O R I G I N A L A R T I C L E
Her-Shyong Shiah Æ Yee Chao Æ Li-Tzong Chen Tzy-Jyun Yao Æ Jin-Ding Huang Æ Jang-Yang Chang Pei-Jer Chen Æ Tsai-Rong Chuang Æ Yung-Hsin Chin Jacqueline Whang-Peng Æ Tsang-Wu Liu
Phase I and pharmacokinetic study of oral thalidomide
in patients with advanced hepatocellular carcinoma
Received: 25 October 2005 / Accepted: 30 January 2006 / Published online: 7 March 2006 Springer-Verlag 2006
Abstract Purpose: To evaluate the dose-limiting toxici-ties (DLT), maximum tolerated dose (MTD), and pharmacokinetics of thalidomide in patients with advanced hepatocellular carcinoma (HCC). Methods: Patients with advanced HCC who were not feasible for definitive local therapy were eligible. Patients were enrolled in a cohort of three to receive thalidomide twice daily for 1 week to determine the MTD. Intra-patient dose escalation was permitted. Pharmacokinetic studies were performed at the first dose level and repeated at the second dose level of each patient. Results: Fifteen
patients were accrued at four dose levels with the start-ing dose range 100–400 mg/day. Two patients at 400 mg/day experienced DLT (grade 3 angioedema and dyspnea, respectively). The MTD of twice-daily schedule was determined as 300 mg/day. The mean steady-state maximal blood concentration and mean steady-state area under the curve had a trend toward positive cor-relation, but non-linear proportionate, to the daily dose of thalidomide. Pharmacokinetic parameters are com-parable for patients of Child-Pugh’s A and B. Apparent mild, transient drug-induced transaminitis was early onset, self-limited, which occurred in 30.7% of patients. Serum hepatitis B or C viral titers was largely not affected. Conclusion: The absorption and elimination of thalidomide are not significantly different in HCC patients with compensated or decompensated hepatic dysfunction.
Keywords Cirrhosis Æ Maximum tolerated dose Æ Angiogenesis inhibitor Æ Hepatitis virus
Introduction
Angiogenesis has recently been demonstrated to play a crucial role in the growth, progression and even chemoresistance of a variety of tumors both in primary and metastatic forms [17–19, 23, 44, 56]. Inhibition of angiogenesis has been proposed as a potential anti-cancer treatment [4, 29]. Thalidomide, a glutamic acid derivative first described in 1953, was marketed as a sleeping pill, but was withdrawn from the European market 30 years ago because of its teratogenic effects [38]. The thalidomide-associated birth defect, phocom-elia (stunted limb growth), might be due to the inter-ference of blood vessel growth in a developing fetal limb bud by thalidomide [8]. Recent studies suggested that oral thalidomide treatment could inhibit the basic fibroblast growth factor (bFGF)- and vascular endo-thelial growth factor (VEGF)-induced rabbit corneal neovascularization [8, 31]. This leads to a revival in the
Li Tzong Chen and Tsang-Wu Liu contributed equally to this work.
H.-S. Shiah Æ L.-T. Chen Æ J.-Y. Chang Æ T.-R. Chuang Y.-H. Chin Æ J. Whang-Peng Æ T.-W. Liu (&)
Divisions of Cancer Research, National Health Research Institutes, Ward 191 Veterans General Hospital, Taipei, Taiwan, ROC
E-mail: walter@nhri.org.tw Fax: 886-2-28716467 L.-T. Chen
Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, ROC
T.-J. Yao
Biostatistics & Bioinformatics and Biotechnology & Pharmaceutical Research, National Health Research Institutes, Taipei, Taiwan, ROC
J.-D. Huang
Biotechnology and Pharmaceutical Research, National Health Research Institutes, Taipei, Taiwan, ROC
Y. Chao
Cancer Treatment Center, Taipei Veteran General Hospital, Taipei, Taiwan, ROC
J.-D. Huang
Department of Pharmacology, Medical College of National Cheng-Kong University, Tainan, Taiwan, ROC
P.-J. Chen
Graduate Institute of Clinical Medicine, Medical College of National Taiwan University, Taipei, Taiwan, ROC DOI 10.1007/s00280-006-0203-z
use of thalidomide in the treatment of some angiogenic tumors, including, hormone-refractory prostate cancer, high-grade glioma, breast cancer, Kaposi’s sarcoma, head and neck squamous cell carcinoma, myelodys-plastic syndrome and hepatocellular carcinoma [2,7,14, 16,24,35,47,50,55]. Recently, single agent thalidomide therapy has been approved by Australia’s Therapeutic Goods and Administration (TGA) for advanced/ refractory multiple myeloma [22]. Another application of thalidomide is in the management of numerous inflammatory and autoimmune diseases, such as Cro-hn’s disease and rheumatoid arthritis [21, 57]. Further investigation suggested that its immunomodulating ef-fects may be derived from the inhibition of tumor necrosis factor-a (TNF-a) secretion from monocytes [48]. Nevertheless, besides teratogenicity, thalidomide management is associated with several adverse events—somnolence, constipation, asthenia, skin rash, peripheral edema, paresthesia and dizziness are the most common, while deep vein thrombosis, peripheral neu-ropathy and Stevens–Johnson syndrome are the most serious [10]. Those toxicities would compromise the dose intensity of thalidomide.
In preclinical in vivo studies, the bFGF-induced angiogenesis was inhibited by the oral administration of thalidomide but not by topical use [8]. Furthermore, thalidomide could inhibit human aortic endothelial cell proliferation and microvessel formation from rabbit aorta in the presence of human or rabbit liver micro-somes ex vivo, whereas thalidomide inhibited neither endothelial cell proliferation nor microvessel formation without the activation by microsomes [3, 5]. These re-sults suggested that thalidomide metabolized by liver was probably a pivotal step to form active anti-angio-genic metabolite(s) of thalidomide in humans. On the other hand, the production of 5-hydroxy compound is the major hepatic thalidomide metabolite catalyzed by cytochrome P-450 in microsomes [52]. Such a produc-tion of 5-hydroxy metabolite is very low. Thalidomide is mainly broken down through a spontaneous nonenzy-matic hydrolytic cleavage at physiological pH [26]. It was even demonstrated that hepatic enzyme-inducing drugs had little effect on the metabolism of thalidomide [16]. Therefore, it gives rise to the question whether an impaired liver function has any impact on the efficacy and toxicity of thalidomide. Up to now, there has been no comprehensive study performed to evaluate the pharmacokinetics of thalidomide in patients with hepa-tic dysfunction, while the pharmacokinehepa-tics of thalido-mide has not changed in patients with impaired renal function or on dialysis [13].
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide [58] and also the leading cause of death due to cancer among the people of Taiwan [34]. Clinically, HCC patients who present with advanced stage of diseases at the time of diagnosis as well as those who have recurrence after definitive local treatments will require a systemic therapy. Since there are issues of intrinsic multidrug resistance and the
relatively poor reserve of liver function in HCC patients who are at an advanced stage, systemic chemotherapy is generally less effective and is associated with greater toxicity [32, 42]. HCC is also a well known angiogenic and angiogenesis-dependent cancer [28, 37]. Strategies aimed at inhibiting angiogenesis, i.e., oral thalidomide, were considered to be potential alternatives for treating this chemo-resistant cancer [6, 24,45,55, 59]. Based on the facts that the underlying reserve of liver function is relatively poor in most of HCC patients and thalidomide might not require a metabolism by liver, it is important to document the pharmacokinetics and the toxicity profiles of thalidomide treatment in such patients.
Herein, we present the first phase I/pharmacokinetic study of oral thalidomide in HCC patients with under-lying hepatic dysfunction.
Patients and methods
Patient population
Patients with measurable, metastatic or locally advanced HCC whose tumors had failed to have definitive local therapy [including surgical resection, percutaneous eth-anol or alcohol injection (PEI or PAI), transcatheter arterial chemoembolization (TACE), or in combination) or whose tumor was too advanced; 18–75 years of age; and an Eastern Cooperative Oncology Group (ECOG) performance score of 0–2 were eligible. The diagnosis of HCC had to be established by cytology or histopathol-ogy. Patients were required to have a Child-Pugh’s Score £ 8 with a serum total bilirubin £ 3 mg/dL, a prothrombin times £ 5 s above normal control, a platelet count ‡7.5·104
/mm3, a white cell count ‡3,000/ mm3, and a serum creatinine <1.5 mg/dL. Female patients of childbearing age should show a negative pregnant test. Sexually active patients, in conjunction with their partners, had to agree to practice birth control measure during and for at least 2 months after thalido-mide therapy. This study has been approved by the Institutional Review Board of the hospital and by the Department of Health, Executive Yuan, Taiwan. All patients gave signed informed consent.
Phase I study
The schema of phase I study and intra-individual study was displayed in Fig.1. For phase I study, patients were enrolled in a cohort of three to receive 1 week of thalidomide (Thado, 50 mg/capsule, TTY Biopharm Co. Ltd, Taipei, Taiwan) therapy. Thalidomide was given orally twice daily (b.i.d.) between 0900–1000 and 2100–2200 hours. The dose of thalidomide started from 100 mg/day and escalated in the subsequent cohorts of patients, with a target dose at 1,200 mg/day. The esca-lation was by 100 mg while receiving dose <400 mg/day and by 200 mg while receiving dose‡400 mg/day. If no
patient had a dose-limiting toxicity (DLT) at a certain dose level, the subsequent three patients would be treated with the next dose level. DLT was defined as: ‡ WHO grade 2 somnolence, ‡ WHO grade 2 peripheral neuropathy, erythema multiforme, Stevens–Johnson syndrome and/or other ‡ WHO grade 2 allergic skin eruption that was unresponsive to antihistamine (± local corticosteroid) therapy, other unmanageable ‡ WHO grade 3 non-hematological toxicity, prolonged (>7 days) ‡ WHO grade 3 hematological toxicity and/ or neutropenic fever; and repetitive, unexpected‡ grade 2 infection. If one out of three patients developed DLT, three additional patients would be accrued to the same dose level. If none of the additional three patients developed DLT, the dose escalation would be contin-ued. If two or more patients developed DLT at a cer-tain dose level, the dose escalation would be terminated, and the prior dose level would be consid-ered as the maximum tolerated dose (MTD). A mini-mum of six patients was required to test at the dose level of MTD.
Intra-individual dose-escalation study
Patients who did not experience DLT during the first week of therapy would have their thalidomide dose escalated by one dose level weekly until the target dose of 1,200 mg/day was achieved, the patient refused or a DLT occurred. For each patient, the dose one level below that associated with DLT or the dose that the patient refused was considered as an individual achievable dose for
further escalation. Subsequent treatment for each patient was maintained at individual achievable dose until the presence of unacceptable toxicity, the patient’s refusal or tumor progression.
Evaluation of patients
Physical examination and symptoms were evaluated before treatment and daily during the phase I study (the first week of treatment), and then evaluated every 2–4 weeks. The serum levels of albumin/globulin, aspartate/alanine transaminase (AST/ALT), alkaline phosphatase (Alk-p), gamma-glutamyltranspeptidase (cGT), total/direct bilirubin, alpha-fetoprotein (AFP), blood urea nitrogen (BUN), creatinine and electrolytes, and complete blood count with differential count, pro-thrombin time/activated partial thrombine time (PT/aPTT), and urine analysis were examined before treatment and then every 2–4 weeks throughout the whole study. Additional serum biochemistry studies were performed before each pharmacokinetic (PK) study. Indocyanine green (ICG) clearance test was per-formed to determine the ICG-R15 (indocyanine green
retention rate at 15 min), which served as an indicator of hepatic function reserve [43], before every PK study. Woman of the childbearing age had urinary HCG test before treatment which was repeated every 4 weeks.
The serum HBV-DNA and HCV-RNA were quan-tified by the signal amplification nucleic acid probe assay (branched DNA assay, HBV DNA Assay and HCV RNA 3.0 Assay, Bayer, USA) at the central
No DLT in first week 3 eligible patients
enrolled at dose level (n)
Number of patient experiencing DLT In first week
If n < 8, go to n+1 If n = 8,
enroll 3 more patient MTD = dose at level (n)
Enroll 3 more patient
Dose-escalation terminated & MTD defined as dose at level (n-1) (Number of patient enrollment at n-1 must be > 6)
> 1 patient with DLT
Intra-individual dose-escalation to n+1
DLT (+) DLT (-)
Dose modification Dose-escalation
until n = 8 or DLT (+) > 2 1 0 No DLT n mg/d 1 100 2 200 3 300 4 400 5 600 6 800 7 1000 8 1200
Fig. 1 Schema of phase I study and dose-escalation study of thalidomide in advanced HCC. DLTdose-limiting toxicity, MTDmaximum tolerated dose
laboratory of Hepatitis Research Center, National Taiwan University Hospital.
Chest X-rays, and abdominal ± chest CT were done before the treatment, and then repeated every 8 weeks or whenever clinically indicated; additional examinations were done 4 weeks after the first radiological evidence of tumor response. The grading of treatment toxicity as well as tumor response was evaluated according to the criteria defined by the WHO [40]. Because the baseline liver function was abnormal in most patients, the grad-ing of hepatic (ALT) toxicity was assessed by compari-son with a baseline value of individual patients rather than the upper normal limits in this study.
Pharmacokinetic study
Blood samples were obtained from all patients for pharmacokinetic studies at their their1st dose level. Two mL of blood were obtained at 0 h (0900 hours, before the first dose) then at 12 h (2100 hours, before the second dose), 24 h (0900 hours, before the third dose), 36 h (2100 hours, before the fourth dose), 48 h (0900 hours, before the fifth dose), 50, 52, 54, 56 and 60 h (2100 hours, before the sixth dose). The studies were repeated at the second dose level and at indi-vidual achievable dose (optional) in patients who re-ceived an escalating dose of thalidomide. The blood sample at the dose level of individual achievable dose was obtained when patients had received thalidomide at one level below that associated DLT for 1 week. The blood samples were immediately mixed with an equal volume of 25 mM sodium citrate buffer (pH 1.5) and stored at -70C until analysis. The whole blood concentration of thalidomide was determined by the high-performance liquid chromatography (HPLC) with ultraviolet detection [12, 13]. The lower limit of quantification was 0.1 lg/mL. The procedure was val-idated through the range of 0.1–10 lg/mL, using 1 mL whole blood. The precision was <10% and the accu-racy was between 90 and 110%. The urine was also collected for the determination of thalidomide con-centration at the interval of 12 h during each blood sampling. Totally six 12 h-urine samples (50 mL) at 0 h, 0–12 h, 12–24 h, 24–36 h, 36–48 h and 48–60 h were measured in each patient. The urine samples were immediately mixed with an equal volume of 25 mM sodium citrate buffer (pH 1.5) and stored at -70C until analysis.
Pharmacokinetic analysis
The blood concentration-time curve for each subject was evaluated. The area under curve (AUC48–60) of
steady-state during every dosage interval, the mean blood concentration at steady state, Cave = AUC/dosage
interval, the maximum blood concentration at steady state (Cmax-ss), elimination half-life (t1/2), time to achieve
maximum blood concentration (tmax) and absorption
coefficient (Ka) were calculated. The elimination half-life
was determined by non-linear regression program [25]. Apparent total (oral) clearance, as a function of bio-availability (CL/F), was calculated as dose/AUC48–60.
The renal clearance (CLr) was estimated by dividing the
total amount of urinary drug elimination (X) by AUC, CLr=X/AUC.
Statistical analysis
The association between discrete variables was assessed using Fisher’s exact test. The two-tailed Wilcoxon rank sum test was used for comparison of pharmacokinetic parameters. The statistical difference of data from three datasets was analyzed using repeated measures ANO-VA. A value of P<0.05 was considered statistically significant.
Results
Demographic features
Fifteen patients (14 male, 1 female) were accrued onto this study. The median age was 57 years (range 31– 75 years), and the median ECOG performance status was 1 (range 0–2). Thirteen patients had underlying cirrhosis (87%, documented by histology in 11 and by radiology in 2) with Child-Pugh’s class of A in 8 and of B in 7. Twelve (80%) patients had extrahepatic meta-static diseases and 6 (40%) had major portal venous invasion. The clinicopathological characteristics of patients are presented in Table1.
Safety evaluation and maximal tolerated dose in Phase I study
The starting daily dose for the 15 patients ranged from 100 mg to 400 mg. The patient number and the adverse events (AE) at each dose level during phase I study (the first week of treatment) were summarized in Table2. In general, oral thalidomide was well tolerated twice daily at dose £ 300 mg/day (150 mg b.i.d.). One patient who had 150 mg b.i.d. suffered from esophageal varices bleeding on the fourth day of therapy and was tempo-rarily removed from the study before his condition sta-bilized. One additional patient was accrued at 150 mg b.i.d. before further dose escalation.
Two of three patients at the dose level 200 mg b.i.d. developed grade 3 AE. One patient had suffered from grade 3 allergic reaction (cutaneous eruption and peri-orbital angioedema) from the fourth day of treatment and was off-study on the sixth day. The other patient suffered from shortness of breath on the second day of thalidomide treatment, without significant electrocar-diogram and chest X-ray film changes. The dyspnea
was promptly resolved after the discontinuation of thalidomide and the intravenous administration of diuretics. It recurred after he was rechallenged with the same dosage of thalidomide and resolved again after diuretics therapy. A similar attack did not happen to him after the dose of thalidomide was tapered to 150 mg b.i.d.. After two patients experienced DLT at the level of 200 mg b.i.d., three additional patients were treated with 150 mg b.i.d. without experiencing signifi-cant toxicity. Therefore, the MTD of this phase I study was 150 mg b.i.d.
Toxicity profile and individual achievable dose in intra-individual dose-escalation study and subsequent therapy Except the two patients who experienced DLT during phase I study, the dose of thalidomide was intra-indi-vidually escalated in the other 13 patients. The individ-ual achievable dose was listed against their starting dose in Table3. The major DLT of intra-individual escala-tion was a grade 2/3 somnolence in 8 of 13 patients. The median individual achievable dose was 250 mg b.i.d. (ranged 100–600 mg b.i.d.), with 250 mg b.i.d. (ranged 100–600 mg b.i.d.) for patients of Child-Pugh’s class A (n=8) and 200 mg b.i.d. (ranged 150–400 mg b.i.d.) for patients of class B (n=7, including the one who had grade 3 allergic reaction at 200 mg b.i.d.).
The AE that occurred during the intra-individual dose-escalation study and subsequent therapy period are listed in Table4. Grade 1–2 somnolence occurred in 60– 75% of patients at all tested dose levels. Skin rash was also frequently observed, especially at lower dose levels (100–150 mg b.i.d.). The cutaneous lesion could be im-proved by the oral anti-histamine ± local corticosteroid therapy and did not recur even at higher dose. The constipation of grade 1–2 was a common AE, which could be easily treated with an increased dose of laxa-tive. Grade 1 peripheral neuropathy, which was usually manifested as mild peri-oral or digital numbness, oc-curred in 13–25% of patients but caused treatment interruption in none. One patient with intra-atrial tumor growth suffered from grade 3 (symptomatic) sick sinus syndrome that was considered probably related to either the tumor or thalidomide itself.
Changes in serum ALT level and hepatitis viral titer In this study, an increase in hepatitis activity induced by drug was defined as an elevation of ALT level to more than twofolds of the pre-treatment value and greater than 100 IU/mL. The apparent mild, transient drug-in-duced transaminitis was found in four patients (4/13,
Table 1 Clinicopathological characteristics
Age, (years) 57 (31–75)a
Sex
Male 14
Female 1
ECOG performance status
0 6
1 8
2 1
Serum albumin (gm/dL) 3.5±0.6 (2.6–4.4)b Serum total bilirubin, (mg/dL) 1.43±0.69 (0.5–2.7)b Serum ALT (IU/dL) 75±53 (14–203)b Ascites Absent 12 (80%) Present 3 (20%) Child-Pugh’s class A 8 (54%) B 7 (46%)
ICG retention at 15 min (%) 31.1±19.1 (8–68)b
HBsAg + 8 (53%) Anti-HCV + 5 (33%) Both negative 2 (13%) Primary tumorsc T0 3 (20%) T1–T2 1 (7%) T3 1 (7%) T4 10 (67%)
Presence of venous invasion
Portal vein, main or first branch 6 (40%) Hepatic vein or inferior vena cava 3 (20%)
amedian (range),bmean ± SD (range),cbased on AJCC Cancer staging Manual 5th edn, 1997
Table 2 Adverse events at each dose level of phase I study (per patient)
a
dose-limiting toxicity,bbelong to grade 1,celevation of ALT as compared with baseline data rather than with upper normal limits
Dose of thalidomide (mg/day)
100 (n=3) 200 (n=3) 300 (n=7) 400 (n=2) Adverse events Grade Grade Grade Grade Grade Grade Grade Grade
Items 1–2 3–4 1–2 3–4 1–2 3–4 1–2 3–4 Somnolence 2b 2b Dizziness 1 1 Constipation 1 1 3 1 Peripheral europathy 1b Cutaneous 1 1 1 1 1a mucositis 1 1 Hair loss 1 Fever 1 1 Dyspnea 1a Hepaticc 1 Hemoglobin 1 Leucopenia 1 Cystitis 2
30.7%). It was observed in two of eight HBsAg-positive patients, in one of three anti-HCV-positive patients, and in one of two seronegative for both HBsAg and anti-HCV patients. The elevation of ALT usually occurred within the first 2 weeks of the treatment and reached its peak at the 4th week. Despite continuation of thalido-mide therapy, the ALT level returned to or below the baseline value in three patients during the 8th–12th week of therapy and remained elevated in one HBsAg-positive patient during his 16 weeks of study period.
In general, thalidomide therapy seemed not to affect the serum hepatitis viral load (titers of HBV DNA [n=8] and HCV RNA [n=5]). Only two patients had an in-crease of serum viral titer after thalidomide therapy, with the elevation of HBV DNA titer in one and HCV
RNA titer in the other one, which was not accompanied with corresponding ALT changes.
Indocyanine green clearance test before and after thalidomide therapy
The ICG-R15 (mean ± SD) before the first and the
second weeks of therapy from 14 patients was 29.6±18.9% and 27.1±19.0%, respectively. The ICG-R15, from 8 patients who had three sets of test, before
the first and the second week of treatment, and after a median of 6 weeks therapy (ranged 5–10 weeks, during treatment at individual achievable dose level), was 19.2±8.3, 18.8±10.6 and 22.6±15.2%, respectively.
Table 3 Individual achievable dose in dose-escalation study Starting dose Individual achievable dose (mg/day)
(case no.) 200 300 400 600 800 1,000 1,200 100 (n=3) 1b 1 1 200 (n=3) 1 1 1c 300 (n=7) 2 1+1b 1+1b 1c 400 (n=2)a 1 Total (n=15)a 1 2 4 3 2 1 1 a
one patient being off-study due to grade 3 allergic reaction at starting dose of 400 mg/day b
patients who refused further dose-escalation in the absence of significant toxicity (satisfactory therapeutic effects in 1, grade 1 somnolence in 1 and grade 2 cutaneous eruption in 1)
cpatients had disease progression without dose-limiting toxicity
Table 4 Adverse events at each dose level during intra-individual dose-escalation study and subsequent therapy period (per patient) Dose of thalidomide (mg/day)
200 (n=4) 300 (n=6) 400 (n=12) 600 (n=11) 800 (n=7) 1,000 (n=4) 1,200 (n=1) Adverse events grade
1–2 grade 3–4 grade 1–2 grade 3–4 grade 1–2 grade 3–4 grade 1–2 grade 3–4 grade 1–2 grade 3–4 grade 1–2 grade 3–4 grade 1–2 grade 3–4 Somnolence 3 4 7 [1] 8 [4] 5 [2] 3 [1] 1 Dizziness 1 3 2 2 1 1 Constipation 3 3 7 4 1a 3 1a 1 Neuropathyb 1 2 2 2 1 Cutaneous 3 5 2 3 1 2d Bradycardia 1 1e Mucositis 1 1 1 1 Hair loss 1 1 Fever 1 1 1 Dyspnea 1 2 2 1 1 Hepatic 2 1 4 1 1 1 Hemoglobin 1 1 Leucopenia 1 2 Cystitis 2 2 1 1
Numbers in the parentheses indicates the number of patients who had grade 2 somnolence which is considered as dose-limiting toxicity a
the patient also received high-dose of morphine phosphate for pain control
bbelong to grade 1 and most of the patients experience mild perioral numbness and none required dose modification
celevation of ALT as compared with baseline data rather than with upper normal limitsdone of the patients requested dose reduction due to grade 2 skin rush
e
There was no statistical difference within these three datasets.
Pharmacokinetic analyses
Totally, 37 sets of distinct time points of blood samples were obtained for pharmacokinetic analyses from 15 patients at various dose level, 100 mg/day in three sets, 200 mg/day in six sets, 300 mg/day in 12 sets, 400 mg/ day in ten sets, 600 mg/day in three sets and 800 or more mg/day in three sets. Since the number of patients at high-dose level (800 or more mg/day) was limited, the presentation of pharmacokinetic study was focused on those on 600 or less mg/day. The pharmacokinetic parameters after multiple doses administered twice daily are listed by the dose level in Table5. The maximum concentration at steady state (Cmax-ss) and the mean area
under curve at steady state (AUC48–60, which measures
the area between 48 and 60 h after first dosage) did not increase linearly proportionate as the daily dose in-creased, as shown in Fig. 2 (P=0.0065). On the other hand, the ratio of AUC48–60/ daily dose showed a trend
toward negative correlation to the daily administration dose, as shown in Fig. 3(P=0.0004). The CLr increased from 76.71 (±24.39) mL/h at dose of 50 mg b.i.d., 99.02 (±22.68) mL/h at 100 mg b.i.d. and up to 150.33 (±40.42) mL/h at dose of 300 mg b.i.d.. The clear-anceoral at steady state (CL/Fss,
clearance/bioavailabil-ity) ranged from 8.63 (±1.67) to 14.33 (±4.35) L/h at dose between 50 and 300 mg b.i.d.. The mean t1/2 of
thalidomide at dose greater than 100 mg b.i.d. was quite consistent, ranged from 7.78 to 10.7 h. The mean tmaxof
thalidomide ranged from 4 (±1.16)–7.33 (±1.33) h at dose between 50 and 300 mg b.i.d.. The effect of dose on Cmax-ss, Cave, AUC48–60 and CL/Fss were statistically
significant (P<0.02).
The influence of the severity of hepatic dysfunction (Child-Pugh’s class A vs. class B) on the PK parameters of oral thalidomide was also studied. The representative data from 12 patients, Child-Pugh’s class of A in 6 and of B in 6, while they were taking 150 mg b.i.d. is presented. The clinicopathological characteristics and pharmaco-kinetic parameters of these patients are listed against
Child-Pugh’s class in Table6. The ICG-R15, serum
bili-rubin and serum albumin were significantly different between patients of Child-Pugh’s class A and of class B, P value=0.038, 0.02 and 0.003, respectively. However, there was no significant difference in any of the tested pharmacokinetic parameters, including Cmax-ss, Cave,
AUC48–60, clearanceoral, elimination half-life, tmax, Ka
and renal clearance, between the two groups of patients.
Table 5 Pharmacokinetic parameters of thalidomide between 48 and 60 h at each tested dose level Cmax-ss (lg /mL)* Cave (lg/mL)* AUC48–60 (mg h/L)* CL /Fss (L/h)* t1/2(h) tmax(h) Ka CLr(ml/h) 100 mg/d, N=3 1.20±0.14 1.03±0.20 12.3±2.35 9.02±3.62 33.10±38.10 4.00±1.16 1.57±1.81 76.71±24.39 200 mg/d, N=6 2.24±0.44 1.70±0.19 20.4±2.29 8.63 ±1.67 36.90±50.70 4.33±0.95 4.32 ±4.76 99.02 ±22.68 300 mg/d, N=12 1.70±0.28 1.26±0.16 15.1±1.95 13.24±4.36 10.70±4.02 4.33±0.41 2.80±2.80 157.65±36.55 400 mg/d, N=10 1.81±0.15 1.37±0.15 16.4±1.83 12.70±5.27 9.53±4.36 5.00±0.61 1.92 ±1.94 180.07±50.59 600 mg/d, N=3 3.19±0.36 2.29±0.48 27.5±5.78 14.33±4.35 7.78±2.45 7.33±1.33 1.17±1.57 150.33±40.42 Mean±SD; Cmax-ss: steady-state maximum blood concentration; Cave: mean blood concentration at steady state; AUC48–60: steady-state area under curve 48–60 h after the first dosage (0–12 h after the fifth dosage) at each dose level; CL/Fss: steady-state clearance/bio-availability (clearanceoral); t1/2: half-life; tmax: time to achieve maximum blood concentration; Ka: absorption coefficient. CLr: renal clearance *P<0.02 0 100 200 300 400 500 600 0 1 2 3 4
Daily dose of thalidomide (mg)
Cm a x -s s ( µ g/ m L )
Fig. 2 The steady-state maximum blood concentration at different dose levels of thalidomide in HCC patients. The P value of correlation between concentration and dose was 0.0065
0 100 200 300 400 500 600 0.00 0.04 0.08 0.12 0.16
Daily dose of thalidomide (mg)
Ra ti o o f A U C48 -6 0 /d ai ly dos e
Fig. 3 The ratio of area under the curve/daily dose (AUC/D) against daily dose of thalidomide in HCC patients. The P value of correlation between AUC/D and dose was 0.0004
Tumor response
Thirteen patients were assessed for response. One patient achieved partial response with an overall response rate of 7.7%. Four patients had a stable disease with a median response duration of 13 weeks (ranged 12–99 weeks), and eight had a progressive disease. On an intention-to-treat analysis, the response rate was 6.7%. Among the seven patients with base-line AFP >100 ng/mL, three patients, two with SD and one with PR, had a sustained (‡4 weeks) reduc-tion of AFP by 30, 45 and greater than 99%, respectively.
The dose of thalidomide for the patient with partial response was 50 mg b.i.d. during the first week, then maintained at 100 mg b.i.d. since the second week of therapy. Among the six patients who had PK studies at 100 mg b.i.d., the PK parameters of patient with PR were not significantly different from those of the others (data not shown).
Discussion
This is the first report of phase I/pharmacokinetic study of oral thalidomide in patients with an underlying hepatic dysfunction. The 300 mg/day (150 mg b.i.d.) of population MTD and 500 mg/day (250 mg b.i.d.) of median individual achievable dose in current study are comparable with the median achievable daily dose of thalidomide in other dose-escalating studies for HCC [30, 33, 49] as well as in some studies for other malig-nancies [1,36,39,51]. The median individual achievable dose for our patients in Child-Pugh’s class A and of class B was 250 mg b.i.d. (ranged, 100–600 mg b.i.d.) and 200 mg b.i.d. (ranged, 100–400 mg b.i.d.), respectively.
These observations demonstrate the high variability of individual compliance to thalidomide and suggest that the severity of underlying hepatic dysfunction does not affect the individual achievable dose and tolerability of thalidomide in HCC patients, at least for those in Child-Pugh’s A and B classes.
In this study, Cmax-ss and AUC48–60 showed a trend
toward positive correlation, but non-linear propor-tionate to the daily dose of thalidomide. The findings are consistent with those observed in a study of pro-portionality assessment of single-dose thalidomide in healthy individuals [53]. These are likely caused by the low aqueous solubility of thalidomide (@50 mg/L) to result in an easy saturation of drug in the gastroin-testinal fluid of absorption site, and further dissolution can only take place when some of the drug is absorbed across the intestinal lumen. As compared with earlier reported multiple-dose pharmacokinetic studies, the 1.81±0.15 lg/mL of mean blood Cmax-ss in our
patients taking 200 mg bid (400 mg/day) was similar to the 1.81±0.81 lg/mL and the 1.52±1.1 lg/mL of plasma values in patients of prostate cancer and of breast cancer taking 200 mg once daily [2, 15]. It suggested that the Cmax-ss was largely determined by
the dose of each administration rather than by the total daily dose.
The renal clearance increased as the dose of thalido-mide increased from 50 mg b.i.d. to 200 mg b.i.d.. The mean clearanceoral (clearance/bioavailability ratio) of
our patients taking 50 mg–200 mg b.i.d. of thalidomide, ranged between 8.63±1.67 L/h and 12.27±5.27 L/h, is similar to those observed in breast and prostate cancer patients taking either 200 mg/day or 800 mg/day [2,15]. The mean half-life of thalidomide at various dose levels in our study was similar (ranged from 7.78±2.45 h to 36.9±50.7 h) and consistent with published data of
Table 6 Pharmacokinetic parameters of oral thalidomide (150 mg twice daily) of HCC patients in Child-Pugh’s class A and class B
Child-Pugh’s A Child-Pugh’s B Pvalue
Age 45.2±13.0 61.0±12.4 0.060 Sex (M/F) 6/0 5/1 Liver tumor (£ T3/T4) 4/2 0/6 Albumin (g/dL) 3.87±0.34 2.73±0.15 0.003 Bilirubin (mg/dL) 0.88±0.52 2.62±1.26 0.02 ALT (IU/dL) 44.0±15.6 196.3±139.8 0.045
Alkaline phosphatase (IU/dL) 134.8±52.5 267.3±147.3 0.083
ICG-R15(%) 16.67±13.02 38.4±17.6 0.038 Cmax-ss(lg/mL) 1.59±0.19 1.81±0.55 0.390 Cave(lg/mL) 1.04±0.29 1.48±0.70 0.203 AUC48–60(mg h/L) 14.9±2.23 15.4±3.43 0.772 CL/Fss 14.2±5.67 12.3±2.79 0.485 t1/2(h) 10.2±3.31 10.8±4.93 0.811 tmax(h) 4.33±1.97 4.33±0.82 1.000 Ka 2.99±2.86 2.44±2.94 0.750 CLr 148.2±44.9 262.2±242.7 0.309
Mean±SD; Cmax-ss: steady-state maximum blood concentration; Cave: mean blood concentration at steady state; AUC48–60: steady-state area under curve 48–60 h after first dosage (0–12 h after the fifth dosage) at each dose level; CL/Fss: steady-state clearance / bioavailability (clearanceoral); t1/2: half-life; tmax: time to achieve maximum blood concentration; Ka: absorption coefficient. CLr: renal clearance
multiple daily dosage studies with half-life ranged from 7.08 h to 16.2 h [2, 15,16]. The Cmax, clearanceoraland
half-life of thalidomide in this study are comparable to those parameters of patients with glioma, breast and prostate cancers, suggesting that the underlying liver disease (i.e. HCC with cirrhosis) does not significantly affect the absorption and elimination of thalidomide. In our study, the ratio of AUC48–60 to daily dose of
tha-lidomide showed a trend of negative correlation when the daily dose was increased (Fig. 3). The known low aqueous solubility, 6–12 h of half-life, and decrease of AUC48–60/daily dose ratio with increasing
administra-tion doses imply that thalidomide had better to be given in divided doses rather than daily administration of it once, especially when a high-dose is to be used.
In this study, although there was a significant differ-ence of serum albumin and bilirubin levels and ICG-R15
between patients of Child-Pugh’s class A and class B, all PK parameters including Cmax-ss, Cave, AUC48–60,
clearanceoral, elimination half-life, tmax, Ka and renal
clearance were not significantly different among those patients. The data indicate that the severity of impaired liver function does not interfere the absorption and elimination of oral thalidomide in patients with com-pensated or decomcom-pensated cirrhosis.
The PK parameters of thalidomide at 100 mg b.i.d. of the responsive patient were not significantly different from other five non-responsive patients. Due to the limited number of cases, it is hard to draw any conclu-sions. Thus, we recommend incorporating pharmacoki-netic studies in future prospective trials to elucidate the correlation between PK parameters and tumor response in the thalidomide-treated HCC patients.
Besides teratogenicity, the incidences of several adverse events varied and were documented, including manifestations of gastrointestinal, cutaneous, cardio-vascular, peripheral and central nervous systems [reviewed in 11]. In the current study, the major toxici-ties comprised somnolence, constipation and skin rash, occurring in one-third or more of the patients. The adverse events in our patients were usually mild to moderate in severity and were similar to those found in healthy volunteers and other types of cancer patients [2, 14, 16, 35, 41, 50, 51, 53]. In our study, the DLTs were dyspnea, somnolence, constipation, allergic reac-tion and sinus bradycardia. Especially, the dyspnea was apparently the most important DLT in our patients receiving higher range of MTD (600–1,200 mg/day), which had been observed in a phase II study of advanced renal cell carcinoma as well [41]. Although the DLT of somnolence could be tachyphylatic, the dose was needed to be adjusted in our patients and patients with HIV, glioma or metastatic breast cancer [2, 16, 35]. Symp-tomatic bradycardia was a less common DLT, which was noted in other studies as well and might even be rescued by a device of cardiac pacemaker [2, 14, 41]. Peripheral neuropathy occurred in patients with long-term use of thalidomide and might become a DLT. In our study, this adverse event was reversible, which
phenomenon was also found in acute myeloid leukemia patients [51]. One of the possible explanations was that the duration of thalidomide use was not longer enough in our patients. One unexpected finding was the rela-tively high incidence (30.7%, 4 of 13 patients who had 4 weeks or more of therapy) of apparent ALT elevation. The increase in ALT level was usually self-limited, not associated with hepatitis viral titer change, and returned to or below the baseline value even with continuation of thalidomide therapy. These observations suggest that the apparent mild, transient transaminitis might be an idiosyncratic reaction to thalidomide rather than by its immunomodulatory effects. In contrast, the hepatotox-icity has not been emphasized in trials of thalidomide for various malignancies, including HCC [1,2,9,14–16,27, 30, 33, 35, 36,39,41,46,49–51, 54]. One of the possi-bilities might be that the serum ALT level was more frequently monitored in our study than in other studies. Therefore, more early but transient events of transami-nitis were observed in our study. Are patients with underlying liver illnesses, such as viral hepatitis or cir-rhosis/HCC, more susceptible to thalidomide-induced hepatocellular injury, as suggested by Fowler and Imire [20], or is the fluctuation of ALT a common event in patients with such end-stage liver diseases just detected by the frequent ALT monitoring? This issue can only be answered by placebo-controlled, randomization phase III study, which is currently going on in the Taiwan Oncology Cooperative Group.
In summary, we describe the first phase I/pharma-cokinetic study of oral thalidomide in patients with underlying hepatic dysfunction. Our results showed that the median individual achievable dose and all the tested pharmacokinetic parameters were equivalent in patients of Child-Pugh’s class A and B. These indicate the compliance, and the absorption and elimination of thalidomide are not significantly affected by the severity of the underlying hepatic dysfunction in patients with compensated or decompensated cirrhosis. The findings of 6–12 h of half-life and decrease of AUC48–60/daily
dose ratio with increasing daily doses suggest that di-vided doses may be a more reasonable schedule for thalidomide administration than the conventional sche-dule of dosing it once daily.
Acknowledgement This work was supported by intramural grant of National Health Research Institutes, no. NHRI-89A1-CA-QOVGHWRD.
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