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Journal of Clinical Oncology, Vol 24, No 28 (October 1), 2006: pp. 4558-4564 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.8123 Clinical and Pharmacologic Study of the Farnesyltransferase Inhibitor Tipifarnib in Cancer Patients With Normal or Mildly or Moderately Impaired Hepatic Function
From the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam; Faculty of Pharmaceutical Sciences, Division of Drug Toxicology, University Utrecht, Utrecht, the Netherlands; Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium; and Johnson & Johnson Pharmaceutical Research & Development, Titusville, NJ Address reprint requests to Wandena S. Siegel-Lakhai, PhD, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; e-mail: wan.les{at}quicknet.nl
PURPOSE: This study explored the feasibility of treating patients with impaired hepatic function with tipifarnib. The safety profile, pharmacokinetics, and relationship between the pharmacokinetics and toxicities were evaluated. PATIENTS AND METHODS: Patients with mildly or moderately impaired hepatic function (Child-Pugh classification) were treated with tipifarnib bid on days 1 to 5 of cycle 1. Further dosing was based on the individual day 5 pharmacokinetic data and absolute neutrophil count. For patients with normal hepatic function, tipifarnib was dosed on days 1 to 14, followed by 1 week of rest. For all patients, in subsequent cycles, tipifarnib was administered for 21 consecutive days out of every 28 days. RESULTS: Twenty-eight patients were included in the normal (n = 16), mild (n = 9), and moderate (n = 3) impairment groups. The most important grade 3 to 4 hematologic toxicity was leukocytopenia/neutropenia, which was mostly observed in patients with moderate impairment. Common nonhematologic toxicities were fatigue, nausea, and vomiting. The pharmacokinetic data showed higher plasma concentrations of tipifarnib in patients with liver impairment compared with patients with normal hepatic function. CONCLUSION: In patients with mildly impaired hepatic function, tipifarnib can be administered safely at a starting dose of 200 mg bid, but it is not safe to treat patients with moderate hepatic impairment.
Tipifarnib (Zarnestra, R115777; Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium) inhibits the enzyme farnesyltransferase, which is required for the activation of such proteins as Ras, RhoB, and CENP-E, which are involved in cell growth, apoptosis, cytoskeletal organization, and mitosis.1-5 In phase I trials in patients with solid and hematologic malignancies, the incidence of neutropenia, the most common toxicity, was related to the dose and systemic exposure of tipifarnib.6-8 The most common regimen for tipifarnib, used in several phase II and III studies in solid tumors and myelodysplastic syndromes, is 300 mg bid for 21 consecutive days followed by a 1-week rest.9-15 Currently, single-agent tipifarnib and combinations with other cytotoxic agents are being studied in hematologic malignancies. Patients with severe liver enzyme elevations have been excluded from all studies. However, a significant number of patients with advanced cancer have impaired hepatic function because of metastases, diffuse hepatic involvement, or underlying disease. The present study was conducted to explore the feasibility of treating patients with impaired hepatic function with tipifarnib. Tipifarnib is primarily metabolized by liver-specific enzymes (CYP3A4, CYP2C19, CYP2A6, CYP2D6, and CYP2C8/9/10) and by the glucuronosyltransferase isozyme UGT1A1.16 It is expected that patients with liver insufficiency have less efficient metabolism of tipifarnib, resulting in higher systemic exposure and more toxicity. Therefore, evaluation of tipifarnib in these patients was warranted. The primary objectives of this study were to monitor the safety profile, to evaluate the pharmacokinetics, and to explore relationships between pharmacokinetics and toxicities.
Eligibility Patients (age  18 years) were eligible if they had a pathologically confirmed advanced solid tumor for which no curative therapy exists, had an Eastern Cooperative Oncology Group performance status of  2, and had given written informed consent. Previous anticancer chemotherapy had to be discontinued for 4 weeks before study entry. All patients had to have acceptable bone marrow function (absolute neutrophil count [ANC] 4,000/µL and platelets > 100,000/µL) and adequate renal function (creatinine clearance 50 mL/min). Patients had to have mildly impaired (grade A), moderately impaired (grade B), or normal hepatic function (Child-Pugh classification; Table 1). 17 The study protocol was approved by the medical ethics committee of the hospital.
Treatment Plan and Study Design Tipifarnib was supplied by Johnson & Johnson Pharmaceutical Research & Development as 50- and 100-mg tablets. The drug was administered orally bid. Initially, six to nine patients with mildly impaired hepatic function, six to nine patients with moderately impaired hepatic function, and nine patients with normal hepatic function were planned to be included. The starting dose for all patients was 200 mg bid administered on days 1 to 5 of cycle 1. For patients with normal hepatic function, dosing of tipifarnib in cycle 1 was continued at 300 mg bid on days 6 to 14, followed by a 1-week rest. In cycle 2 and subsequent cycles, tipifarnib was administered at 300 mg bid for 21 consecutive days out of every 28 days. For patients with hepatic impairment, the first cycle consisted of 5 consecutive days of tipifarnib bid, followed by a rest period of 16 days. The starting dose for cycle 2 was based on the individual area under the plasma concentration-time curve from 0 to 12 hours (AUC0-12 hours) value of tipifarnib estimated on day 5 of cycle 1 (Table 2). Patients were treated at the adjusted dose for 21 consecutive days out of every 28 days.
During the initial part of the study, one patient with moderately impaired hepatic function experienced fatal neutropenic sepsis after 5 days of tipifarnib 200 mg bid. This event was associated with high plasma drug concentrations. As a result, the study was amended, and the starting dose of tipifarnib in cycle 1 was decreased to 50 mg bid for all patients. Dosing of patients with normal hepatic function for days 6 to 14 of cycle 1 remained at 300 mg bid. For patients with hepatic impairment, the starting dose for cycle 2 was based on the combination of individual ANC and AUC0-12 hours values of tipifarnib on day 5 of cycle 1 (Table 3). For all patients, further dose adaptation was performed in the event of grade 3 to 4 toxicity.
Patient Evaluation and Follow-Up Complete patient history, physical examination, hematology, and clinical chemistry were performed at baseline and before each cycle of treatment. Clinical chemistry was repeated on day 5 of cycle 1, on day 15 of subsequent cycles, and at study termination. Hematology was repeated on days 5, 8, and 15 of cycle 1; on days 8, 15, and 22 of subsequent cycles; and at study termination. Although objective tumor response was not a primary objective of this study, tumor lesions were, if possible, measured and evaluated, according to the Response Evaluation Criteria in Solid Tumors, at baseline and on treatment.18 All adverse events were graded according to the National Cancer Institute Common Toxicity Criteria version 2.0.19
Pharmacokinetics
Pharmacokinetic Analysis
Statistical Analysis
Pharmacokinetic-Pharmacodynamic Analysis This pharmacokinetic-pharmacodynamic analysis could only be performed for patients with an impaired hepatic function. For patients with normal hepatic function, the AUC0-12 hours measured on day 5 could not be used as a measure for drug exposure during cycle 1 because these patients received additional tipifarnib treatment with another dose (300 mg bid) on days 6 to 14 compared with days 1 to 5 (200 or 50 mg bid).
Patient Characteristics Baseline characteristics for all 28 patients entered onto the study are listed in Table 4. Overall, 16 patients with normal hepatic function, nine patients with mildly impaired hepatic function, and three patients with moderately impaired hepatic function were included. Initially, nine patients with normal hepatic function were included as a control group and were treated with a starting dose of 200 mg bid tipifarnib. One additional patient was mistakenly classified in the mild impairment group but had a normal hepatic function and was reclassified accordingly. Three patients were included in the moderately impaired hepatic function group. One of these patients developed grade 4 neutropenia on day 7 and experienced fatal sepsis after administration of tipifarnib 200 mg bid for 5 days. This event was associated with high AUC0-12 hours levels on day 1 (5,199 ng/h/mL) and on day 5 (14,703 ng/h/mL). The latter value was approximately four times as high as the expected average AUC0-12 hours (3,300 ng/h/mL) for tipifarnib 200 mg bid in patients with normal hepatic function. Therefore, it was decided to reduce the starting dose by a factor of 4. All subsequent patients received a starting dose of 50 mg bid on days 1 to 5 of cycle 1. At this dose, nine patients were included in the mildly impaired hepatic function group and six patients were included in the control group to allow comparison between these groups. No further patients with moderately impaired hepatic function were included because of safety reasons.
Adverse Events All patients were assessable for toxicity (Table 5). Grade 3 to 4 hematologic toxicities were observed in seven (25%) of 28 patients. Neutropenia (including febrile neutropenia) and leukocytopenia were the most frequently observed hematologic toxicities. All three patients with moderately impaired hepatic function developed severe hematologic toxicities. One patient, who was treated at 300 mg bid in cycle 2, experienced grade 4 leukocytopenia and neutropenia and went off-study. The second patient developed grade 3 thrombocytopenia in cycle 2 that recovered within 1 week. The last patient experienced grade 3 thrombocytopenia, grade 3 anemia, grade 4 leukocytopenia, and grade 4 neutropenia during the first cycle; these toxicities were complicated by severe infection, leading to fatal neutropenic sepsis as described previously.
The main nonhematologic grade 3 toxicity was fatigue (11%). Grade 1 to 2 nausea and vomiting occurred in 39% and 29% of all patients, respectively. Hepatic function did not worsen during treatment with tipifarnib. One patient developed sensory neuropathy and recovered within 11 days. The majority of patients discontinued treatment as a result of progressive disease (23 of 28 patients, 82%), including one death due to progressive disease. Four patients (14%), including all those with moderate impairment, discontinued treatment because of adverse events. One patient was discontinued from therapy because of continued stable disease, without further improvement, at the end of cycle 14. In the control cohort, none of the patients had a dose reduction. In the mild impairment cohort, four patients who started cycle 2 were treated at a lower dose based on the pharmacokinetic ANC rule. In the moderate impairment group, one patient did not start cycle 2, whereas the other two patients received the full dose of 300 mg bid; both of these patients went off-study as a result of adverse events.
Pharmacokinetics
The AUC0-12 hours in the mildly impaired hepatic function group was 1.8 times as high as in the normal group (Table 7). Again, the difference was not statistically significant because of considerable interpatient variability: (%CV was 84% in the mild group and 52% in the normal group). There were no significant differences in tmax and Cmax.
Pharmacokinetic-Pharmacodynamic Analysis
Response The best tumor responses are listed in Table 8. Five of the 28 patients were not assessable; four patients went off-study as a resultof toxicity, and one patient died before response evaluation. Six patients (21%) had stable disease for a median of one cycle (range, one to 12 cycles).
In this study, tipifarnib was investigated in patients with impaired and normal hepatic function. Conforming with the US Food and Drug Administration guidelines, the Child-Pugh classification was used to classify patients in the mildly and moderately impaired cohorts. Liver function parameters, such as AST, ALT, gamma glutamyl transpeptidase, and alkaline phosphatase (AP), were not included in the stratification procedure. Nevertheless, the patients included in the normal cohort had normal or slightly elevated AST, ALT, AP, and gamma glutamyl transpeptidase values according to the classification system described by Doroshow et al.23 The pharmacokinetic data of tipifarnib showed that the mean systemic exposure was about 1.3 to 1.8 times higher in patients with impaired hepatic function compared with patients with normal hepatic function. The observed differences did not reach statistical significance because of the high interpatient variability (this is in agreement with other studies20,21) and the small sample size for patients with moderate impairment. The pharmacokinetic assessment at the 50-mg bid dose had an adequate number of patients included in the normal function group (n = 6) and the mildly impaired hepatic function group (n = 9) to make a comparative evaluation of the pharmacokinetics.17 The higher tipifarnib plasma concentrations observed in patients with impaired hepatic function were as expected because tipifarnib is primarily metabolized by liver-specific CYP450 enzymes and UGT1A1.16 Genetic polymorphisms of the CYPP450 enzymes and UGT1A1 could also contribute to the high plasma concentrations, but other studies have shown that mutations in the metabolizing enzymes CYP3A4/5 and UGT1A1 have no clinically relevant impact on the pharmacokinetics of tipifarnib (data on file).16 The present study has some limitations. We used one classification system to include patients in the different cohorts. The US Food and Drug Administration guidelines recommend the use of the Child-Pugh classification (used in this study), whereas others have favored criteria based on transaminase and bilirubin levels.23 Because of the data from prior population pharmacokinetic analyses showing no impact of these parameters, such classification was not used. Moreover, the patients included in the normal cohort had normal or slightly elevated transaminase and bilirubin levels. Furthermore, the study was begun at the time tipifarnib was primarily developed in solid tumors. Currently, tipifarnib is being studied more extensively in hematologic malignancies. These patients do not develop hepatic dysfunction due to extensive metastases, but it can still be encountered because of diffuse leukemic infiltration or concomitant disease. In that perspective, this study remains of importance. Although myelosuppression is a targeted effect in the treatment of hematologic disorders, this adverse event, for tipifarnib, remains most closely linked to exposure. Therefore, it is appropriate to use this toxicity as a measure of safety of the drug as linked to exposure changes. The pharmacokinetic-pharmacodynamic analysis revealed no correlation between the systemic exposure of tipifarnib and the incidence of myelosuppression in patients with mild impairment. This was probably because the AUC0-12 hours values were less than 5,000 ng/h/mL, below which the incidence of grade 3 to 4 neutropenia is negligible.22 In the moderate impairment group, high systemic exposure was linked to severe myelosuppression in one patient. The other two patients had systemic exposures closer to that in the control group. These two patients were treated with the full dose recommended for normal function patients in cycle 2, but one patient went off-study during this cycle because of severe myelosuppression, and the other patient went off-study as a result of nonhematologic adverse event. It could be argued that the Child-Pugh classification may not be the best system for estimating the impact of liver function on the clearance of tipifarnib. Before this study, a population pharmacokinetic analysis of tipifarnib was performed using the nonlinear mixed effects model software. These analyses characterized the pharmacokinetic properties of tipifarnib (including the degree of variability) and evaluated the impact of patient and treatment-related covariates as potential sources of pharmacokinetic variability. The variability in clearance could not be explained by patient-related covariates or by liver parameters (AST, ALT, lactate dehydrogenase, AP, and total bilirubin), renal function (creatinine clearance), serum concentration of total protein, albumin, prothrombin time, and tumor type. Thus, the adjustment of tipifarnib dose on the basis of any of these covariates tested is not warranted, and accordingly, a priori stratification for these parameters was not performed. Also for this study, no relationship was apparent between these covariates and the plasma AUC0-12 hours (data not shown). Although response evaluation was not a primary objective of this study, tumor measurements were performed in most patients. Stable disease was observed in 21% of the patients, all without liver insufficiency. This study demonstrated that it is safe to treat solid cancer patients with mildly impaired hepatic function using tipifarnib, provided that there is close monitoring of toxicity with dose reduction when indicated. For these patients, the starting dose should likely be 200 mg bid rather than 300 mg bid based on observed pharmacokinetic data with slightly higher accumulation as well as the observation that half of the patients needed a dose reduction to 200 mg bid for the second cycle. Furthermore, increased sensitivity of normal organs to the toxic effects of tipifarnib in patients with mildly impaired liver function cannot be excluded. In conclusion, patients with worse than mild liver function impairment should not be treated with tipifarnib.
Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-$99,900 (C)
Supported by Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
), platelets (
), and leukocytes (
) observed during cycle 1 versus area under the plasma concentration-time curve from 0 to 12 hours (AUC0-12 hours) measured on day 5 in patients with (A) moderately and (B) mildly impaired hepatic function treated with tipifarnib 200 mg bid (moderately impaired hepatic function) and 50 mg bid (mildly impaired hepatic function).
