminal half-life.

Samples for FTase inhibition in peripheral blood mononuclear cells (PBMC) were drawn at baseline, once at steady state on single agent tipifarnib during cycle 1 between days 5 and 7, and once at steady state during cycle 2 between days 7 and 15 on combined therapy. Venous blood was collected before a morning dose of tipifarnib; PBMCs were collected, washed in PBS, and stored at –70°C until analysis. FTase activity in PBMCs was measured with a scintillation proximity assay (Amersham Biosciences, Piscataway, NJ) as previously described (10). Radioactivity (cpm) from the bead-streptavadin-biotin-Lamin-B-3H-F complex was measured on a TopCount NXT Microplate Scintillation Counter (Packard BioSciences, Boston, MA). Radioactivity (cpm) from the captured complex is proportional to the FTase activity in the sample.

Statistical Considerations. For a direct comparison of tipifarnib alone versus tipifarnib with tamoxifen, the AUC0-12h was normalized to the 200 mg dose with an assumed linear relationship of AUC to dose and the differences between paired values were then assessed using the Wilcoxon signed rank test. The correlation between AUC0-12h and percent FTase inhibition was tested with the Spearman rank correlation. Repeated measures ANOVA was used to test associations among the square root–transformed AUC0-12h, the tipifarnib dose level, the combination with tamoxifen and the FTase inhibition percentage.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Study Profile and Patient Characteristics. From October 2002 to September 2003, 12 patients were enrolled in the trial. Patients were enrolled at one of two dose levels of tipifarnib (200 mg p.o. BID or 300 mg p.o. BID for 21 of 28 days). The study initially planned for three to six patients in the first cohort and three to six patients in the second cohort depending on toxicity. Because toxicity assessment was not complete at the lower dose after enrolling three patients, a total of six patients were enrolled at this level before proceeding to the higher dose. At the 300 mg dose, six patients were also enrolled according to protocol.

Patient and tumor characteristics are listed in Table 2. The median age was 50 years and all patients were postmenopausal. Three quarters of patients had visceral disease and 83% of patients had two or more sites of disease. All patients had received prior chemotherapy and hormonal therapy as adjuvant and/or metastatic treatment. Patients had received a median of three prior chemotherapy regimens and three prior hormonal regimens. All patients had disease progression on a prior hormonal agent before enrolling on the trial and had received prior tamoxifen in either the adjuvant or metastatic setting. In addition, over half of the patients enrolled had prior treatment with high-dose chemotherapy and stem cell transplantation.


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  		Table 2 Baseline patient/tumor characteristics (n = 12)

 
Toxicity. Hematologic and nonhematologic toxicities for both dose levels of tipifarnib are listed in Table 3A and B. At the first tipifarnib dose level (200 mg p.o. BID), one of six patients required dose reduction for nonhematologic toxicity greater than grade 1; this patient experienced grade 2 dry mouth and nausea which resolved with dose reduction to 100 mg p.o. BID. One patient had grade 2 neutropenia that did not require treatment or dose modification. The most common nonhematologic toxicity was nausea, which occurred in half of the patients; however, this was usually mild and transient in nature. One patient had a pulmonary embolus, which required removal from the study; this event was felt to be possibly related to tamoxifen but unlikely to be related to tipifarnib.


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  		Table 3 Tipifarnib toxicities

 
At the higher tipifarnib dose level (300 mg p.o. BID), there was a notable increase in toxicity. Based on conservative dose modification guidelines described in the methods, all six patients required dose reduction during the first two cycles for ANC <1,200/mm3 (n = 3), grade 3 diarrhea (n = 1), grade 2 nausea (n = 1), grade 2 rash (n = 1), and grade 2 fatigue (n = 1). One patient required two further dose reductions for recurrence of neutropenia. Other common toxicities included myelosuppression, nausea/vomiting, fatigue, hypoalbuminemia, and myalgias. Despite toxicities leading to dose reductions, only one of six patients developed dose-limiting toxicity per protocol definition with grade 3 diarrhea. All toxicities resolved within 3 weeks of stopping tipifarnib.

Pharmacokinetics. Blood samples for pharmacokinetic analysis were obtained from all 12 patients on cycle 1 (tipifarnib alone), and from nine patients on cycle 2 (tipifarnib with tamoxifen). Tipifarnib was rapidly absorbed after oral administration with a median Tmax of 1 hour. Table 4A shows tipifarnib pharmacokinetic variables with all 12 patients normalized to 200 mg. The mean AUC0-12h increased in proportion to dose at the 300 mg dose versus the 200 mg dose with values of 4,270 ng h/mL (n = 6) and 2,910 ng h/mL (n = 6), respectively.


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  		Table 4 The Pharmacokinetics tipifarnib

 
The nine paired pharmacokinetic sample sets were used to compare pharmacokinetic variables of tipifarnib alone and with tamoxifen (Table 4B). With tipifarnib alone, the median normalized AUC0-12h was 3,160 compared with 2,820 ng h/mL for tipifarnib with tamoxifen. This difference was not statistically significant. (P = 0.21).

Pharmacodynamics. FTase inhibition studies in PBMCs were obtained in nine patients on cycle 1 and six patients on cycle 2. All samples were drawn at steady state immediately before the morning dose of drug. Only two patients had paired samples of tipifarnib alone and in combination with tamoxifen at the same dose of tipifarnib for direct comparison. In these two patients, FTase inhibition was similar with and without tamoxifen (27% and 28% with tipifarnib alone and 23% and 30% with tipifarnib + tamoxifen).

At the 200 mg dose, the mean FTase inhibition was 41.5% (n = 11) whereas at 300 mg, the mean FTase inhibition was 53.5% (n = 4; Fig. 2). This difference was not statistically significant. In addition, there was no significant correlation between FTase inhibition and tipifarnib AUC (Rho = 0.31, P = 0.26, Spearman rank correlation, n = 14).



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  		Fig. 2 Pharmacodynamics of tipifarnib. FTase inhibition was determined by [3H] scintillation proximity assay on PBMCs. % Inhibition of baseline activity. Samples were obtained with and without concurrent tamoxifen therapy.

 
Clinical Activity. Of the 12 patients treated, two patients (17%) had a partial response and one patient (8%) had stable disease for over 6 months. The overall clinical benefit rate (partial response + stable disease) was 25% with clinical benefit in patients at both dose levels. Overall, the patients who had clinical benefit had a similar amount of prior therapy in comparison with other patients with an average of two prior chemotherapy regimens and three prior hormonal regimens before enrolling in the study; all patients had received prior tamoxifen therapy. In addition, disease progression on hormonal therapy was documented before starting the trial for all three patients who had clinical benefit. One patient had progressed on fulvestrant after just 1 month. In addition, all three of these patients had received prior high-dose chemotherapy with stem cell transplantation.

Of the two patients who achieved a partial response, one patient had liver, pleural, soft tissue, and bone disease; the other patient had soft tissue and bone disease. Both partial responses lasted 6 months. The patient with stable disease was on study for over 12 months and had bone only disease.

The three patients who had clinical benefit had tipifarnib AUC0-12h's that were similar to patients without clinical benefit. In addition, mean FTase inhibition in PBMCs was similar in the clinical benefit and nonclinical benefit groups at 46.2% and 46.4%, respectively.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study provides the first reported experience using a FTase inhibitor in combination with hormonal therapy for metastatic breast cancer. Given preclinical studies showing synergy, this trial was designed to provide a low toxicity, chronic therapy for use in both the metastatic and adjuvant settings. This phase I experience shows that tipifarnib can be given in combination with tamoxifen safely without a clinically significant pharmacokinetic interaction. In addition, in this heavily pretreated population, with prior progression on hormonal therapy, there was notable clinical activity.

In comparison with the 300 mg dose, tipifarnib at 200 mg was associated with less toxicity and similar biological activity as assessed by FTase inhibition in PBMCs. The higher dose produced grade 3 diarrhea (n = 1) and grade 3 neutropenia (n = 2), and dose reduction was required in all six patients based on conservative dose modification guidelines. In prior tipifarnib studies in hematologic malignancies, neither increased dose nor inhibition of FTase activity correlated with improved clinical response suggesting that lesser inhibition of the enzyme is sufficient to affect susceptible tumors (16). Given the toxicity results we observed, the recommended dose of tipifarnib for this combination is 200 mg BID for 21 of 28 days.

Whereas a number of reported phase II trials have used doses of ≥300 mg, dose reductions in these trials were frequent and toxicity was significant (16–20). Regardless, our experience at 300 mg showed more toxicity than prior studies. Our pharmacokinetic data suggests that this disparity is due to differences in patient population and prior therapies rather than due to an interaction with tamoxifen. Tamoxifen did not seem to have a clinically significant effect on tipifarnib pharmacokinetics suggesting that dose modification of tipifarnib is not necessary when used with tamoxifen.

As was expected based on other studies, there was no apparent relationship between clinical response and either pharmacokinetic (AUC0-12h) or surrogate pharmacodynamic (FTase inhibition) variables. Interestingly, AUC0-12h also did not correlate with FTase inhibition in PBMCs suggesting that factors other than drug concentration may affect inhibition of the enzyme. These factors may include differences in intracellular drug levels or FTase susceptibility to inhibition. The lack of associations between pharmacokinetic, pharmacodynamic, and clinical variables, however, may be due to the small size and low power of this study.

Whereas the study was not designed to assess clinical efficacy, the clinical benefit rate of 25% was encouraging for this heavily pretreated population of patients who had all received prior tamoxifen and progressed on prior hormonal therapy. As a single agent, tipifarnib showed similar benefit in a patient population that was much less heavily pretreated (12). Given that these agents have a synergistic antitumor effect in preclinical studies, the tolerability and early clinical activity of this regimen argues for the initiation of a randomized phase II or III trial to determine if concurrent administration of tipifarnib with tamoxifen can improve clinical outcomes as compared with hormonal therapy alone.

In conclusion, this phase I study shows that tipifarnib can be given with tamoxifen (20 mg/d) with minimal toxicity at 200 mg p.o. BID 21 of 28 days. In addition, no clinically significant interaction was shown. Finally, despite the small size of the study, evidence of clinical activity in this population was encouraging.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: The article has not been previously published, nor has it been submitted to another journal, although preliminary results have been presented in abstract form at the American Society of Clinical Oncology Annual Meeting Volume 23.

The work is a U.S. government work and cannot be copyrighted. None of the authors have any proprietary interest in the compounds used in the trial or any financial interest in the pharmaceutical companies supplying the drugs.

Received 7/16/04; accepted 9/ 8/04.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Knight WA III, Osborne CK, McGuire WL. Hormone receptors in primary and advanced breast cancer. Clin Endocrinol Metab 1980;9:361–8.[Medline]
  2. Schiff R, Massarweh S, Shou J, et al. Breast cancer endocrine resistance: how growth factor signaling and estrogen receptor coregulators modulate response. Clin Cancer Res 2003;9:447S–54.[Abstract/Free Full Text]
  3. Kelly MJ, Levin ER. Rapid actions of plasma membrane estrogen receptors. Trends Endocrinol Metab 2001;12:152–6.[CrossRef][Medline]
  4. Johnston SR, Head J, Pancholi S, et al. Integration of signal transduction inhibitors with endocrine therapy: an approach to overcoming hormone resistance in breast cancer. Clin Cancer Res 2003;9:524S–32.[Abstract/Free Full Text]
  5. Dy GK, Adjei AA. Farnesyltransferase inhibitors in breast cancer therapy. Cancer Invest 2002;20 Suppl 2:30–7.
  6. Sepp-Lorenzino L, Ma Z, Rands E, et al. A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines. Cancer Res 1995;55:5302–9.[Abstract/Free Full Text]
  7. Lebowitz PF, Prendergast GC. Non-Ras targets of farnesyltransferase inhibitors: focus on Rho. Oncogene 1998;17:1439–45.[CrossRef][Medline]
  8. Bishop WR, Kirschmeier P, Baum C. Farnesyl transferase inhibitors: mechanism of action, translational studies and clinical evaluation. Cancer Biol Ther 2003;2:S96–104.[Medline]
  9. Ellis CA, Vos MD, Wickline M, et al. Tamoxifen and the farnesyl transferase inhibitor FTI-277 synergize to inhibit growth in estrogen receptor-positive breast tumor cell lines. Breast Cancer Res Treat 2003;78:59–67.[CrossRef][Medline]
  10. End DW, Smets G, Todd AV, et al. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 2001;61:131–7.[Abstract/Free Full Text]
  11. Kelland LR, Smith V, Valenti M, et al. Preclinical antitumor activity and pharmacodynamic studies with the farnesyl protein transferase inhibitor R115777 in human breast cancer. Clin Cancer Res 2001;7:3544–50.[Abstract/Free Full Text]
  12. Johnston SR, Hickish T, Ellis P, et al. 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;21:2492–9.[Abstract/Free Full Text]
  13. Harvey JM, Clark GM, Osborne CK, et al. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 1999;17:1474–81.[Abstract/Free Full Text]
  14. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–16.[Abstract/Free Full Text]
  15. Zujewski J, Horak ID, Bol CJ, et al. Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol 2000;18:927–41.[Abstract/Free Full Text]
  16. Karp JE, Lancet JE, Kaufmann SH, et al. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Blood 2001;97:3361–9.[Abstract/Free Full Text]
  17. Cohen SJ, Ho L, Ranganathan S, et al. Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma. J Clin Oncol 2003;21:1301–6.[Abstract/Free Full Text]
  18. Cortes J, Albitar M, Thomas D, et al. Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies. Blood 2003;101:1692–7.[Abstract/Free Full Text]
  19. Crul M, de Klerk GJ, Swart M, et al. Phase I clinical and pharmacologic study of chronic oral administration of the farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol 2002;20:2726–35.[Abstract/Free Full Text]
  20. Adjei AA, Mauer A, Bruzek L, et al. Phase II study of the farnesyl transferase inhibitor R115777 in patients with advanced non-small-cell lung cancer. J Clin Oncol 2003;21:1760–6.[Abstract/Free Full Text]



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