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Phase I and Pharmacokinetic Study of Imatinib Mesylate in Patients With Advanced Malignancies and Varying Degrees of Liver Dysfunction: A Study by the National Cancer Institute Organ Dysfunction Working Group

Ramesh K. Ramanathan, Merrill J. Egorin, Chris H.M. Takimoto, Scot C. Remick, James H. Doroshow, Patricia A. LoRusso, Daniel L. Mulkerin, Jean L. Grem, Anne Hamilton, Anthony J. Murgo, Douglas M. Potter, Chandra P. Belani, Michael J. Hayes, Bin Peng, S. Percy Ivy

From the Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine; the Biostatistics Department, University of Pittsburgh Graduate School of Public Health; and the Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, PA; the University of Texas, San Antonio, TX; Case Western Reserve University, Cleveland, OH; City of Hope National Medical Center, Duarte, CA; Wayne State University, Detroit, MI; the University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, WI; New York University, New York, NY; the Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute; the National Naval Medical Center, Bethesda, MD; and Novartis Pharmaceuticals, East Hanover, NJ

Corresponding author: Ramesh K. Ramanathan, MD, Translational Genomics Research Institute, 13208 E Shea Blvd, Ste 100, Scottsdale, AZ 85259; e-mail: rramanathan{at}tgen.org

	ABSTRACT

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

 
Purpose To develop dosing guidelines and to evaluate the pharmacokinetics of imatinib in patients with liver dysfunction (LD).

Patients and Methods Patients (N = 89) with varying solid tumors and liver function were stratified into four groups according to serum total bilirubin and AST and were treated with escalating doses of imatinib. Plasma and urine were assayed for concentrations of imatinib and its active metabolite, CGP74588.

Results In the mild LD group, dose-limiting toxicity, specifically nausea/vomiting and fatigue, occurred in two patients at the 600 mg/d dose level. In the moderate and severe LD groups, the maximal dose evaluated was 300 mg/d. Grade 3 to 4 toxicities consisted primarily of liver function test elevations (24%), nausea/vomiting (10%), fatigue (6%), and edema (5%). After the first imatinib dose, the mean (± SD) dose-normalized areas under the plasma concentration-time curve from time 0 to infinity (AUC_0-) were 162 ± 155, 171 ± 72, 182 ± 157, and 185 ± 172 (µg/mL x h)/mg for normal, mild, moderate, and severe LD groups, respectively. Renal excretion of imatinib was less than 10% of the total dose in all groups.

Conclusion Imatinib exposure (as measured by the dose-normalized AUC) did not differ between patients with normal liver function and those with LD. The maximal recommended dose of imatinib for patients with mild LD is 500 mg/d. Dosing guidelines for patients with moderate and severe LD remain undetermined.

	INTRODUCTION

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

 
Imatinib (STI571, Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) is a protein kinase inhibitor of BCR-ABL, c-kit, platelet-derived growth factor receptor, and stem-cell factor receptor.^1-4 Imatinib is now a standard treatment for chronic myeloid leukemia (CML) and for gastrointestinal stromal tumors (GIST).^5-8 The recommended daily oral dose of imatinib ranges from 400 to 800 mg, and 400 mg is the common starting dose. A phase I dose-escalation study was conducted in 83 patients with chronic-phase CML.⁵ The dose of imatinib was escalated from 25 mg/d to 1,000 mg/d across 14 dose levels. The maximum tolerated dose (MTD) was not identified. Most patients who were administered a dose of 300 mg/d or greater responded, and the dose recommended for the treatment of CML was 400 mg/d based on clinical and preclinical data.^5,9

In patients with normal liver function, imatinib exposure is proportional to dose between 25 mg/d and 1,000 mg/d, with a 1.5- to 3-fold increase in serum concentration at steady-state compared with day 1.^9,10 Imatinib is metabolized in the liver and is excreted through the bile, primarily by CYP3A4 and 5, to its main metabolite, CGP74588,^11-13 and less than 10% of a daily imatinib dose is excreted in the urine.¹⁴ Although safety and pharmacokinetics (PK) data are available for healthy volunteers and cancer patients with normal hepatic function,^9,10 the toxicity and PK of imatinib in patients with liver dysfunction (LD) have not been characterized.

LD is a common occurrence in patients with cancer, and drugs that undergo hepatic metabolism or excretion may require dose reduction in patients with LD. Guidelines for dose adjustments of anticancer drugs are typically based on liver function tests (LFTs), such as serum total bilirubin (TB), AST, ALT, or alkaline phosphatase (AP). Recent clinical trials have used these criteria to evaluate agents such as gemcitabine, paclitaxel, irinotecan, docetaxel, and oxaliplatin in patients with LD.^15-19 The primary objective of the current study was to establish the MTD and the dose-limiting toxicities (DLT) of imatinib in patients with mild, moderate, or severe LD. Secondary objectives included evaluating the safety, response, toxicity, and PK of imatinib in such patients. At the time of study initiation, imatinib was an investigational agent and was being evaluated in a variety of tumor types; therefore, all tumor types were included on this study. This study and a parallel study of imatinib in patients with renal dysfunction²⁰ were conducted by the National Cancer Institute Organ Dysfunction Working Group (NCI ODWG).

	PATIENTS AND METHODS

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Patient Characteristics and Study Design
Patients were older than 16 years, had a histologically confirmed, surgically incurable malignancy, and had an Eastern Cooperative Oncology Group performance status of 0 to 2. Acceptable renal (serum creatinine < upper limit of normal or calculated creatinine clearance [Cockroft and Gault formula] 60 mL/min/1.73 m²) and bone marrow (leukocytes 1,500/µL, absolute neutrophil count [ANC] 1,500/µL, platelet count 100,000/µL) functions were required. Biliary stents were allowed if the stenting procedure was done 10 days or more before the first dose of imatinib. Ineligibility criteria included untreated brain metastases, history of organ transplant, therapeutic doses of warfarin, uncontrolled intercurrent illness, and HIV-positive status with current antiretroviral therapy. Written informed consent, according to federal and institutional guidelines, was required of all participants before enrollment.

Patients were assigned to one of four groups based on their degree of LD, which was defined by serum TB and AST levels that were measured within 24 hours before start of therapy (Table 1). Patients with normal LFTs (n = 12) served as controls. Initially, three patients were accrued to the lowest dose level of each group and proceeded to escalate to the next level in the absence of a DLT (Table 1). If one patient had a DLT, three additional patients were to be accrued at the same level. No intrapatient dose escalation was allowed. Accrual stopped if two or more patients at a dose level had DLTs, and the MTD (the dose recommended for future phase II studies) was defined as the next lower dose level. The MTD cohorts could be expanded to 6 to 12 patients. Dose escalation was independent in each LD group; however, the design included a second stage (which was not used) to ensure that the final MTD for each group could be no greater than that for any group with lesser LD.

Toxicity was graded by the National Cancer Institute Common Toxicity Criteria, version 2.0. Patients were observed for DLTs until completion of the first 4 weeks of therapy. However, patients with severe LD often experienced rapid deterioration in liver function because of progressive disease, so they were unable to complete one cycle of therapy. Therefore, the protocol was amended in April 2002, so that patients with severe LD were considered evaluable after completing all PK sampling and a minimum of 2 weeks of therapy.

Drug Administration
Imatinib was supplied as hard-gelatin, 100-mg capsule by the NCI Cancer Therapy and Evaluation Program (Rockville, MD), under a collaborative research and development agreement with Novartis Pharmaceuticals (East Hanover, NJ). Patients followed instructions similar to those in the imatinib product brochure for self-administration. The 800-mg dose was administered as 400 mg bid. Patients were asked to complete a study medication diary on a daily basis, and the diary was reviewed every 2 weeks to assess patient-reported compliance. Each treatment cycle was 4 weeks. Intrapatient dose escalation was not allowed.

Study Procedures and Assessments
This study was conducted at 10 sites in the United States. The coordinating center was the University of Pittsburgh Cancer Institute. Baseline laboratory measurements were conducted at least 2 weeks before, and radiologic tests were performed at least 4 weeks before, the start of protocol therapy. The baseline Child-Pugh (CP) score was calculated for all patients.²¹ LFTs were repeated within 24 hours before starting treatment. A history and a physical examination were performed every 2 weeks. A complete blood count and a comprehensive metabolic panel were obtained at baseline and weekly, and radiologic tests were performed every 7 to 8 weeks while on study, for disease assessment that utilized the Response Evaluation Criteria in Solid Tumors Group criteria.²²

Dose Modifications
Dose modifications were based on weekly laboratory tests and on toxicity assessments. There was no dose reduction for patients starting at 100 mg/d. For patients treated with 200 mg/d, one dose reduction to 100 mg/d was allowed. At the 300, 400, 500, and 600 mg/d dose levels, two 100-mg dose decreases were allowed. At the 800 mg/d dose level, two 200-mg dose decreases were allowed. Therapy was held for any grade 2 or greater nonhematologic or any grade 3 or greater hematologic toxicity, and dosing was resumed at a lower dose level when toxicity had resolved to grade 1 or less. If the TB or AST level increased by 1.5 x baseline values, therapy was held until a decrease in the level was seen. Therapy was then resumed at one lower dose level, according to cohort. If there was no improvement in TB and AST levels within 2 weeks, patients were removed from the study.

Pharmacokinetic Methods
On day 1, all doses, including 800 mg/d, were taken as a single dose. No drug was taken on days 2 and 3, and daily dosing resumed on day 4. On day 1, 7 mL of heparinized, venous whole blood were obtained before and at 0.5, 1, 2, 3, 4, 8, 12, 24, 36, 48, and 72 hours after imatinib ingestion. On day 15, samples were obtained on a similar schedule but, because of the daily dosing schedule, ended at 24 hours. On day 1, urine was collected for 24 hours after imatinib ingestion. Plasma and urinary concentrations of imatinib and of its active metabolite, CGP74588, were determined by a validated, liquid chromatography-tandem mass spectrometry assay.²³ Imatinib protein binding was determined by equilibrium dialysis using a different, validated, liquid chromatography-mass spectrometry assay.²⁴ Serum alpha-1 acid glycoprotein (AGP) concentrations were measured before therapy and on day 15 by immunonephelometry (Dade Behring nephelometer; Covance CLS, Indianapolis, IN).

The following PK parameters for imatinib and for CGP74588 were estimated using noncompartmental methods (WinNolin Pro, Version 3.2; Pharsight Corp, Mountain View, CA): area under the plasma concentration-time curve from time 0 to 24 hours(AUC_0-24), area under the plasma concentration-time curve from time 0 to infinity (AUC_0-), dose-normalized AUC (AUC/dose), maximum plasma drug concentration after dose administration (C_max), time to reach C_max (T_max), half-life (t_1/2), and renal clearance (CL_R). The apparent total body clearance, or CL/F, and the apparent volume of distribution based on the terminal phase, or V/F, were determined only for imatinib. The effect of LD on the PK of imatinib and of CGP74588 was assessed by 90% CIs for the geometric mean ratio:

(g [imatinib in patients with impaired hepatic function]) ÷ (g [imatinib in patients with normal hepatic function])

in which g stands for either AUC/dose or dose-normalized C_max. All PK parameters were log-transformed before analysis. An absence of the effect of LD was assumed if the CI fell completely in the no-effect range of 0.75 to 1.33.

	RESULTS

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Patient Characteristics
Ninety-one patients were entered between August 2001 and January 2004, and 89 received at least one dose of imatinib (Table 2). In all patients except one with Gilbert's syndrome, the cause of LD was hepatic metastases.

Most adverse events were mild in nature (Table 4). Worsening liver function was expected, particularly in the moderate and severe LD groups, because of progression of liver metastases. An increased TB level was common, and it tended to increase in severity and frequency in the moderate and severe LD groups. The most frequently reported adverse events (all grades) considered related to imatinib therapy were LFT elevations (TB, 19%; AST, 19%; and AP, 12%), gastrointestinal disorders (nausea, 44%; vomiting, 28%; anorexia, 19%; and diarrhea, 18%), fatigue (32%), edema (23%), decreased hemoglobin (23%), rash/desquamation (16%), and abdominal pain or cramping (10%). Twenty-six patients required dose reductions, a dosing delay, or withdrawal from the study because of toxicity or failure to meet laboratory criteria for continuation of drug administration.

PK Data
PK data following the first dose of imatinib (day 1) and at steady-state (day 15) were available for 84 and 40 patients, respectively (Table 5, Fig 1). No significant relationships were observed between imatinib PK and the severity of LD. The rate of imatinib absorption, as reflected by T_max, was similar in all groups of patients. Although considerable interpatient variation existed, the mean exposure to imatinib, as represented by AUC/dose, and the t_1/2 were not greater in patients with LD, regardless of severity, than in patients with normal liver function (Table 5). In most patients, CGP74588 was detected in the plasma 30 minutes after administration of imatinib. As with imatinib, no significant relationship was observed between CGP74588 PK and the severity of LD. There was a weak correlation between the AGP concentration and the total imatinib AUC_(0-24) on day 15 (data not shown). However, there was no clear relationship between the AGP concentration and the free imatinib concentration in plasma at 24 hours after dosing on day 15. The urinary excretion of imatinib was not significantly different among the groups with varying degrees of LD (Table 5). As indicated by the ratio of renal clearance to apparent total body clearance and by the calculated urinary excretion of imatinib and CGP74588, urinary excretion accounted for less than 10% of a dose of imatinib (Table 5). The ratio of urinary excretion of CGP74588 to that of imatinib for all patients was 0.18 ± 0.08 and did not vary across groups or across doses within a group.

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Mean plasma concentrations of imatinib. (A) patients with normal liver function tests; (B) patients with mild liver dysfunction (LD); (C) patients with moderate LD; and (D) patients with severe LD.

	DISCUSSION

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

Although the MTD was not determined for the moderate and severe LD groups, imatinib was tolerated up to 300 mg/d in both groups. Furthermore, despite considerable interpatient variability, the plasma PK and urinary excretion of imatinib did not differ between patients with normal liver function and those with varying degrees of LD. Based on these data, it is unlikely that a 400-mg dose of imatinib in patients with moderate or severe LD would result in greater exposure to imatinib than in patients with mild LD or with normal liver function. This hypothesis is supported by the study of Ecker et al,²⁵ which reported similar data compatible with ours in patients with primary liver cancer.

The data from our study have implications for patients with GIST or CML who might also have LD, because such patients are still likely to derive a substantial benefit from imatinib. Because the minimum effective dose of imatinib appears to be at least 350 mg/d in patients with CML,⁹ two strategies can be followed in dosing imatinib in patients with CML or GIST and with moderate or severe LD. Imatinib could be started at 300 mg/d and, in the absence of toxicity, escalated to 400 mg/d. Based on PK data that showed no correlation between drug exposure and LD, imatinib could also be initiated at 400 mg/d, although this dose was not evaluated in this study. In both cases, careful and at least weekly monitoring of LFTs and toxicity would be required, and dose reduction would be necessary if patients developed any unacceptable toxicity.

In the current study, 55% and 58% of patients with moderate or severe LD, respectively, were withdrawn from study because of a progressive elevation of LFTs. This high withdrawal rate before completion of one cycle of therapy may be in part due to the patient population and to the study-specific requirements for the discontinuation of imatinib. Phase I studies in patients with LD typically have used toxicity as the primary end point. Other end points need to be considered because of the demonstrated inability of patients, especially those with moderate and severe LD, to complete the first cycle of therapy. A surrogate end point could be the PK profile, with the aim of defining drug exposure in patients with moderate or severe LD equivalent to that of biologically active concentrations in patients with normal LFTs.²⁶

Although imatinib is metabolized by hepatic CYP enzymes, our study failed to show a correlation between the imatinib PK and LFTs or the occurrence of DLTs. However, LFTs appear to be a poor predictor of CYP activity. The erythromycin breath test or midazolam clearance may better predict clearance of drugs metabolized by the liver.^27,28 However, such tests are not done in routine practice to assess liver function before administration of therapy. The intent of this study was to provide dosing guidelines for imatinib in LD by using readily available laboratory parameters. Serum AGP binds to imatinib and has been postulated to lower the amount of free imatinib available for biologic activity.^29,30 However, our study does not support that hypothesis, as AGP levels did not correlate with free concentrations of imatinib.

In our study, we utilized TB and AST as parameters to assess LD. There is no consensus on standard LFT criteria to assess LD cohorts in clinical trials. The US Food and Drug Administration has issued draft guidelines for clinical trials in patients with LD that recommend the use of CP criteria,²¹ which are a composite score of TB, albumin, prothrombin time, ascites, and encephalopathy.³¹ In the current study, CP criteria were collected on all patients, and there appears to be a good correlation with the NCI ODWG criteria (Appendix Table A1, online only). Thirty-five patients were classified as CP-A; 57% and 37% of these fell into normal and mild LD groups, respectively. In the group of 37 patients with CP-B classification, 30% had mild LD, 38% had moderate LD, and 27% had severe LD. In the 17 patients with CP-C classification, 24% had moderate LD, and 76% had severe LD.³² In our opinion, the NCI ODWG criteria, which utilize the two readily measurable laboratory parameters of TB and AST, provide a simple and effective way of assessing LD for the purposes of clinical trials and community practice. Our opinion is reinforced by the fact that the dosing guidelines established by the current study for patients with LD have been incorporated into the product labeling for imatinib.³³

	Authors' Disclosures of Potential Conflicts of Interest

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

 
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.

Employment: Michael J. Hayes, Novartis Pharmaceuticals; Bin Peng, Novartis Pharmaceuticals Leadership: N/A Consultant: Merrill J. Egorin, Novartis Pharmaceuticals Stock: N/A Honoraria: Merrill J. Egorin, Novartis Pharmaceuticals Research Funds: Merrill J. Egorin, Novartis Pharmaceuticals; Chris H.M. Takimoto, Novartis Pharmaceuticals Testimony: N/A Other: N/A

	Author Contributions

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

 
Conception and design: Ramesh K. Ramanathan, Merrill J. Egorin, Douglas M. Potter, Chandra P. Belani, S. Percy Ivy

Administrative support: Ramesh K. Ramanathan, Chandra P. Belani, S. Percy Ivy

Provision of study materials or patients: Ramesh K. Ramanathan, Chris H.M. Takimoto, Scot C. Remick, James H. Doroshow, Patricia A. LoRusso, Daniel L. Mulkerin, Jean L. Grem, Anne Hamilton, Anthony J. Murgo, Bin Peng, S. Percy Ivy

Collection and assembly of data: Ramesh K. Ramanathan, Merrill J. Egorin, Chris H.M. Takimoto, Scot C. Remick, Chandra P. Belani, Michael J. Hayes, S. Percy Ivy

Data analysis and interpretation: Ramesh K. Ramanathan, Merrill J. Egorin, Douglas M. Potter, Chandra P. Belani, S. Percy Ivy

Manuscript writing: Ramesh K. Ramanathan, Merrill J. Egorin, Scot C. Remick, Patricia A. LoRusso, Anne Hamilton, Douglas M. Potter, Chandra P. Belani, S. Percy Ivy

Final approval of manuscript: Ramesh K. Ramanathan, Merrill J. Egorin, Chris H.M. Takimoto, James H. Doroshow, Daniel L. Mulkerin, Jean L. Grem, Anthony J. Murgo, Douglas M. Potter, Chandra P. Belani, Bin Peng, S. Percy Ivy

	Appendix

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

 

	ACKNOWLEDGMENTS

 
We thank Kim Wood of Technical Resources International for preparation of the study report, Theodore F. Lagutta for the assessment of free imatinib concentration, and the University of Pittsburgh Hematology/Oncology Group for helpful suggestions regarding the manuscript.

	NOTES

 
Supported in part by Grant Nos. UO1-CA69855, P30CA47904, and NIH/NCCR/GCRC #5M01 RR 00056 from the University of Pittsburgh Cancer Institute and Medical Center; Grant No. U01-CA069853 from the Institute for Drug Development, Cancer Therapy, and Research Center, University of Texas Health Science Center; Grant No. CA62502 from Case Western Reserve University; Grant No. U01 -CA62505 from the City of Hope National Medical Center; Grant No. 5U0-1CA062487-14 from Wayne State University; Grant Nos. UO1-CA062491and NIH/GCRC M01 RR03186 from the University of Wisconsin; and Grant No. U01-CA76642 from New York University. Sponsored by the Cancer Therapy and Evaluation Program of the National Cancer Institute, Bethesda, MD.

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

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

	REFERENCES

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

 
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Submitted February 5, 2007; accepted August 9, 2007.

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				I. R. Judson Imatinib for Patients With Liver or Kidney Dysfunction: No Need to Modify the Dose J. Clin. Oncol., February 1, 2008; 26(4): 521 - 522. [Full Text] [PDF]

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