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Dose-Ranging Pharmacodynamic Study of Tipifarnib (R115777) in Patients With Relapsed and Refractory Hematologic Malignancies

From the Department of Medicine, Section of Hematology/Oncology University of Chicago, Chicago, IL

Address reprint requests to Todd M. Zimmerman, MD, University of Chicago, 5841 S Maryland Ave, MC 2115, Chicago, IL 60637; e-mail: tzimmerm{at}medicine.bsd.uchicago.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Tipifarnib, an orally bioavailable inhibitor of farnesyl transferase, has activity in hematologic malignancies, but the dose required to achieve the proposed biologic end point, inhibition of farnesylation, is unknown.

PATIENTS AND METHODS: The impact on post-translational farnesylation was assessed in 42 patients with refractory hematologic malignancies and bone marrow involvement. Tipifarnib was taken orally for 21 days of a 28-day cycle. For cycle 1, patients were randomly assigned to one of four dose levels: 100 mg bid, 200 mg bid, 300 mg bid, and 600 mg bid. In cycle 1, peripheral blood and bone marrow mononuclear cells were analyzed for inhibition of HDJ2 prenylation by Western blot analysis at baseline and on day 21.

RESULTS: Twenty-three patients were assessable for analysis of HDJ2 prenylation before and after therapy. Inhibition of farnesylation was noted at all dose levels, although the highest level of inhibition was noted at the 300-mg-bid dose. The inhibition of farnesylation in the peripheral blood correlated with the inhibition in the bone marrow (r = 0.62). Of the 26 patients assessable for clinical activity after cycle 1, three patients had a significant decrease in total blasts count (acute myeloid leukemia in two patients, and chronic myelogenous leukemia in one patient). The inhibition of farnesylation was greater in the three responders than the nonresponders (P = .03).

CONCLUSION: Farnesylation as measured by HDJ2 analysis was inhibited at all dose levels administered. Clinical activity may correlate with the degree of farnesylation inhibition, rather than dose of tipifarnib, and escalation beyond 300 mg bid might not result in additional clinical activity.

	INTRODUCTION

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The ras family of proto-oncogenes is crucial to the malignant transformation and growth of many solid tumors and hematologic malignancies.^1-4 The mammalian proto-oncogenes H-ras, N-ras, and K-ras encode for p21^ras, a group of GTP/GDP binding proteins that are only functionally active when localized to cellular membrane.⁵ Prenylation, a post-translational modification event, is required for membrane localization of p21^ras.^6,7 p21^ras acts downstream of various growth factors and cytokines to activate a number of signaling pathways that ultimately lead to cell growth and proliferation. The main naturally occurring prenylation event for p21^ras is farnesylation, in which a 15-carbon farnesyl group is covalently bound to the conserved CAAX motif. The enzyme responsible for this process is farnesyl protein transferase (FT). While ras is perhaps the best-described target, post-translational farnesylation is also necessary for other key regulatory proteins.^8,9 As such, FT is a potential therapeutic target for new anticancer agents.¹⁰

Tipifarnib (R115777) is an orally bioavailable FT inhibitor¹¹ that is being evaluated in a broad range of hematologic malignancies and solid tumors.^1-4 It acts as a competitor for the CAAX motif to potently and specifically inhibit FT activity. In tumor cell culture systems, tipifarnib inhibits cellular proliferation in cell lines carrying H-ras, K-ras, and N-ras mutations, as well as in ras wild type cell lines.¹² In mouse xenograft models, oral administration of tipifarnib at doses up to 100 mg/kg bid inhibited growth of H-ras transfected tumors and tumors bearing mutated K-ras. Clinically tipifarnib has been tested in a wide array of solid tumors and hematologic malignancies with particular activity noted in patients with acute myeloid leukemia (AML). In one series of AML patients, clinical responses were noted in 10 of 34 patients with poor risk features, demonstrating the promise of this agent.²

While the drug is generally well tolerated, the dose required to achieve the proposed biologic end point, inhibition of farnesylation, is not well described, and this dose may be significantly lower than the currently defined maximally tolerated dose. As such, we explored the impact of dose on the inhibition of farnesylation in a broad range of patients with hematologic malignancies, in order to determine the biologically effective dose of tipifarnib required to inhibit farnesylation measured by HDJ2 Western blot analysis in bone marrow and peripheral blood samples.

	PATIENTS AND METHODS

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Eligibility
Forty-two patients with hematologic malignancies were enrolled onto this trial, which had been approved by the University of Chicago institutional review board. After giving written informed consent, patients underwent eligibility testing. Patients were eligible if they had a refractory or relapsed hematologic malignancy with evidence of bone marrow involvement. No chemotherapy or radiotherapy was allowed within 4 weeks of study entry, excluding carmustine and mitomycin, for which 6 weeks was required. Hydroxyurea was allowed up to 72 hours before study entry. Systemic steroid therapy (excluding physiologic doses) was not allowed within 4 weeks of study entry for patients with multiple myeloma. A Karnofsky performance status of 60% was required, as well as adequate renal function (serum creatinine 2.0 mg/dL) and hepatic function (total bilirubin < 1.5 mg/dL and serum albumin > 2.5 g/dL). Patients with bone marrow dysfunction were eligible regardless of the degree of cytopenias provided they were free of infection or bleeding complications at the time of study entry. Patients with conditions causing malabsorption, including but not limited to inflammatory bowel disease, or prior gastrectomy or ileostomy, were excluded. Patients who had received prior therapy with tipifarnib were ineligible.

Treatment Schema
After completion of eligibility testing, aliquots of peripheral blood and bone marrow were collected and processed as detailed below. Tipifarnib was provided by the National Cancer Institute under a clinical trials agreement with Johnson and Johnson. The patients were then randomized using the permuted blocks method to one of four doses of tipifarnib for the first 21 days of a 28 day cycle: 100 mg bid, 200 mg bid, 300 mg bid, and 600 mg bid. One early patient was randomized to 100 mg daily, but that dose level was later removed after a protocol amendment. On day 21 of the first cycle of therapy, second samples of peripheral blood and bone marrow aspirate were collected and processed as detailed below. For cycle 2 and beyond, intrapatient dose escalation up to the maximally tolerated dose (600 mg bid) was allowed at the discretion of the treating physician and principal investigator.

Toxicity Criteria
All toxicities were assessed according to the National Cancer Institute Common Toxicity Criteria (Version 2.0). Hematologic toxicities were graded according to the NCI criteria for leukemia or bone marrow/myelophthisic processes. Any treatment-related grade 4 hematologic toxicity or febrile neutropenia, or grade 3 or greater nonhematologic toxicity resulted in discontinuation of therapy until resolution of the toxicity to grade 1 or less.

Sample Processing
Heparinized blood and bone marrow aspirate samples (approximately 20 mL each) were drawn before the first dose of tipifarnib (pre) and again after 3 weeks of therapy. Mononuclear cells were prepared from each sample by centrifugation over a Lymphoprep (Axis-Shield, Oslo, Norway) gradient, and the cells were cryopreserved for later batch analysis.

Western Blot
Protein extracts were prepared from each sample after thawing the cryopreserved samples and washing them with phosphate-buffered saline.² The cells were pelleted and lysed in ice-cold RIPA (radioimmunoprecipitation assay) buffer (50 mmol/L Tris-HCl, pH 7.5, 150 mmol/L NaCl, 0.1% Triton X-100, 0.5% deoxycholate, 0.1 mmol/L ethyleneglycoltetracetic acid, 0.1 mmol/L EDTA) with protease inhibitors for 5 minutes on ice.¹³ Unsolubilized material was pelleted and discarded. The protein concentration of each lysate was quantified using a colorimetric assay (BCA Protein Assay; Pierce, Rockford, IL) and 50 µg of total protein was loaded on an 8% sodium dodecyl sulfate (SDS) polyacrylamide gel. The Western blots were transferred to polyvinyledene difluoride membrane and probed with a mouse monoclonal antibody against HDJ2 (KH2A5.6; NeoMarkers, Fremont, CA). Bound antibody was detected using a horseradish-peroxidase-conjugated secondary antibody and visualized by treating the membrane with enhanced chemiluminescence reagents (Amersham Pharmacia Biotech Inc, Piscataway, NJ) and exposing it to film.

Densitometry Analysis
Films were scanned and the data stored as graphic (bmp) files. Each HDJ2 sample was divided into an upper and lower quadrangle (corresponding to unfarnesylated and farnesylated HDJ2 protein respectively) of the same size, and the number of pixels contained in each quadrangle determined using UN-SCAN-IT gel automated digitizing system software (Silk Scientific, Orem, UT). The fraction of unfarnesylated HDJ2 protein was determined for all samples, and the percent shift for each patient was calculated by subtracting the percent unfarnesylated protein in the pretreatment sample from the percent in the post-treatment sample.

In Vitro Modeling
In vitro modeling of inhibition of farnesylation and tumor cell proliferation was performed utilizing the K562 cell line. K562 cells were cultured in complete RPMI medium (RPMI 1640 supplemented with 10% fetal bovine serum, penicillin, streptomycin, HEPES buffer and L-glutamine) in the presence or absence of tipifarnib for 24 hours. Inhibition of farnesylation was assessed at 0, 8, 40, 200, and 1,000 nmol/L tipifarnib as described above. In addition, inhibition of cellular proliferation was assayed at 0, 1.6, 8, 40, 200, 1,000, 5,000, and 10,000 nmol/L tipifarnib using thymidine incorporation as a measure of proliferation. After the 24-hour culture, K562 cells were harvested and counted. Triplicate samples of 5 x 10⁴ cells/well were plated on 96-well plates, in the continued presence of tipifarnib where appropriate. 1 µCi of [³H]thymidine was added to each well and cultures collected after overnight incubation. Cells were harvested using a Filtermate harvester and incorporated [³H]thymidine was detected using a TopCount NXT microplate scintillation and luminescence counter with TopCount NXT software (Packard BioScience, Meriden, CT).

Statistical Analysis
All analyses were conducted using STATA 7.0. Analysis of variance (ANOVA) was used to evaluate the relationship between the dose of tipifarnib and the percent inhibition of farnesylation in the bone marrow and peripheral blood. Quadratic regression models were also fit to these data. The correlation between bone marrow and peripheral blood levels was determined using Pearson's product-moment correlation coefficient. The nonparametric, Wilcoxon rank sum test was used to compare the percent inhibition of farnesylation between those with and without evidence of clinical response to tipifarnib.

	RESULTS

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Patient Characteristics
Forty-two patients were enrolled onto the study with a summary of the patient characteristics detailed in Table 1. The majority of patients had AML, and the distribution of diseases by dose level is shown in Table 2. One patient was enrolled and randomized to a 100 mg daily dose before the discontinuation of this dose level via a protocol amendment; this dose was replaced by the addition of the 600 mg bid dose. The 100 mg daily dose level and the single patient were not analyzed further. One additional patient did not start therapy secondary to declining performance status after signing consent and completion of eligibility testing. Of the remaining 40 patients, 26 completed the first cycle of therapy and were evaluated for disease response. Reasons for discontinuation included grade 3 or 4 toxicity including febrile neutropenia, bleeding, and fatigue during the first cycle.

Toxicity
Tipifarnib therapy was generally well tolerated. A detailed listing of the toxicities is noted in Table 3. Only one grade 3 toxicity, fatigue, was directly attributable to tipifarnib, occurring at the 600-mg-bid dose level. The fatigue improved considerably when the dose was decreased to 300 mg bid with the subsequent cycle. The remaining grade 3 or 4 toxicities as noted in Table 3 were attributed to the underlying disease, as each of the patients experiencing grade 3 or 4 hematologic toxicity had significant bone marrow dysfunction before study entry.

View larger version (29K): [in this window] [in a new window]   Fig 1. Western blot from a patient before (pre) and after (post) 21-day course of tipifarnib. Protein extracts from peripheral blood (A) or bone marrow (B) were made and equal amounts of protein resolved using SDS-PAGE. HDJ2 protein was detected as a marker of the level of inhibition of farnesylation. U, unfarnsylated; F, farnesylated.

View larger version (9K): [in this window] [in a new window]   Fig 2. Relationship between dose of tipifarnib and inhibition of farnesylation. (A) The percent inhibition of farnesylation in bone marrow. The level of farnesylation for each patient before treatment and at day 21 was determined using HDJ2 Western blotting and densitometry analysis. (B) The percent inhibition of farnesylation in peripheral blood.

While measurement of farnesylation status of cellular proteins addresses whether tipifarnib acts as an inhibitor of farnesylation, we also wanted to determine the extent of inhibition of farnesylation that correlates with an antiproliferative effect of the drug. To investigate this question, we chose an in vitro modeling system using K562 cells—a leukemia cell line originally derived from a patient with CML. In vitro, 50% inhibition of farnesylation occurred with concentrations of tipifarnib around 200 nmol/L as shown in Figure 3A. In a parallel experiment, assessment of thymidine incorporation demonstrated that inhibition of proliferation began to occur after the concentration of tipifarnib exceeded 1,000 nmol/L (Fig 3B). This result suggests that a high degree of inhibition of farnesylation (ie, > 50%), as measured by the degree of HDJ2 gel retardation, is required for the inhibition of tumor cell proliferation in vitro.

View larger version (17K): [in this window] [in a new window]   Fig 3. In vitro analysis of the effect of tipifarnib on K562 cells. (A) Relationship between inhibition of farnesylation and concentration of tipifarnib. K562 cells were treated with the indicated concentrations of tipifarnib for 24 hours. (B) Relationship between concentration of tipifarnib and proliferation of K562 cells using a [3H] thymidine incorporation assay. U, unfarnsylated; F, farnesylated; cpm, counts per minute.

	DISCUSSION

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Of the four doses of tipifarnib tested, the lowest dose (100 mg bid) resulted in the lowest mean level of unfarnesylated proteins in the peripheral blood samples, whereas the highest mean inhibition occurred at the 300-mg-bid dose. However, no significant differences were detected among the bone marrow samples. The absence of a statistically significant relationship in the bone marrow is most likely related to the single outlier at the 100-mg-bid dose as noted in Figure 2A; however, since this outlier had evidence of clinical activity, it was included in the analysis. Karp et al² also noted inhibition of farnesylation in the patients treated at 100 mg bid, but the degree of inhibition at this dose level was less predictable, suggesting that doses higher than 100 mg bid are required to reproducibly inhibit farnesylation. Of note, the overall mean inhibition of farnesylation was lower in our series (around 33%) than that which was reported in the Karp series (75%). This difference could be related to the more heterogenous patient population in our current report, or to a difference in the time point analyzed (day 21 compared with day 8 in the Karp et al series). It may be of interest to assess farnesylation at multiple time points in future studies.

Three patients had evidence of modest clinical activity after the first 21-day course of therapy. While these three patients would not meet the standard definition of clinical response, more liberal criteria were used since clinical activity assessments were made after only one cycle of therapy in order to correlate with the biochemical data. While the number of those with evidence of clinical activity is small, we did find greater inhibition of farnesylation in those with evidence of clinical activity. This finding is in contrast to the Karp et al series,² in which there was no apparent association between clinical activity and inhibition of farnesylation. The association noted in our series, however, is based on only a limited number of patients; thus, a firm conclusion regarding the association between FT inhibition and clinical activity cannot be drawn. This should be explored in future clinical trials.

Taken together with the observation that intrapatient dose escalation failed to result in clinical activity and no further increase of inhibition of farnesylation above the 300-mg-bid dose, our results suggest that doses of tipifarnib higher than 300 mg bid are not likely to be associated with increased clinical activity in this patient population. Although earlier studies have demonstrated that a higher C_max level (1,700 ng/mL) can be achieved at the 600-mg-bid dose than the 300-mg-bid dose,² this increase does not seem to affect either FT inhibition or clinical activity.

It must be noted that the inhibition of farnesylation of ras or other proposed targets within the malignant cell was not directly assessed in this study. Prenylation of HDJ2 was used as a readout for protein farnesylation because it is expressed at high levels and has a higher molecular weight, increasing the accuracy of the Western blot analysis at distinguishing the farnesylated and unfarnesylated species. While HDJ2 prenylation is a good surrogate, it is possible that analysis of other prenylated proteins might show a greater or lesser effect of tipifarnib treatment. In addition, each bone marrow aliquot analyzed contained both malignant and normal hematopoieitic mononuclear cells, with malignant cells ranging from less than 5% to more than 95% of the marrow elements at baseline. As such, a differential inhibition of farnesylation between malignant and normal cells cannot be ruled out. Separation of tumor cells from normal cells could help sort this out in future trials.

As seen with other targeted agents, the inhibition of Ras farnesylation may not be the most clinically relevant target of tipifarnib, or alternately may represent only one of several molecular targets of this agent. In vitro studies have demonstrated antiproliferative activity of tipifarnib against tumor cell lines that lack ras mutations.⁸ An association with inhibition of Rho family GTPases and antitumor activity also has been observed.^9,17 In vivo, higher levels of vascular endothelial growth factor were associated with a better response to tipifarnib in patients with agnogenic myeloid metaplasia, arguing for a potential activity against angiogenic factors.¹

Although the primary end point of our study was not clinical response, there was modest clinical activity noted in three patients. While it may seem that the clinical activity noted among the AML patients in our series was slightly lower than previously reported² the patients in this series were evaluated after only one cycle of therapy and earlier reports have shown that a longer duration of therapy is required in order to achieve a maximal response. Other potential explanations include differences due to biologic characteristics of the patients enrolled, such as AML subtype, immunophenotypic characteristics, and cytogenetics. These are already well-established predictors of response in AML, but differential responses to tipifarnib based on these characteristics will only be detected through trials that enroll larger numbers of patients. In addition, recent reports have shown higher clinical response rates in untreated patients as opposed to heavily pretreated patients similar to our series.^18,19

Assuming that inhibition of farnesylation is the correct biomarker, the in vitro data suggest that substantial inhibition of farnesylation is required in order for tipifarnib to exert its cytotoxic effect. While translating in vitro models to the clinical setting has limitations, only one patient in this series had near-complete inhibition of farnesylation (99%) and intriguingly, this patient was the one with the greatest reduction in bone marrow blast count. If however, near-complete inhibition of farnesylation is required for clinical activity, then our dose-response results suggest that escalation of the tipifarnib dose would not be sufficient for this to occur. As the concentrations of tipifarnib required to significantly inhibit farnesylation in the in vitro experiments are not achievable clinically, alternate methods to inhibit farnesylation may be required. It is also formally possible that molecular targets other than FT are inhibited by this agent.

Tipifarnib is also being evaluated in a number of solid tumors including breast cancer and glioblastoma and has potential in other malignancies such as pancreatic carcinoma²⁰ or melanoma,²¹ where the ras family of oncogenes is hypothesized to play a crucial role in the pathogenesis of the disease. While recognizing the limitations of comparing the impact of tipifarnib in the peripheral blood and bone marrow compartments, the correlation noted between the inhibition of farnesylation in peripheral blood mononuclear cells and malignant cells may help to guide future studies where repeated biopsies of the tumor are not feasible. Our finding that doses above 300 mg bid do not result in increased inhibition of farnesylation may also be useful for future studies. Future investigations exploring alternate biomarkers should improve even further our understanding of the activity of this agent.

	Authors' Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Mark J. Ratain, Alza Pharmaceutical. For a detailed description of this category, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration form and the "Disclosures of Potential Conflicts of Interest" section of Information for Contributors found in the front of every issue.

	NOTES

 
Supported by National Institutes of Health grants U01 CA-69852, U01 CA-14599, and K23 CA-87044, and by a gift from the O'Connor Foundation.

Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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5. Rebollo A, Martinez A: Ras proteins: Recent advances and new functions. Blood 94:2971-2980, 1999[Free Full Text]

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8. Jiang K, Coppola D, Crespo NC, et al: The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. Mol Cell Biol 20:139-148, 2000[Abstract/Free Full Text]

9. Lebowitz PF, Predergast GC: Non-ras targets of farnesyl transferase inhibitors: Focus on Rho. Oncogene 17:1439-1445, 1998[CrossRef][Medline]

10. Johnston SRD: Farnesyl transferase inhibitors: A novel targeted therapy for cancer. Lancet Oncol 2:18-26, 2001[CrossRef][Medline]

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12. 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 61:131-137, 2001[Abstract/Free Full Text]

13. Shiels H, Li X, Schumacker PT, et al: TRAF4 deficiency leads to tracheal malformation with resulting alterations in air flow to the lungs. Am J Pathol 157:679-688, 2000[Abstract/Free Full Text]

14. Slamon DJ, Leyland-Jones B, Shal S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001[Abstract/Free Full Text]

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17. Du W, Lebowitz PF, Predergast GC: Cell growth inhibition by farnesyltransferase inhibitors is mediated by a gain of geranylgeranlyated RhoB. Mol Cell Biol 19:1831-1840, 1999[Abstract/Free Full Text]

18. Harousseau JL, Reiffers J, Lowenber B, et al: Zarnestra TM (R115777) in patients with relapsed and refractory acute myelogenous leukemia (AML): Results of a multicenter phase 2 study. Blood 102:176a, 2003 (abstr 614)

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Submitted March 29, 2004; accepted September 17, 2004.

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