Phase III randomized trial of toremifene versus tamoxifen for Japanese postmenopausal patients with early breast cancer.

BACKGROUND: Toremifene, a selective estrogen receptor modulator, is used as adjuvant therapy for postmenopausal patients with breast cancer in Japan. For Japanese patients, however, only limited data are available on the efficacy and safety profile of toremifene. To establish the long term efficacy and safety of toremifene for Japanese patients, we conducted a prospective, multicenter, randomized phase III trial comparing toremifene and tamoxifen. PATIENTS AND METHODS: The subjects were postmenopausal Japanese patients who had undergone surgery for node-negative breast cancer. Toremifene or tamoxifen was administered for 2 years. The primary endpoint was demonstration of the non-inferiority of toremifene compared with tamoxifen in respect of 5-year survival. Secondary endpoints were cumulative overall survival, cumulative disease-free survival, effects on lipid profiles, and adverse events. RESULTS: A total of 253 patients were enrolled. The baseline characteristics of the two treatment groups were well-balanced. Median follow-up was 66.5 months. Five-year survival was similar for toremifene and tamoxifen (97.0 vs. 96.9 %; 90 % confidence interval -3.9 to 4.1), indicating that toremifene is not inferior to tamoxifen for postmenopausal Japanese patients with early breast cancer. Cumulative overall survival and cumulative disease-free survival were also very similar for toremifene and tamoxifen (97.5 vs. 97.3 %, log-rank test P = 0.9458; 88.4 vs. 90.6 %, log-rank test P = 0.3359, respectively). Adverse events in both groups were similar and mostly mild or moderate. Thus, both are equally effective and well tolerated. CONCLUSION: Our results suggest that the efficacy and safety of toremifene and tamoxifen are equivalent for postmenopausal Japanese patients with early breast cancer.

Effects of toremifene and tamoxifen on lipid profiles in post-menopausal patients with early breast cancer: interim results from a Japanese phase III trial.

OBJECTIVE: Toremifene and tamoxifen have been used for adjuvant therapy in post-menopausal patients with breast cancer in Japan. Dyslipidemias are common in post-menopausal women. However, limited data are available on the effects of these agents on lipid profiles in Japanese patients. The Japan Toremifene Cooperative Study Group has been conducting a Phase III randomized trial of post-menopausal patients with breast cancer. One of its secondary endpoints is to confirm the effects of these agents on serum lipid profiles. METHODS: The subjects were post-menopausal Japanese patients who had undergone surgery for early breast cancer. Toremifene or tamoxifen was administered for 2 years. Lipid levels were measured before and up to 24 months after initiation. RESULTS: Compared with baseline, at 24 months, the toremifene group (n = 123) showed significantly decreased total cholesterol (P < 0.001) and low-density lipoprotein cholesterol levels (P < 0.001), and significantly increased high-density lipoprotein cholesterol levels (P < 0.001). Their triglyceride levels were not affected (P = 0.677). The tamoxifen group (n = 120) also showed significantly decreased total cholesterol (P < 0.001) and low-density lipoprotein cholesterol levels (P < 0.001); no significant changes occurred in high-density lipoprotein cholesterol (P = 0.297) or triglyceride levels (P = 0.120). CONCLUSIONS: Distinct differences between two selective estrogen receptor modulators on lipids were observed. Toremifene improved lipid profiles, particularly as an enhancer of high-density lipoprotein cholesterol. To a large extent, tamoxifen improved low-density lipoprotein cholesterol levels. The impact of these improved lipid profiles on the risk of cardiovascular diseases needs further confirmation.

Randomized trial of cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil with node-positive breast cancer in Japan.

BACKGROUND: To compare the cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy and the anthracycline-containing regimen cyclophosphamide, epirubicin, and fluorouracil (CEF) to evaluate the efficacy and safety of the latter. METHODS: A total of 294 patients with axillary node-positive primary breast cancer of STAGE I-IIIa were randomly assigned to either CEF [cyclophosphamide (CPA) 500 mg/m(2) i.v. days 1 and 8; epirubicin (EPI) 60 mg/m(2) i.v. day 1; and 5-fluorouracil (5-FU) 500 mg/m(2) i.v. days 1 and 8] or CMF [CPA 500 mg/m(2) i.v. days 1 and 8; methotrexate (MTX) 40 mg/m(2) i.v. days 1 and 8; and 5-FU 500 mg/m(2) i.v. days 1 and 8]. Both treatment regimens were comprised of six cycles at 4-week intervals. Tamoxifen (TAM) 20 mg/day was concomitantly given to estrogen receptor (ER)-positive patients and those with undetermined ER status for 2 years. RESULTS: The overall 5-year survival was 77.1% for CEF and 71.4% for CMF [p = 0.24; hazard ratio 0.79 (95% CI 0.50-1.24)], and the 5-year disease-free survival was 55.7% for CEF and 48.9% for CMF [p = 0.15; hazard ratio 0.80 (95% CI 0.57-1.12)]. Although the log-rank test did not show a significant difference, both overall and disease-free survivals were higher for CEF according to the point estimates. Adverse drug reactions (ADRs) occurred more frequently in CEF. CONCLUSION: Whereas CEF had a good trend compare with CMF, it could not be proven statistically significant. The principal cause of the failure seems to be insufficient power, that is, the dose intensity (EPI: 60 mg/m(2)) set 10 years ago, when the trial began, was low, and the number of trial subjects was small because of the background of the times, which made the accumulation of cases extremely difficult. However, the trial should be considered to be meaningful, as it was the first, formally conducted controlled trial on chemotherapy in Japan.

Blocking mast cell-mediated type I hypersensitivity in experimental allergic conjunctivitis by monocyte chemoattractant protein-1/CCR2.

PURPOSE: To characterize the roles played by monocyte chemoattractant protein-1 and its preferential receptor CCR2 (MCP-1/CCL2) in acute allergic inflammation. METHODS: The direct effects of MCP-1 were evaluated histologically after a subconjunctival injection of recombinant MCP-1 into naïve mice. The mice were sensitized to ragweed pollen, and allergic conjunctivitis was induced by an allergen challenge. The location of the induced MCP-1 was determined by immunohistochemistry. Anti-MCP-1 antibody and CCR2-specific antagonist, RS 504393, were used to determine whether an inhibition of MCP-1 or CCR2 signals would suppress the allergen-induced immediate hypersensitivity reaction. The effect of blocking CCR2 was tested in vitro with isolated mast cells from connective tissue, to evaluate the co-stimulatory signals mediated by CCR2 in mast cells directly. RESULTS: A subconjunctival injection of MCP-1 stimulated conjunctival mast cell degranulation and recruited monocytes/macrophages. In the allergic conjunctivitis model, the allergen-induced MCP-1 protein was located in the monocytes/macrophages in the substantia propria of the conjunctiva. Blocking MCP-1 significantly suppressed the allergen-induced clinical signs and mast cell degranulation without affecting the allergen-specific IgE, or the release of Th2 cytokine from the isolated draining lymph node cells. Inhibition of CCR2 similarly suppressed the acute inflammatory responses. Consistent with the outcome of the disease model, inhibition of CCR2 suppressed allergen-specific degranulation of IgE-primed, isolated conjunctival mast cells. CONCLUSIONS: Stimulation of the co-stimulatory axis of CCR2 by MCP-1 is essentially required for mast cell-mediated hypersensitivity reactions in mouse eyes.

Efficacy of doxifluridine combined with weekly paclitaxel therapy in the treatment of advanced or recurrent breast cancer: results of the JMTO BC01 phase II trial.

We conducted a phase II study to determine the availability and safety of combination chemotherapy with weekly paclitaxel and doxifluridine (a capecitabine metabolite) in the treatment of advanced or recurrent breast cancer. Patients were treated with a combination chemotherapy regimen: doxifluridine was orally administered at 800 mg/day for 14 days, followed by a 7-day washout period. Paclitaxel was given intravenously on days 1 and 8 at 80 mg/m2 for 1 h, followed by a 1-week washout period. This 3-week cycle of therapy was repeated as long as possible (at least eight cycles) until the progression of the tumor and drug-related adverse effects were no longer observed. From May 2003 to December 2005, 26 patients were enrolled in the study. The overall response rate was 53.8% (95% confidence interval, 33.4-73.4%). The clinical benefit rate, including long-term no change, was 65.4% (95% confidence interval, 44.3-82.8%). Time to progression and survival time were 297 and 1182 days, respectively, for the 26 enrolled patients. No severe toxicities were observed. Grade 3/4 leucopenia in three patients, neutropenia in five patients, increased serum creatinine in three patients, hypercalemia in one patient, hypocalcemia in one patient, nausea/vomiting in two patients, and diarrhea in one patient. The good response rate and long time to progression and overall survival time of this doxifluridine combined with weekly paclitaxel therapy indicate its potential as a first-line or second-line treatment for advanced or recurrent breast cancer patients.

Randomized trial of the efficacy of adjuvant chemotherapy for colon cancer with combination therapy incorporating the oral pyrimidine 1-hexylcarbamoyl-5-fluorouracil.

BACKGROUND AND AIMS: The purpose of the present trial was to clarify the efficacy of postoperative adjuvant chemotherapy including an oral fluoropyrimidine anticancer drug, the 1-hexylcarbamoyl-5-fluorouracil (HCFU), for the treatment of colon cancer. METHOD: Patients with clinical stage Dukes' B and C colon cancer, who had been treated surgically, were assigned to a chemotherapy group treated with mitomycin C, 5-fluorouracil (5-FU), and HCFU and to a control group that received no postoperative adjuvant chemotherapy. RESULTS: Of the 1,001 patients registered for the study, 17 (1.7%) were ineligible. The incidence of toxicity was significantly higher in the chemotherapy group than in the control group. However, there were few severe side effects and no deaths related to the treatment. Overall survival showed no significant difference between the groups. The disease-free survival or the recurrence-free intervals was significantly higher in the chemotherapy group than in the control group. The incidence of hepatic recurrence was significantly (P=0.003) lower in the chemotherapy group than in the control group. CONCLUSION: The results of this study demonstrated the efficacy of adjuvant chemotherapy for colon cancer, i.e., combined chemotherapy that included the 5-FU oral anticancer drug HCFU.

[Clinical trials of vnorelbine in breast cancer--its scientific usefulness and development history until regulatory approval].

Vinorelbine, a novel vinca alkaloid derivative developed in France, has been widely used for the treatment of breast cancer and non-small cell lung cancer since the 1990s in many foreign countries. In Japan, it has been available for the treatment of non-small cell lung cancer since 1999, and the additional indication of breast cancer was approved in May 2005. Japanese phase I clinical trials started in 1988. A total of six trials have been conducted in patients with advanced or recurrent breast cancer, and have provided evidence of efficacy in all groups of patients, including those receiving vinorelbine as first-line monotherapy and those previously treated with both anthracyclines and taxanes. This report reviews the data from these studies and also presents the results of combination therapy evaluated outside Japan. In addition,we explain why it took 17 years for vinorelbine to be approved despite the fact that as early as the beginning of development, it was scientifically proven to be very useful in patients with breast cancer, and that the new drug application was submitted in 1993. The relationship between healthcare professionals, patients and the regulatory agency is also discussed to point out related issues.

[Late phase II clinical study of KW-2307 in advanced/recurrent breast cancer patients (II)].

A late phase II clinical study (II) of a novel vinca alkaloid derivative KW-2307 (vinorelbine ditartrate) in advanced/recurrent breast cancer patients was performed at 22 institutions throughout Japan. An intravenous dose of KW-2307, 20 mg/m2, was administered once a week. Of the 60 patients enrolled in the study, 58 were eligible and 56 were evaluable. The response rate was 33.9% (19/56; 95% confidence interval: 21.8 to 47.8%) with one CR and 18 PRs. The response rate was as high as 37.0% (17/46; 95% confidence interval: 23.2 to 52.5%) when KW-2307 was used as a first-line chemotherapy for advanced/recurrent disease. The most common adverse event was myelosuppression including leukopenia in 96.4% (54/56) and neutropenia in 94.3% (50/53). Other events observed were increased GOT in 51.8% (29/56), increased GPT in 55.4% (31/56), LDH increased in 50.0% (27/54), serum total protein decrease in 39.3% (22/56), anorexia in 41.1% (23/56), nausea and vomiting in 66.1% (37/56), constipation in 30.4% (17/56), alopecia in 33.9% (19/56) and general fatigue in 46.4% (26/56). None of them were serious. This study demonstrated that KW-2307 was an effective and safe treatment for advanced/recurrent breast cancer patients.

1-hexylcarbamoyl-5-fluorouracil + cyclophosphamide + tamoxifen versus CMF + tamoxifen in women with lymph node-positive breast cancer after primary surgery: a randomized controlled trial.

We studied the usefulness of the oral 5-FU anti-cancer drug 1-hexylcarbamoyl-5-fluorouracil (HCFU) + cyclophosphamide (CPM) + tamoxifen (TAM) (HCT group) in comparison with CMF + TAM (CMFT group) in adjuvant therapy for breast cancer by a non-inferiority study based on a multi-institutional joint study. Clinical stage I, II primary breast cancers with histologically positive axillary lymph node metastasis were randomly assigned to the HCT group or the CMFT group after primary surgery. We registered 136 cases (HCT group 68 cases, CMFT group 68 cases). No significant difference in the 5-year overall survival rate (OS) and the 5-year disease-free survival rate (DFS) was found between the two groups. In the stratified analysis, DFS in cases in which the number of metastatic lymph nodes was 1-3 was significantly better in the HCT group (HCT group 84.3%, CMFT group 69.4%, log-rank test p=0.0496). No significant difference in the total incidence of adverse effects was found between the two groups, but there were significantly less adverse effects of grade 2 or over in the HCT group (p=0.034). The QOL survey at 3 months after surgery showed a significant decline of the QOL regarding lassitude, degree of difficulty in daily life, satisfaction with treatment and present mood in the CMFT group. Study results suggest that 2-year HCT therapy including the oral 5-FU anti-cancer drug HCFU is a useful adjuvant therapy which can replace CMFT therapy in early breast cancer cases with 3 or lower metastatic lymph nodes.

Combination chemotherapy with docetaxel and doxifluridine showed a beneficial outcome in advanced or recurrent breast cancer patients with longer disease-free interval.

UNLABELLED: Fundamental studies have confirmed that combination chemotherapy with docetaxel and doxifluridine (a capecitabine metabolite) is very useful in the treatment of breast cancer. This study investigated the usefulness and tolerability of a combination chemotherapy consisting of docetaxel administration on day 8 of doxifluridine therapy in 40 advanced/recurrent breast cancer patients. The overall response rate was 41.0% in 39 eligible patients. The median time to progression (TTP) for all patients was 295 days. Many responders had lung metastasis, soft tissue metastasis or a good performance status, whereas the clinical response showed no correlations with the estrogen receptor status or prior treatment with an anthracycline. The most common hematological toxicities were leukopenia and neutropenia, but dose reduction or delay of administration of either drug was unnecessary. CONCLUSION: The good response rate and long TTP of this doxifluridine plus docetaxel regimen indicate its potential as a first- or second-line treatment for advanced/recurrent breast cancer patients.

Randomized controlled trial of the efficacy of adjuvant immunochemotherapy and adjuvant chemotherapy for colorectal cancer, using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-fluorouracil and uracil/tegafur.

BACKGROUND: We investigated the efficacy and safety of adjuvant immunochemotherapy and adjuvant chemotherapy for colorectal cancer, using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-fluorouracil (carmofur, HCFU) and uracil/tegafur (UFT). METHODS: Patients with stage II, III, or IV (Dukes' B, C) colorectal cancer were enrolled and randomly assigned to one of three groups: an immunochemotherapy group (mitomycin C [MMC] + 5-fluorouracil [5-FU] + HCFU + OK-432), a chemotherapy group (MMC + 5-FU + HCFU), and a control group (surgery alone) for those with colon cancer (study 1); and an immunochemotherapy group (MMC + 5-FU + UFT + OK-432), a chemotherapy group (MMC + 5-FU + UFT), and a control group (surgery alone) for those with rectal cancer (study 2). RESULTS: A total of 760 patients with colon cancer and 669 patients with rectal cancer were entered into this randomized clinical trial (RCT). The incidence of side-effects was in the order of: immunochemotherapy group >> chemotherapy group >> control group in both the cohort of patients with colon cancer and the cohort with rectal cancer. In particular, the frequency of leucopenia and skin disorders was significantly higher than control groups. There were no severe adverse events such as death related to the adjuvant therapy. In both the colon cancer and rectal cancer cohorts, no significant difference in the 5-year survival rate and disease-free survival rate was noted among the three groups. CONCLUSION: The results of an RCT demonstrated that the combination of MMC + 5-FU + HCFU + OK-432 for colon cancer and that of MMC + 5-FU + UFT + OK-432 for rectal cancer could not prolong the survival of patients with surgically resected colorectal cancer, but that both combinations were well tolerated as adjuvant therapy. We investigated the efficacy and safety of adjuvant immunochemotherapy and adjuvant chemotherapy for colorectal cancer, using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-fluorouracil (carmofur, HCFU) and uracil/tegafur (UFT).

Early phase II study of the new aromatase inhibitor YM511 in postmenopausal patients with breast cancer. Difficulty in clinical dose recommendation based on preclinical and phase I findings.

BACKGROUND: A phase II study of a non-steroidal selective aromatase inhibitor, YM511, 4-[N-bromobenzyl]-N-(4H-1,2,4-triazol-4-yl)amino) benzonitrile, was conducted to evaluate the anti-tumor response, dose-dependence of response rate and tolerability in postmenopausal patients with advanced breast cancer. PATIENTS AND METHODS: Patients were randomly allocated to a dose of 0.3, 1, 3, 10 or 30 mg after stratification according to PS, previous therapy and ER, and were administered the drug orally once a day. RESULTS: Of 98 eligible patients, 6 achieved complete response (CR) and 14 partial response (PR), resulting in an objective response rate of 20.4%. In addition, 13 patients achieved NC lasting more than 24 weeks (L-NC), resulting in an overall success rate of 33.7%. However, no clear dose-dependence of response rate was observed. Significant reduction of serum estradiol level was observed at all doses. Median time to progression of disease was 61-233 days. Toxicity was mild or moderate in severity. Fifty-five adverse events were reported in 38 patients, the most common being gastrointestinal disorders such as nausea, vomiting and anorexia (18 events) and constitutional symptoms such as asthenia, hot flushes and common cold syndrome (14 events). The frequency of drug-related adverse events was not dose-related. Abnormalities in hematological laboratory values and blood biochemistry, which were probably drug-related, were less than 5% in frequency except for cholesterol level, and were light or moderate in severity. CONCLUSION: YM511 appeared to be effective and safe in postmenopausal patients with breast cancer. Dose-dependent increase in response rate was not clearly observed at doses from 0.3 mg/day to 30 mg/day. The recommended dose of YM511 for further studies is 0.3 mg or less than 0.3 mg.

[Evaluation of weekly paclitaxel and doxifluridine (5'-DFUR) combination therapy in patients with advanced or recurrent breast cancer].

To evaluate the feasibility and efficacy of weekly paclitaxel and 5'-DFUR combination therapy in advanced or recurrent breast cancer, 13 patients were enrolled in this pilot study. 5'-DFUR was administered orally at a dose of 800 mg/day for 14 consecutive days, and paclitaxel was administered by 1 hour infusion at a dose of 80 mg/m2 after short premedication on day 1 and 8. This was repeated every 3 weeks, until disease progression or severe side effects precluded further treatment. Antiemetic agents and G-CSF were also administered, as needed. Nine patients had not received prior therapy, and four patients had received prior anthracycline containing therapy, two of whom were concomitantly receiving docetaxel treatment. Median administration time was 14 weeks, and median time to progression was 16.6 weeks. The overall response rate was 46.2% with 7.7% complete response and 38.5% partial response, and the response rate was consistent regardless of metastatic sites. Two patients achieved stable disease for at least 6 months and the clinical benefit was 61.5%. Responses were observed in 25% of the patients with prior anthracycline therapy. Grade 3/4 side effects involved leukopenia in 15.4%, peripheral neuropathy in 7.7%, malaise in 23.1% and nausea in 7.7%. There were no complaints of severe diarrhea. Although one patient withdrew from this study because of a hypersensitive reaction, this regimen was generally well tolerated and QOL was high enough so that it was possible to continue the regimen. Weekly paclitaxel and 5'-DFUR combination therapy seems to be feasible and effective in patients with advanced or recurrent breast cancer.

Randomized controlled trial comparing oral doxifluridine plus oral cyclophosphamide with doxifluridine alone in women with node-positive breast cancer after primary surgery.

PURPOSE: We compared the therapeutic usefulness of doxifluridine (5'-DFUR) alone and a combination of 5'-DFUR plus cyclophosphamide (CPM), both of which are considered effective against advanced and recurrent breast cancer, to determine which treatment is more beneficial as postoperative adjuvant chemotherapy. PATIENTS AND METHODS: A total of 1,131 women with node-positive primary breast cancer were randomly assigned after primary surgery to receive 5'-DFUR alone or 5'-DFUR plus CPM. All patients initially received 5'-DFUR in an oral dose of 1,200 mg/d for 4 weeks, starting 4 weeks after surgery. Chemotherapy was then not given for 2 weeks. Patients in the 5'-DFUR group subsequently received five 4-week cycles of treatment consisting of oral 5'-DFUR (1,200 mg/d) for the first 2 weeks and no chemotherapy for the next 2 weeks. Those assigned to the 5'-DFUR plus CPM group also received oral CPM 100 mg/d for the first 2 weeks and no chemotherapy for the next 2 weeks. Women 50 years or older concurrently received 20 mg/d of tamoxifen for 2 years in both groups. RESULTS: Of the 1,088 eligible women, 546 were assigned to receive 5'-DFUR alone and 542 were assigned to receive 5'-DFUR plus CPM. Overall disease-free survival was significantly better in women who received 5'-DFUR plus CPM than in those who received 5'-DFUR alone (log-rank test, P =.021). Toxic effects occurred in 20.0% of patients (109 of 546) in the 5'-DFUR group and 32.3% of patients (175 of 542) in the 5'-DFUR plus CPM group (chi(2) test, P <.001). CONCLUSION: Combination therapy with 5'-DFUR plus CPM is more effective in preventing recurrence than 5'-DFUR alone.

[Phase I single-dose administration study of exemestane in postmenopausal women].

A single-dose administration study of a new type of aromatase inactivator, exemestane, was performed in normal healthy postmenopausal Japanese women. The study was conducted to investigate the safety, effect on serum and urinary estrogen concentrations, and pharmacokinetics of exemestane at 25 or 50 mg. A crossover study using a single dose (25 mg) was also conducted in order to study the effect of meals on these parameters. Adverse events, in which a causal relationship with the study drug could not be excluded, were as follows: hot flushes (2/4), sleepiness (1/4), and glycogeusia (1/4), all of which were mild and transient. There were no clinically significant laboratory test or physical finding abnormalities with either dose, except for one patient in the 50 mg group who had an increase in levels of GPT, ALP and gamma-GTP. Maximal suppression of serum estrogen concentration (22-37% suppression) was achieved 3-4 days after single-dose administration of exemestane (25 mg or 50 mg), and almost no suppression was observed 2 weeks later. A significant decrease in the amount of urinary estrogen excretion occurred on day 4 and day 8 after exemestane administration. The level of urinary estrogen excretion almost returned to baseline levels in the 25 mg group and returned to 65% of baseline levels in the 50 mg group 2 weeks after drug administration. Both serum estrogen concentration and the amount of urinary estrogen excreted decreased in a similar fashion under both fasting and fed conditions, suggesting no effect of meals on the suppression of estrogen concentrations. Exemestane was adsorbed immediately after single-dose administration, and this was followed by a gradual decrease in serum concentrations in a multiphase pattern. An increase in Cmax and AUC0-tz values was observed after meals compared with those values obtained under fasting conditions, yet the increase was not statistically significant, suggesting that the increase was not clinically relevant. The results of this study verified the safety and the estrogen suppressive effects on serum and urinary concentrations of estrogen of a single dose of exemestane up to 50 mg. Furthermore, results suggest that the suppression of serum and urinary estrogen concentrations and pharmacokinetics of exemestane were not affected by food.

[Phase I multiple-dose administration study of exemestane in postmenopausal women].

A multiple-dose administration study of exemestane (0.5-50 mg/day after breakfast for 7 days) was conducted in 32 normal healthy postmenopausal Japanese women using a single-blind, 3-step dose-titration method in order to investigate the safety, effect on serum concentration, amount of urinary estrogen excretion, and pharmacokinetics of the drug. Subjective/objective symptoms, in which a causal relationship with exemestane administration could not be excluded, were as follows: headache (8 cases: 1 each in the 0.5 and 25 mg groups, 2 in the 10 mg group and 4 in the 50 mg group), dizziness (2 cases: 1 each in the 0.5 and 25 mg groups), and fever (1 in the 25 mg group), all of which were mild and disappeared without treatment. The only abnormal laboratory findings were a mild increase in levels of GOT and GPT in 1 case and in the number of basophils in another case. There were no notable abnormal findings in vital signs, body weight or EKG. A dose-dependent decrease in serum estrogen level was observed between doses of 0.5 mg and 25 mg. The decrease was maximal at 25 mg, at which serum estrogen concentrations decreased to 14-27% of those observed at day 0. This decrease was maintained for one week, returning to baseline levels 2 weeks after the completion of drug administration. A similar result was also observed in the suppression of 24-hour urinary estrogen excretion. Exemestane was absorbed immediately after initial administration, reaching Cmax 0.9-2.6 hours post-administration. This was followed by a rapid decrease over the next 4-8 hours followed by a gradual decrease Cmax reached normal steady state values on day 5. Cmax and AUC0-24 values taken between administration of the first and final doses increased proportionally in a dose-dependent manner, suggesting that exemestane has a linear pharmacokinetic profile. Furthermore, results of the comparison of the trough concentrations of the initial dose with those of the final dose suggested no accumulative effects of the study drug.

Pharmacokinetic and pharmacodynamic study of IST-622, a novel synthetic derivative of chartreusin, by oral administration in a phase II study of patients with breast cancer.

The aim of this study was to analyze the pharmacokinetics and pharmacodynamics (PK/PD) of 6- O-(3-ethoxypropionyl)-3',4'- O-exo-benzylidene-chartreusin (IST-622) and its metabolites, and to develop limited sampling models (LSM). Based on the data from 18 patients with breast cancer who were treated orally with 280 or 525 mg/m(2) of IST-622 once daily after breakfast for five consecutive days, we analyzed the relationship between the area under the plasma concentration versus time curve (AUC) and toxicities using a sigmoid E-max model and logistic regression. Plasma concentrations of IST-622 and its metabolites, 3',4'- O-exo-benzylidene-chartreusin (A-132) and 3"-demethyl-3',4'- O-exo-benzylidene-chartreusin (A-132M), were measured at 1, 2, 4, 8 and 24 h after administration on day 1. The AUC was calculated using the trapezoidal method. We also developed a LSM using stepwise linear regression analysis. IST-622 was detected in very few patients, and its concentration was very low and could be disregarded. It was suggested that meals promoted absorption of IST-622. AUCs of A-132 plus A-132M showed a better correlation with the rates of decrease and nadir counts of leukocytes, neutrophils and platelets than the AUC of each metabolite separately. Patients with the sum of AUCs more than 70 microg.h/ml showed severe myelotoxicities. Moreover, logistic regression analysis showed that grade 4 myelotoxicities would be seen in 30% of patients at an AUC of 65 microg.h/ml. We also developed an unbiased and precise LSM: AUC_0-24h=C_8hx17.6-0.95, where C(8h) denotes the sum of plasma concentrations of A-132 and A-132M. Myelotoxicities showed a good correlation with AUC(0-24h), and based on the results, it was decided that the target AUC was 65 microg.h/ml. The LSM was very convenient for estimating AUC(0-24h) and sufficiently accurate. These results show the possibility of predicting toxicities and dose adaptation for interpatient variability using LSM.

[CGS20267 (Letrozole), a new aromatase inhibitor: late phase II study for postmenopausal women with advanced or recurrent breast cancer (no. 1)--investigation of recommended clinical dose CGS20267 Study Group].

To determine the recommended clinical dose of CGS20267 (Letrozole), we conducted a randomized comparative study as a late phase II study (first part) in postmenopausal women with advanced or recurrent breast cancer. Forty-one patients were randomly assigned to receive 0.5 mg or 1.0 mg once daily. There were no statistically significant differences in background between the two groups. Although there was no significant difference in the objective response rates between the two groups, the rate was higher at 1.0 mg (44.4%) than at 0.5 mg (38.1%). We also combined these data with the results of an early phase II study. The objective response rates (CR + PR) were 31.4% at 0.5 mg and 42.2% at 1.0 mg, and response rates consisting of CR, PR, and NC for longer than 6 months were significantly higher at a dose of 1.0 mg (68.9%) than 0.5 mg (41.2%). Side effects included drug-related adverse events in 36.8% at 0.5 mg and in 31.6% at 1.0 mg. All of the events were grade 2 or lower, indicating a favorable tolerability of CGS20267. These results demonstrated that CGS20267 1.0 mg once daily is more effective than 0.5 mg, and has comparable safety, in the treatment of postmenopausal women with advanced or recurrent breast cancer. We conclude the recommended clinical dose of CGS20267 should be 1.0 mg once daily.

[CGS20267 (Letrozole), a new aromatase inhibitor: late phase II study in postmenopausal women with advanced or recurrent breast cancer (no. 2)--evaluation of efficacy and safety at the recommended clinical dose CGS20267 Study Group].

In the first part of this late phase II study, we determined the recommended clinical dose of CGS20267 to be 1.0 mg once daily for the treatment of postmenopausal women with advanced or recurrent breast cancer. To further evaluate the efficacy and safety of CGS20267 at the derived or recommended clinical dose, 30 more patients were enrolled in the second part of the study, and were added to the patients treated at 1.0 mg in the first part. As a result of putting the first and second parts together, the objective response rate at 1.0 mg was found to be 38.3%, which was almost equal to that of the early phase II study (40.7%). Drug-related adverse events occurred in 35.4% of the patients at 1.0 mg, and all of the events were of grade 2 or lower. These results demonstrated that CGS20267 1.0 mg once daily is effective and well tolerated in the treatment of postmenopausal women with advanced or recurrent breast cancer.