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Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

Preclinical models have shown that TAC-101 (4-[3,5-bis(trimethylsilyl) benzamide] benzoic acid), an oral synthetic retinoid, has antitumor activity in hepatocellular carcinoma (HCC). We conducted a phase I study in Japanese patients with advanced HCC to examine the pharmacokinetics, recommended dose, safety, and efficacy of TAC-101. The administered dose of TAC-101 was 10 mg/day in four patients (level 1), 20 mg/day in six (level 2), and 30 mg/day in three (level 3). There was no dose-limiting toxicity at level 1. Only one patient each had dose-limiting toxicity at level 2 (grade 2 fatigue, recovery requiring eight or more consecutive days of rest) and at level 3 (grade 3 splenic vein thrombosis). Level 3 (30 mg/day) was considered the maximum tolerated dose and 20 mg/day the recommended dose by a panel of medical experts, placing maximum emphasis on safety. The most frequent adverse events were fatigue, headache, and dermal symptoms such as rash. Pharmacokinetic parameters in Japanese patients with HCC were similar to those in patients in the United States, most of whom were Caucasian. Although no patient had a complete or partial response, the disease control rate was 38.5%. In conclusion, the recommended dose of TAC-101 for patients with HCC is 20 mg/day. TAC-101 had an acceptable toxicity profile, warranting further evaluation in clinical trials. (Cancer Sci, doi: 10.1111/j.1349-7006.2012.02334.x, 2012)

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. Outcomes remain poor because disease is usually advanced at diagnosis and associated with hepatic impairment and a high rate of recurrence, resulting from either intrahepatic metastases from the primary tumor or multicentric lesions. Surgical resection, liver transplantation, radiofrequency ablation (RFA) or percutaneous ethanol injection (PEI) are the mainstays of treatment in patients with potentially curable disease. Transcatheter arterial chemoembolization (TACE) is the procedure of choice for noncurative HCC. Currently marketed systemic chemotherapeutic agents, with the exception of sorafenib, provide only marginal benefits.[1-3] Despite the survival benefit demonstrated for sorafenib, more effective systemic therapy for HCC is required.

TAC-101 (4-[3,5-bis(trimethylsilyl) benzamido] benzoic acid) is an orally absorbed synthetic retinoid. This analogue of vitamin A (retinol) binds to nuclear retinoic acid receptor-α (RAR-α), activates RAR-α transcriptional activity, and has shown antitumor activity in primary and metastatic preclinical models of liver cancer.[4, 5] TAC-101 inhibits tumor growth in the liver with low toxicity and markedly improves survival in both primary HCC and metastatic colon cancer models.[6]

In the United States, an initial dose-escalation study was performed in patients with advanced cancer. TAC-101 was orally administered daily, without a rest period. The most frequent toxicities were skin and mucosal membrane disorders, myalgia/arthralgia, fatigue, and triglyceridemia. Dose-limiting toxicities (DLT) occurring during the first 28 days of treatment (cycle 1) were fatigue, arthralgia/joint pain, myalgia, and venous thromboembolism (VTE). VTE developed in nine of 29 patients as a characteristic adverse reaction of TAC-101; the dose ranged from 12 to 34 mg/m2.[7] In a phase I/II study, TAC-101 was administered orally in 21-day cycles (14 days on/7 days off) to patients with advanced HCC. In the phase I portion of the study, the initial dose was 40 mg/day. Two patients had DLT, and the dose was reduced to 20 mg/day. Since only 1 of 6 assessable patients had DLT during the first two cycles of therapy, 20 mg/day was designated as the maximum tolerated dose (MTD) for the 21-day treatment cycle. At this dose level, TAC-101 was generally well tolerated, and the most common drug-related adverse events were increased blood triglyceride levels, fatigue, dermatitis, pruritus, nausea, dry skin, myalgias, dry mouth, arthralgias, anorexia, diarrhea, and headache. Among 21 evaluable patients, no patient had a complete response (CR) or partial response (PR), but 12 (57%) had stable disease (SD). Median progression free survival (PFS) and overall survival (OS) were 3.4 months and 19.2 months, respectively.[8]

We report the results of the first phase I study of TAC-101 in Japanese patients with HCC. Our major goals were to evaluate safe dose levels, tolerability, pharmacokinetics, and efficacy.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

Eligibility

Eligible patients had pathologically or clinically proved advanced HCC that was not amenable to standard treatments. A hypervascular mass on diagnostic imaging was considered a sufficient non-invasive diagnostic criterion for HCC. At least one measurable lesion on CT or MRI (not including necrotic lesions caused by prior treatment) was required. Other eligibility criteria included an age of 20 to 75 years; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2; an estimated life expectancy of at least 60 days; adequate hematologic function (white blood cell [WBC] ≥3000/mm3, hemoglobin ≥8.0 g/dL, platelets ≥5.0 × 104/mm3); adequate hepatic function (aspartate aminotransferase [AST] and alanine aminotransferase [ALT] ≤5 times the upper limit of normal [ULN], total bilirubin ≤2.0 mg/dL, serum albumin ≥2.8 g/dL, and prothrombin activity ≥40%); adequate renal function (serum creatinine ≤1.5 times the ULN); and a Child–Pugh class of A or B. Resection was permitted if the procedure had been performed at least 180 days before registration in the study. Other prior treatments for HCC were permitted if such treatment had been performed at least 30 days before registration. Patients were excluded if they had tumors involving more than 50% of the liver; brain or bone metastases or vascular invasion of the main trunk and first branch(es) of the portal vein, the main trunk of the left/middle/right hepatic veins, the inferior right hepatic vein, the short hepatic veins, or the inferior vena cava; severe complications; other malignancies; or inability to comply with the protocol requirements. Patients were also excluded if they had a history of VTE. Patients who were receiving anticoagulants or hormone replacement therapy were excluded. Written informed consent was obtained from each patient. The study was approved by the local institutional review boards of the National Cancer Center Hospital, Japan.

Study design and treatment plan

TAC-101 was supplied by Taiho Pharmaceutical Co., Ltd. (Tokyo, Japan). This study evaluated the pharmacokinetics of TAC-101 and established the MTD for two courses of treatment. Patients received the assigned dose of TAC-101 once daily (after breakfast) for 14 consecutive days, followed by a 7-day rest (a 21-day treatment course). If grade 3 or higher hematologic toxicity or grade 2 or higher nonhematologic toxicity occurred, the dose of TAC-101 could be reduced (minimum dose, 10 mg/day). If DLT occurred, treatment with TAC-101 could be temporarily suspended. Treatment was continued until evidence of disease progression. Treatment was terminated if recovery from an adverse event required more than 21 days, if the patient requested treatment to be discontinued, or if unacceptable toxicity developed in the opinion of the investigator.

The starting dose of TAC-101 (level 1) was 10 mg/day, level 2 was 20 mg/day, level 3 was 30 mg/day, level 4 was 40 mg/day, level 5 was 50 mg/day, and level 6 was 60 mg/day. Patients were enrolled in cohorts of three for each dose level. The dose was escalated according to cohort and was not increased in the same patient. If none of the first three patients had DLT during the first two cycles of therapy, the dose was increased to the next dose level. If one or two of the first three patients had DLT, three additional patients were assigned to the same dose level; if only one or two of the first six patients had DLT, the dose was increased to the next dose level; if all of the first three patients or three or more of the first six patients had DLT, the dose was defined as the MTD; the recommended dose (RD) was defined as the level one step below the MTD. A total of six patients received the RD to confirm the safety profile. DLT was defined as any of the following: (i) hematologic toxicity ≥Grade 4; (ii) nonhematologic toxicity ≥Grade 3; (iii) AST, ALT ≥10 times the ULN; or (iv) a rest period of eight or more consecutive days was required.

Pharmacokinetics

Blood samples for pharmacokinetic analysis were collected before and 2, 4, 6, 8, 10 to 12, and 24 h after administration of TAC-101 on day 1 and after repeated treatment (days 8–13) during the first cycle (approximately 4 mL for each time point). The blood samples were centrifuged, and the resulting plasma samples were stored at −20°C until analysis. Spontaneously voided urine was collected before treatment on day 1 (baseline urine), from 0 to 8 h after treatment (0–8 h pooled urine), and from 8 to 24 h after treatment (8–24 h pooled urine). The urine samples were stored at −20°C until analysis.

Plasma concentrations of TAC-101 were measured using a validated method. The analyte was extracted with tert-butyl methyl ether and analyzed by liquid chromatography/tandem mass spectrometry (LC/MS/MS; Waters 2690/Finnigan MAT TSQ7000) with negative ion-electrospray ionization mode, using deuterium-labeled TAC-101 as an internal standard. Pharmacokinetic parameters were calculated from the plasma concentrations of TAC-101 by non-compartmental analysis using WinNonlin software, version 4.1 (Pharsight, Cary, NC, USA).

For both plasma and urine samples, the metabolites of TAC-101 were preliminarily analyzed using an ultraviolet detector-equipped, high-performance liquid chromatograph and LC/MS/MS (Agilent 1100 series/Applied Biosystems API 4000, Carlsbad, CA, USA). The metabolites TAC-101-M-1, TAC-101-M-2, and TAC-101-M-3 were identified by comparison with authentic samples synthesized by Taiho Pharmaceuticals (Tokyo, Japan). The structures of conjugates were estimated by analyzing the mass fragmentation spectra. Concentrations of TAC-101-M-1 and TAC-101-M-2 were determined using an LC/MS/MS method similar to that used for the assay of TAC-101.

Assessment of efficacy and toxicity

All eligible patients who received at least one dose of the study drug were included in the evaluations of response and toxicity. The criteria of the Japan Society of Clinical Oncology, which closely resemble the World Health Organization criteria, were used to evaluate unblended radiographic tumor responses at the study site. Computed tomography or MRI was used to evaluate measurable disease; the same imaging modality was used at baseline and follow-up. The efficacy endpoints were the overall response rate, the duration of antitumor effect, OS, time to progression (TTP), and time to treatment failure (TTF). Vital signs, physical findings, and the results of hematological and biochemical testing, including thrombosis panel and urine analyses, were assessed at 2-week intervals during treatment and after the 7-day recovery period. The severities of all adverse events were evaluated according to the National Cancer Institute Common Toxicity Criteria, version 2.0 (NCI-CTC Ver. 2.0). The durations of all adverse events and their relations to TAC-101 were initially assessed by the attending physicians. Subsequently, an independent review committee reassessed data on adverse events and evaluated the radiologic tumor responses in a blinded manner using Response Evaluation Criteria in Solid Tumors (RECIST).[9]

Statistical considerations

All data were summarized using descriptive statistics for continuous variables and frequencies and percentages for discrete variables. Median times to events were estimated using the Kaplan–Meier method.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

Patient characteristics and treatment

Between October 2003 and May 2005, a total of 13 patients were enrolled at a single site in Japan. All patients were eligible for the evaluation of toxicity and efficacy. The first four patients received dose level 1 (10 mg/day), the next six patients received dose level 2 (20 mg/day), and the last three patients received dose level 3 (30 mg/day). The characteristics of the patients are summarized in Table 1. At study entry, three (23.1%) of the 13 patients had metastatic disease. All 13 patients had received some prior treatment, including one previously given systemic chemotherapy with the oral fluoropyrimidine tegafur-uracil (UFT).

Table 1. Summary of patient background characteristics
Background characteristics10 mg/day20 mg/day30 mg/dayTotal (%)
  1. a

    According to the staging system of the Liver Cancer Study Group of Japan (4th edition). ECOG, PS Eastern Cooperative Oncology Group performance status.

No. eligible patientsn = 4n = 6n = 3n = 13
GenderMale35311 (84.6)
Female1102 (15.4)
Age (years)<652024 (30.8)
≥652619 (69.2)
Median64726070
Min., Max.59, 7066, 7445, 7045, 74
ECOG, PS045312 (92.3)
10101 (7.7)
StageaStage I0000 (0.0)
Stage II1102 (15.4)
Stage III2428 (61.5)
Stage IVA0000 (0.0)
Stage IVB1113 (23.1)
Child–Pugh classificationA3238 (61.5)
B1405 (38.5)
C0000 (0.0)
Grade of histological differentiationWell differentiated2103 (23.1)
Moderately differentiated0314 (30.8)
Poorly differentiated0011 (7.7)
Unknown2215 (38.5)
Extrahepatic metastasisNo35210 (76.9)
Yes1113 (23.1)
History of hepatectomyNo1326 (46.2)
Yes3317 (53.8)
History of nonsurgical therapyNo0000 (0.0)
Yes46313 (100.0)

Dose-limiting toxicity and recommended dose

One of the first three patients assigned to level 1 (10 mg/day) discontinued the study medication before completing two courses of treatment because of non-drug-related serious adverse events mentioned in the section of adverse events. Therefore, another patient was assigned to this level, and safety was evaluated in a total of four patients. Because no DLT occurred at this level, the dose was increased to level 2 (20 mg/day). One of the first three patients given level 2 had DLT, and three patients were additionally assigned to this dose level; safety was thus assessed in a total of six patients. The DLT was grade 2 fatigue requiring eight or more consecutive days of rest for recovery. Because no other patient had DLT, the dose level was increased to level 3 (30 mg/day). Splenic vein thrombosis, a grade 3 drug-related adverse event, occurred in one patient at this level. Although only one patient given 30 mg/day of the study drug had DLT, this dose level was designated as the MTD and 20 mg/day as the RD by a panel of medical experts on an independent monitoring committee, who considered the thromboembolic event to be of great importance on the basis of the results of studies conducted in the United States, in which the event developed in nine of 29 patients and was potentially fatal.

Treatment delivered

Four patients received a total of 14 cycles of treatment at 10 mg/day (median, three cycles per patient; range, 1–7). Six patients received a total of 21 cycles of treatment at 20 mg/day (median, three cycles per patient; range, 2–8). Three patients received a total of seven cycles of treatment at 30 mg/day (median, three cycles per patient; range, 2–3). The dose of TAC-101 was not reduced in any patient. The reasons for terminating treatment were progressive disease in nine patients (69.2%), adverse events in two (15.4%), and other reasons in two (15.4%; one required 21 or more consecutive days of rest, and one withdrew consent).

Adverse events

Drug-related adverse events occurring in the 13 patients are shown in Table 2. Treatment with TAC-101 was generally well tolerated throughout the study. Grade 3 or 4 toxicity (splenic vein thrombosis) occurred in only one patient, who received 30 mg/day of TAC-101. The patient was a 70-year-old, HCV-positive man with Child–Pugh A liver cirrhosis, hypersplenism, and hypertension. He had multiple tumors smaller than 3 cm in diameter in the liver, without vascular invasion or extrahepatic metastasis. Splenic vein thrombosis was noted during a routine restaging CT scan of the target lesion at the end of the third course of therapy. The patient received aspirin, and the thrombosis was considered resolved 85 days after the initiation of treatment with aspirin. The most common toxic effects were fibrin D dimer increased (84.6%), blood triglycerides increased (76.9%), thrombin-antithrombin III complex increased (69.2%), headache and rash (53.8%). Serious adverse events were anorexia, hepatic encephalopathy, renal disorder, aspiration pneumonia, and sepsis in one patient who received 10 mg/day. These events were considered unrelated to the study medication. As for differences in drug-related adverse events between the Child–Pugh A and B groups, the incidences of some events were at least 20 percentage points higher in the Child–Pugh B group than in the Child–Pugh A group, such as cough (25% vs 80%), rhinorrhea (13% vs 60%), fatigue (38% vs 60%), and fibrin D dimer increased (75% vs 100%). However, the incidences and severities of most other events were similar in the two groups.

Table 2. Drug-related adverse events with incidence >20% or grade 3–4
Drug-related adverse event10 mg/day (n = 4)20 mg/day (n = 6)30 mg/day (n = 3)Child–Pugh A (n = 8)Child–Pugh B (n = 5)Total (n = 13)
All grade (%)Grade ≥ 3 (%)All grade (%)Grade ≥ 3 (%)All grade (%)Grade ≥ 3 (%)All grade (%)Grade ≥ 3 (%)All grade (%)Grade ≥ 3 (%)All grade (%)Grade ≥ 3 (%)
  1. The worst grade was used to calculate the incidence according to grade.

Splenic vein thrombosis0 (0)0 (0)0 (0)0 (0)1 (33)1 (33)1 (13) 1 (13)0 (0)0 (0)1 (8)1 (8)
Headache4 (100)0 (0)2 (33)0 (0)1 (33)0 (0)5 (63)0 (0)2 (40)0 (0)7 (54)0 (0)
Cough1 (25)0 (0)5 (83)0 (0)0 (0)0 (0)2 (25)0 (0)4 (80)0 (0)6 (46)0 (0)
Rhinorrhea1 (25)0 (0)3 (50)0 (0)0 (0)0 (0)1 (13)0 (0)3 (60)0 (0)4 (31)0 (0)
Alopecia1 (25)0 (0)2 (33)0 (0)1 (33)0 (0)2 (25)0 (0)2 (40)0 (0)4 (31)0 (0)
Eczema1 (25)0 (0)3 (50)0 (0)0 (0)0 (0)2 (25)0 (0)2 (40)0 (0)4 (31)0 (0)
Rash3 (75)0 (0)1 (17)0 (0)3 (100)0 (0)6 (75)0 (0)1 (20)0 (0)7 (54)0 (0)
Arthralgia1 (25)0 (0)3 (50)0 (0)1 (33)0 (0)3 (38)0 (0)2 (40)0 (0)5 (39)0 (0)
Myalgia2 (50)0 (0)0 (0)0 (0)1 (33)0 (0)3 (38)0 (0)0 (0)0 (0)3 (23)0 (0)
Fatigue1 (25)0 (0)4 (67)0 (0)1 (33)0 (0)3 (38)0 (0)3 (60)0 (0)6 (46)0 (0)
Blood cholesterol increased1 (25)0 (0)0 (0)0 (0)3 (100)0 (0)4 (50)0 (0)0 (0)0 (0)4 (31)0 (0)
Blood lactate dehydrogenase increased1 (25)0 (0)1 (17)0 (0)3 (100)0 (0)4 (50)0 (0)1 (20)0 (0)5 (39)0 (0)
Blood triglycerides increased3 (75)0 (0)4 (67)0 (0)3 (100)0 (0)7 (88)0 (0)3 (60)0 (0)10 (77)0 (0)
Fibrin D dimer increased2 (50)0 (0)6 (100)0 (0)3 (100)0 (0)6 (75)0 (0)5 (100)0 (0)11 (85)0 (0)
Thrombin-antithrombin III complex increased1 (25)0 (0)5 (83)0 (0)3 (100)0 (0)6 (75)0 (0)3 (60)0 (0)9 (69)0 (0)
Blood alkaline phosphatase increased2 (50)0 (0)1 (17)0 (0)1 (33)0 (0)3 (38)0 (0)1 (20)0 (0)4 (31)0 (0)

Efficacy

Response could be evaluated in all 13 patients. No patient had a CR or PR. A total of nine patients (69.2%, 9/13) had no change (NC): two of four patients at 10 mg/day, five of six at 20 mg/day, and two of three at 30 mg/day. Four patients (30.8%, 4/13) had progressive disease (PD): two of four at 10 mg/day, one of six at 20 mg/day, and one of three at 30 mg/day. No change was maintained for 8 weeks (56 days) or longer (long-term NC) in five patients, and the disease control rate (CR + PR + long-term NC) was thus 38.5% (5/13 patients). Median TTF was 60.0 days (95% CI, 46.0-65.0). Median TTP and OS were 86.0 days (95% CI, 58.0–146.0) and 427.0 days (95% CI, 369.0-unknown), respectively. When response was evaluated according to RECIST, none of the 13 patients had a PR or CR, 7 (53.8%) had SD, and five (38.5%) had PD.

Pharmacokinetic analysis

Mean plasma concentration-time profiles after administration of TAC-101 on day 1 and on day 8 are shown in Figure 1. The calculated pharmacokinetic parameters of TAC-101 are summarized in Table 3. TAC-101 concentrations in plasma reached peak values approximately 6 h after administration and declined with a half-life (t1/2) of 5–8 h. Consistent with the relatively short t1/2, increased plasma concentrations after multiple doses of TAC-101 once daily were not apparent. The relations between the dose of TAC-101 and the maximum plasma concentration (Cmax), area under the plasma concentration-time curve up to 24 h post-dose (AUC0–24), and area under the plasma concentration-time curve up to infinity (AUCinf) after a single dose (day 1) are shown in Figure 2. These variables generally increased proportionally to the dose of TAC-101 (10–30 mg/day). The relation between the dose of TAC-101 and pharmacokinetic parameters was generally unchanged after adjusting the dose according to individual body surface area. The t1/2 of 5.54 to 6.92 h, the apparent volume of distribution (Vd/F) of 32.2 to 45.5 L, and the oral clearance (CL/F) of 4.08 to 4.98 L/h after a single dose of TAC-101 did not differ among the dose levels. All pharmacokinetic parameters were generally similar after a single dose and after repeated doses of TAC-101, suggesting that repeated treatment was not associated with changes in TAC-101 metabolism or with drug accumulation.

image

Figure 1. Plasma concentration-time profile of TAC-101 (4-[3,5-bis(trimethylsilyl) benzamide] benzoic acid) in patients with hepatocellular carcinoma.

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Table 3. Pharmacokinetic values of TAC-101 in patients with hepatocellular carcinoma
Blood sampling dayPK parameter10 mg/day20 mg/day30 mg/day
No. patientsMeanSDNo. patientsMeanSDNo. patientsMeanSD
  1. AUCinf, area under the plasma concentration-time curve up to infinity; AUC0-24, area under the plasma concentration-time curve up to 24 h post-dose; CL/F, oral clearance; Cmax, maximum plasma concentration; SD, standard deviation; tmax, time of maximum concentration; t1/2, elimination half-life; Vd/F, apparent volume of distribution.

Day 1Cmax (ng/mL)4189.285.56333.088.63512.1149.5
tmax (h)45.51.065.72.036.00.0
AUC0-24 (ng h/mL)42084640639001140357801489
AUCinf (ng h/mL)32526497446801657362611596
t1/2 (h)35.540.7546.921.6735.570.57
Vd/F (L)332.25.6445.512.7339.99.6
CL/F (L/h)34.080.8944.832.1534.981.11
Day 8Cmax (ng/mL)4207.771.06326.066.93543.9138.9
tmax (h)46.02.965.72.034.00.0
AUC0-24 (ng h/mL)42401630641911063360991772
AUCinf (ng h/mL)3290675544674820372572410
t1/2 (h)36.470.9247.500.9738.163.59
Vd/F (L)332.95.1446.96.4349.313.9
CL/F (L/h)33.621.0544.390.8134.551.87
image

Figure 2. Relation between TAC-101 (4-[3,5-bis(trimethylsilyl) benzamide] benzoic acid) dose and Cmax or AUC in patients with hepatocellular carcinoma on day 1 (single dose). The x axes of the left- and right-hand figures represent the dose per day and dose per m2, respectively.

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In this clinical study, a total five patients with Child–Pugh class B disease were enrolled, but the oral clearance of TAC-101 was available for only three of the five patients at the dose level of 20 mg/day. The calculated oral clearance of TAC-101 ranged from 3.44 to 5.67 L/h in patients with Child–Pugh class A disease (n = 7, 10–30 mg/day) and from 3.19 to 7.92 L/h in those with Child–Pugh class B disease (n = 3, 20 mg/day). Although there was no apparent difference in oral clearance between the two groups, firm conclusions were precluded by the limited number of patients in this study.

The pooled plasma and urine samples were analyzed to characterize the metabolites of TAC-101. After a single dose of TAC-101, the hydroxylated metabolites TAC-101-M-1 and TAC-101-M-2 were simultaneously detected in plasma samples along with parent TAC-101. The concentrations of TAC-101-M-1 and TAC-101-M-2 in plasma as determined by LC/MS/MS were approximately 16% and 11% of the concentration of unchanged TAC-101 6 h after treatment and approximately 23% and 16% of the concentration of unchanged TAC-101 10.6 h after treatment (mean sampling time; range, 10–12 h), respectively. The respective percentages on day 8 were comparable to those after the initial dose. These results indicate that the majority of absorbed TAC-101 circulates in the body as a parent drug, with minor proportions of metabolites. In urine samples, the hydroxylated metabolite TAC-101-M-3 and the glucuronide conjugates of TAC-101-M-1 and TAC-101-M-2 were detected. The parent drug TAC-101 was not detected in urine, suggesting that hepatic metabolism is the major elimination pathway of TAC-101, which underwent hydroxylation or glucuronide conjugation, followed by partial excretion of metabolites into urine. Based on these exploratory analyses of human plasma and urine, the metabolic pathways of TAC-101 were determined as shown in Figure 3.

image

Figure 3. Metabolic pathways of TAC-101 (4-[3,5-bis(trimethylsilyl) benzamide] benzoic acid) and its metabolites.

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Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

In one patient given 30 mg/day, CT revealed splenic vein thrombosis, which was considered DLT. Although DLT developed in only one patient receiving 30 mg/day of TAC-101, this dose level was judged to be the MTD by a panel of medical experts who placed maximum emphasis on safety. Mechanisms that potentially trigger thromboembolic events have been studied, but the role of TAC-101 in such events remains unclear.

The most common treatment-related adverse events were fatigue, headache, and dermal symptoms such as rash. However, most adverse events were mild (grade 1 or 2), confirming that TAC-101 is well tolerated at the recommended dose of 20 mg/day. DLT comprised grade 2 fatigue in one patient given 20 mg/day and grade 3 splenic vein thrombosis in one patient given 30 mg/day. The latter was the only grade 3 drug-related adverse event. There were no treatment-related adverse events of grade 3 or higher in patients given 10 or 20 mg/day. In general, the toxic effects of TAC-101 were consistent with those of previous studies.[7, 8]

Higginbotham et al. reported the results of pharmacokinetic studies of TAC-101 in patients with advanced hepatocellular carcinoma treated in the United States.[8] The mean pharmacokinetic parameters (tmax, 4.3 h; Cmax, 242 ng/mL; AUC0–24, 3067.6 ng h/mL; AUCinf, 4241.1 ng h/mL) obtained for a dose of 20 mg were generally consistent with our data in Japanese patients. The slightly lower Cmax and AUCs values in the American study might be attributed to general differences in body size between Caucasians and Japanese.

Both maximum (Cmax) and overall exposures (AUCs) to TAC-101 were generally dose-related within the range of 10 to 30 mg/day. The parent compound TAC-101 was not excreted into urine, suggesting that hepatic metabolism is the major elimination pathway of TAC-101. The primary metabolism of TAC-101 was characterized by hydroxylation of the trimethylsilyl group, producing some primary metabolites, which then underwent glucuronide conjugation. However, the concentrations of the metabolites in plasma were low, suggesting that the biologic activity of TAC-101 is generally attributed to systemic exposure to unchanged TAC-101.

On the basis of the pharmacokinetic and safety profiles of TAC-101 in this study, 20 mg/day, the dose one level below the MTD, was determined to be RD. This dose is the same as the RD in the United States.

As for antitumor effect, no patient had a CR or PR, but nine had NC (69.2%, 9/13 subjects). The median TTF was 60.0 days, the median TTP was 86.0 days, and the MST was 427.0 days. The results for efficacy in this study were also similar to those in the study performed in the United States.[8] Unfortunately, tumor shrinkage was not evident, and the median TTP seemed to be unfavorable on the basis of MST. However, we believe that further evaluations are warranted, because the mechanisms of action of TAC-101 and other retinoids are considered cytostatic as opposed to cytotoxic, and the TTP in this study may be comparable to those in studies of sorafenib (2.8–5.5 months).[2, 3]

In conclusion, our results suggest that TAC-101 is well tolerated at an oral dose of 20 mg/day (dose level 2). This dose, given once daily after breakfast for 14 consecutive days followed by a 7-day rest period, was determined to be the RD for HCC. Additional studies of TAC-101 as a single agent as well as in combination with molecular-targeted agents such as sorafenib are warranted to further delineate potential clinical benefits and risks.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

We thank Drs M. Kurihara, K. Tanaka, and T. Kawasaki for their kind advice, and Drs N. Moriyama, and W. Koizumi for their extramural review. The authors are indebted to Peter Star of Medical Network K.K., Tokyo, Japan for his review of this manuscript. This study was supported by Taiho Pharmaceutical Co. Ltd.

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References
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