What is Compassionate Use?

Chemical name: N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinepropoxy) quinazolin-4-amine

Chemical Structure:

Iressa (gefitinib tablets), the indication is suitable for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with previous chemotherapy. Previous chemotherapy mainly refers to platinum and docetaxel. The efficacy of this product in patients with locally advanced or metastatic non-small cell lung cancer who have previously received chemotherapy is based on the survival advantage of the Asian subgroup preset in a large-scale placebo-controlled clinical trial (Note: the trial did not show improvement in the overall population Disease-related symptoms and prolonged survival) and survival data from Chinese uncontrolled clinical trials. The results of two large randomized controlled clinical trials show that first-line treatment of locally advanced or metastatic NSCLC with gefitinib combined with platinum-containing chemotherapy does not show clinical benefit, so such a combination is not recommended.

Drug Name

Iressa

Drug type

prescription

Use classification

Other antitumor drugs

Iressa ingredients

Chemical name: N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinepropoxy) quinazolin-4-amine

Chemical Structure:

Molecular formula: C ₂₂ H ₂₄ ClFN ₄ O ₃

Molecular weight: 446.90

Iressa traits

Brown, round, film-coated pieces; "IRESSA 250" printed on one side.

Iressa indications

This product is suitable for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with previous chemotherapy. Previous chemotherapy mainly refers to platinum and docetaxel.

The efficacy of this product in patients with locally advanced or metastatic non-small cell lung cancer who have previously received chemotherapy is based on the survival advantage of the Asian subgroup preset in a large-scale placebo-controlled clinical trial (Note: the trial did not show improvement in the overall population Disease-related symptoms and prolonged survival) and survival data from Chinese uncontrolled clinical trials.

The results of two large randomized controlled clinical trials show that first-line treatment of locally advanced or metastatic NSCLC with gefitinib combined with platinum-containing chemotherapy does not show clinical benefit, so such a combination is not recommended.

Iressa specifications

0.25 g.

Iressa dosage

The recommended dose of this product is 250mg (1 tablet), once a day, orally, on an empty stomach or with food.

If you have difficulty swallowing, disperse the tablet in half a cup of drinking water (non-carbonated beverages). Do not use other liquids. Throw the tablet into the water without crushing, stir until completely dispersed (about 10 minutes), and drink the liquid immediately. Rinse the cup with half a glass of water and drink. The medicinal solution can also be administered through a nasal-gastric tube.

There is no need to adjust the dosage according to the following conditions: age, weight, gender, ethnicity, renal function, and moderate to severe liver function impairment due to liver metastases.

Dose adjustment: When patients have intolerable diarrhea or skin adverse reactions, they can be resolved by short-term suspension of treatment (up to 14 days), and then resume the 250mg daily dose (see Adverse Reactions).

Use in children

There is no information on the safety and efficacy of this product for children or adolescents, so it is not recommended.

Iressa adverse reactions

The most common (above 20%) adverse drug reactions (ADRs) are diarrhea and skin reactions (including rash, acne, dry skin, and itching), which are usually seen within the first month after taking the medication and are usually reversible. About 8% of patients have serious adverse drug reactions (CTC criteria grade 3 or 4). About 3% of patients discontinued due to ADR.

Adverse events occurring in each body system are listed in descending order according to their frequency of occurrence (more common:] 10%; common:] 1% and [10%; rare:] 0.1% and [1%; rare:] 0.01% and [0.1% ; Extremely rare: [0.01%)

The possible adverse events are summarized as follows:

# Based on clinical studies conducted globally, expanded use / compassionate use, and data on post-market use, the total estimated reporting rate for interstitial lung disease outside Japan is approximately 0.3% and approximately 3% in Japan.

A double-blind, phase III clinical study comparing this product plus Best Supportive Therapy (BSC) with placebo plus BSC for one or two chemotherapy regimens in the past and ineffective or intolerant to recent treatment In patients with locally advanced NSCLC, the incidence of interstitial lung disease type events was similar in the general population, with approximately 1% in both treatment groups. The vast majority of reported interstitial lung disease events were from the Oriental population. The incidence of interstitial lung disease was similar among patients in the Oriental population receiving this product or placebo, at approximately 3% and 4%, respectively. One interstitial lung disease-type event resulted in death and was a patient receiving placebo.

In a post-marketing drug surveillance study in Japan (3350 patients), the reported incidence of interstitial lung disease type events in patients receiving this product was 5.8%.

Iressa Taboo

Those who are known to have a severe allergic reaction to the active substance or any of the excipients of the product.

Iressa notes

Interstitial lung disease has been observed in patients receiving this product, which can be acute. Patients often experience acute dyspnea with cough, low fever, respiratory tract discomfort, and arterial oxygen saturation. The symptoms can develop very quickly in the short term and there have been reports of deaths. Radiological examinations often show lung infiltrates or interstitial ground-glass shadows. It has been observed that patients with this condition have a higher mortality rate in patients with primary pulmonary fibrosis / interstitial pneumonia / pneumoconiosis / radiative pneumonia / drug-induced pneumonia.

The prescribing doctor should closely monitor the signs of interstitial lung disease. If the patient's respiratory symptoms worsen, he should discontinue the treatment of this product and immediately check it. When interstitial lung disease is confirmed, the use of this product should be stopped and the patient should be treated accordingly.

Elevated liver transaminase has been observed (see adverse reactions), with rare manifestations of hepatitis. Therefore, it is recommended to check liver function regularly. Patients with mild to moderately elevated liver transaminase should use this product with caution. If liver transaminase is exacerbated, drug withdrawal should be considered.

Elevated INR (International Normalised Ratio) and / or bleeding events (see Adverse Reactions) have been reported in some patients taking warfarin. Patients taking warfarin should regularly monitor changes in prothrombin time or INR.

Patients should be advised to seek medical attention immediately when the following conditions have worsened:

Any ocular symptoms

Severe or persistent diarrhea, nausea, vomiting or anorexia

These symptoms should be treated as clinically needed (see Adverse Reactions).

Randomized controlled trials have shown that there is no additional benefit of combining this product with a platinum-based standard two-drug combination chemotherapy regimen in patients with advanced non-small cell lung cancer. Therefore, this product should be used only in patients with non-small cell lung cancer who have previously received cytotoxic chemotherapy.

In a phase I / II clinical study of pediatric patients with this product and radiotherapy, 45 patients were selected (these patients were newly diagnosed with brainstem gliomas or incompletely resected supramental gliomas ), 4 cases (1 death) of central nervous system bleeding occurred. In a clinical study using this product alone, a child with ependyma also developed central nervous system bleeding. The risk of cerebral hemorrhage in adult NSCLC patients treated with this product is unlikely to increase.

Impact on the ability to drive and manipulate machines

During the treatment of this product, symptoms of fatigue can occur, and patients with these symptoms should be reminded when driving or operating machinery.

Iressa medication for pregnant and lactating women

Use during pregnancy

There are no data on the use of this product in pregnant women. The increase in the incidence of maternal toxicities of gefitinib during organogenesis can be observed in rats with an increased incidence of osteogenesis imperfecta, and fetal weight can be observed in rabbits. No malformations were observed in rats, only in rabbits at doses that produced severe maternal toxicity. During the treatment of this product, women of childbearing age should be advised to avoid pregnancy.

Use during lactation

During the treatment of this product, breastfeeding mothers should be advised to stop breastfeeding.

There is no information on this product for breastfeeding women. It is unknown whether gefitinib or its metabolites will be secreted into human milk, but when administered to lactating rats orally 5mg / kg gefitinib (0.2 times the clinical dose based on body surface area), gefitinib and Certain metabolites are widely secreted into milk.

Gefitinib was administered at a dose of 20 mg / kg / day (0.7 times the clinical dose based on body surface area) during pregnancy and childbirth in rats, which could reduce the survival rate of young rats.

Iressa children's medication

There is no information on the safety and efficacy of this product for children or adolescents, so it is not recommended.

Iressa medication for the elderly

See usage and dosage.

Iressa drug interactions

In vitro tests on human liver microsomes confirmed that gefitinib is mainly metabolized by the CYP3A4 of the liver cytochrome P-450 system. So gefitinib may interact with drugs that induce, inhibit, or metabolize the same liver enzymes. Animal studies have shown that gefitinib has little enzymatic induction, and in vitro studies have shown that gefitinib inhibits CYP2D6 to a limited extent.

The following is a list of drugs or drug classes that interact with or may produce clinically significant drugs with gefitinib:

Gefitinib drugs

Proven interaction

[u] Drugs that inhibit CYP3A4 [/ u]

In combination with gefitinib and itraconazole, a CYP3A4 inhibitor, in healthy volunteers, the average AUC of gefitinib increased by 80%. Since adverse drug reactions are related to dose and exposure, this increase may be clinically significant. Although no interaction with other CYP3A4 inhibitors has been studied, this class of drugs such as ketoconazole, clotrimazole, and Ritonovir may also inhibit the metabolism of gefitinib.

[u] Medicine that raises the pH of the stomach [/ u]

Clinical studies in healthy volunteers have shown that combination with drugs that can significantly increase gastric pH to 5 can reduce the average AUC of gefitinib by 47%, which may reduce the efficacy of gefitinib.

[u] Rifampicin [/ u]

Gefitinib was administered in healthy volunteers at the same time as rifampicin (a known strong CYP3A4 inducer), and the average AUC of gefitinib was reduced by 83% compared with single administration.

Drugs that could theoretically interact

[u] Other CYP3A4 inducers [/ u]

Substances that induce CYP3A4 activity can increase the metabolism of gefitinib and reduce its plasma concentration. Therefore, combination with CYP3A4 inducers (such as phenytoin, carbamazepine, barbiturates, or St. John's wort) can reduce efficacy.

Effect of Gefitinib on Other Drugs

Proven interaction

[u] Drugs metabolized by CYP2D6 [/ u]

In a clinical trial, the combination of gefitinib with metoprolol, a CYP2D6 enzyme substrate, increased metoprolol exposure by 35%, which was not considered clinically relevant. Gefitinib taken with other drugs metabolized by CYP2D6 may increase the latter's blood concentration.

Drugs that could theoretically interact

[u] Warfarin [/ u]

Although no formal drug interaction studies have been conducted to date, increased INR and / or bleeding events have been reported in some patients taking warfarin. Patients taking warfarin should be regularly monitored for changes in their prothrombin time or INR (see Precautions).

[u] Changchun Ruibin [/ u]

In phase II clinical studies, taking this product at the same time as vinorelbine showed that this product may exacerbate the neutropenia effect caused by vinorelbine.

Iressa overdose

There is no special treatment for overdose of this product, and the possible symptoms of overdose are unknown. In Phase I clinical trials, a small number of patients took a dose of 1000 mg per day, and increased frequency and severity of some adverse reactions were observed, mainly diarrhea and rash. Adverse reactions caused by drug overdose should be treated symptomatically, especially severe diarrhea should be treated appropriately.

Iressa clinical trials

Phase II clinical study

Two large-scale phase II clinical studies evaluated the efficacy and safety of this product as a single drug in the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). The patient's WHO physical status score is 0-2 and must be a failure of previous chemotherapy:

* IDEAL 1 (Study 0016), who previously received 1 or 2 chemotherapy regimens, and at least one of which included platinum therapy (median age 59.6 years [28-85 years]; n = 209)

* IDEAL 2 (Study 0039), who had previously received 2 or more chemotherapy regimens, which included concurrent or sequential treatment with platinum and docetaxel (median age 61 years [30-84 years]; n = 216)

Two study designs were similar, both double-blind, parallel, multicenter, and evaluated with two oral doses of gefitinib: 250 mg / day and 500 mg / day. Patients were randomly assigned to these two dose groups. In IDEAL 1, the primary study endpoint was tumor objective response rate, and the secondary study endpoint was disease-related symptom improvement; in IDEAL 2, the primary study endpoint was tumor objective response rate and disease-related symptom improvement rate (measured by LCS every week).

Phase III clinical study

In a double-blind, placebo-controlled, parallel-group phase III clinical study, this product was compared with placebo in patients with advanced non-small cell lung cancer who had previously received one or two chemotherapy regimens. The primary observational indicator was overall survival, and the secondary observational indicators included time to treatment failure, objective response, and QoL. Another exploratory goal is the status of EGFR and other related biomarkers, including the relationship between EGFR expression and EGFR mutation status and efficacy.

Efficacy results

Phase II clinical study

A summary of the efficacy results for IDEAL1 and IDEAL2 is shown in the table below. Regardless of the WHO performance status score (0, 1 or 2) and the number of previous chemotherapy treatments, the tumor objective response rate results obtained in the two studies were similar. The objective remission of tumors in most patients occurs in the first month of treatment, and the objective remission of a few patients can occur as late as the fourth month of treatment.

a In the IDEAL1 trial, whether 250mg or 500mg, the objective response rate of Japanese patients is higher than that of non-Japanese patients (250mg is 27.5%: 9.6%, 500mg is 27.5%: 11.1%)

+ Continues at data deadline

PFS progression-free survival

Phase III clinical study

In the general population or in patients with adenocarcinoma subgroups, this product did not show significant prolonged survival (overall population: HR 0.89, CI 0.77 to 1.02, p = 0.09, median survival time of this product was 5.6 months, comfort The dose was 5.1 months; in the subgroup of adenocarcinoma patients: HR 0.84, CI 0.68 to 1.03, p = 0.09, median survival time of this product was 6.3 months, and placebo was 5.4 months). For the improvement of quality of life and symptoms, this product has not shown any obvious benefits. Pre-set subgroup analysis showed that compared with placebo, this product significantly prolonged the survival of patients in the Oriental population and patients who had never smoked (in the Oriental population: HR = 0.66, CI 0.48 to 0.91, p = 0.01, the median survival time of this product is 9.5 months, and the placebo is 5.5 months; in patients who have never smoked: HR = 0.67, CI 0.49 to 0.92, p = 0.01, the median survival time of this product is 8.9 months, (Placebo is 6.1 months).

Analysis of the number of EGFR gene replication data shows that compared with placebo, this product has a longer survival rate for patients with a higher number of EGFR gene replication than for patients with a low number of EGFR gene replication (interaction p value = 0.0448). This product has a hazard ratio (HR) to placebo. It is 0.61 (N = 114; 95% CI 0.36-1.04, p = 0.067) in patients with a high number of EGFR gene replication, and in patients with low EGFR gene replication. The group was 1.16 (N = 256; 95% CI 0.81-1.64, p = 0.42). For the group of patients who did not detect the number of EGFR gene copies (N = 1322; HR = 0.85; CI 0.73-0.99, p = 0.032), as expected, the hazard ratio was similar to the hazard ratio of the total study population. EGFR gene replication number analysis was measured by the fluorescence in situ hybridization (FISH) method, that is, using the LSI EGFR SpectrumOrange / CEP 7 SpectrumGreen probe. If the patient's tumor has high polysomy (4 replication in 40% of cells) or gene amplification (there is a dense EGFR gene population and the gene / chromosome ratio in each cell is 2, or 10% of the cells analyzed, each cell has 15 EGFR replication), which means that the patient's EGFR gene replication is high.

Analysis of EGFR protein expression data shows that when treated with this product, compared with placebo (N = 264, HR = 0.77, CI 0.56-1.08, p = 0.13), patients with EGFR-positive tumors are better than patients with EGFR-negative patients. Survival results (N = 115, HR = 1.57, CI 0.86-2.87, p = 0.14), but none of the subgroup analyses reached statistical significance. For the group of patients who did not detect EGFR expression (N = 1313; HR = 0.84; CI 0.73-0.98, p = 0.03), as expected, the hazard ratio was similar to the hazard ratio of the total study population. A positive EGFR expression status is defined as the detection of EGFR in at least 10% of the cells, compared with 1% in the DAKO EGFR pharmDx reagent protocol.

Analysis of EGFR gene mutation data shows that patients with EGFR mutations have a higher remission rate than patients without EGFR mutations, tending to women, non-smokers, or people with adenocarcinoma tissues. However, sufficient data are not yet available for meaningful survival assessments.

safety

The safety profile of this product was similar in all studies, and the incidence and severity of adverse events were dose-related (see Adverse Reactions).

in conclusion

Clinical research data prove that some patients with locally advanced or metastatic non-small cell lung cancer can achieve continuous objective remission by treatment with this product. In phase III clinical studies, this product did not extend survival in the general population or in patients with adenocarcinoma subgroups. The patients most likely to benefit from this product are patients from the Oriental population, patients who have never smoked, or patients with a high number of EGFR gene copies. Patients with low EGFR gene replication or negative EGFR expression are unlikely to benefit from survival with this product.

Clinical research conducted in China

Clinical studies were conducted at five clinical research sites in China to evaluate the objective response rate of 250 mg / day of gefitinib tablets in non-small cell lung cancer patients who had previously received chemotherapy.

A total of 159 subjects took 250 mg of gefitinib at least once. The demographic and disease characteristics of the subjects are shown in Table 2. Among them, 75 patients (47.2%) had received 1 chemotherapy regimen before enrollment, and 50 (31.4%) were treated by 2 or more (including 3) chemotherapy regimens. And 34 (21.4%). A validity analysis was performed on 159 subjects (intent-to-treat clusters).

Table 3 summarizes the efficacy. The objective response rate in different treatment subgroups shows some differences (grouped according to baseline characteristics at the time of enrollment, and the objective response rate of the subjects is shown in Table 4). Similar differences are also seen in other international multicenter clinical studies . Although the number of subjects in certain subgroups was not sufficient, the effects of gefitinib on these subjects were as expected.

safety

Gefitinib was well tolerated overall. Most adverse events were mild and did not require treatment. Adverse events reported by more than 10% of subjects were rash (44.0%), pruritus (15.7%), and diarrhea (11.3%). The severity and frequency of adverse events were consistent with those observed in other clinical studies.

Iressa Pharmacology and Toxicology

Pharmacological action

Gefitinib is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, which is usually expressed in solid tumors of epithelial origin.

Gefitinib extensively inhibits the growth of human tumor cells xenografted in nude mice and inhibits angiogenesis. In vitro, it can increase apoptosis of human tumor cell-derived lines and inhibit the invasion and secretion of angiogenic factors. Gefitinib has been shown to increase the antitumor activity of chemotherapy, radiotherapy and hormone therapy in animal tests or in vitro studies.

Toxicology research

Non-clinical (in vitro) research data indicate that gefitinib has the potential to inhibit cardiac action potential repolarization processes (such as the QT interval). However, safety data obtained from clinical studies and post-marketing surveillance have not suggested any adverse effects of gefitinib on the heart.

Carcinogenic, teratogenic and reproductive toxicity

Gefitinib did not show genotoxic effects in gene mutation analysis (bacterial and in vitro mammalian cells) and lysis tests (in vitro mammalian cell and in vivo rat micronucleus tests).

Gefitinib administered at a dose of 20 mg / kg / day from 4 weeks before mating to 7 days of pregnancy (0.7 times the clinical dose based on body surface area) can affect ovulation in female mice, leading to a decrease in luteal weight.

The increase in the incidence of maternal toxicities of gefitinib during organogenesis can be observed in rats with an increased incidence of osteogenesis imperfecta, and fetal weight can be observed in rabbits. No malformations were observed in rats, only in rabbits at doses that produced severe maternal toxicity.

When administered to lactating rats orally at 5 mg / kg gefitinib (0.2 times the clinical dosage based on body surface area), gefitinib and certain metabolites are widely secreted into milk.

Gefitinib was administered at a dose of 20 mg / kg / day (0.7 times the clinical dose based on body surface area) during pregnancy and childbirth in rats, which could reduce the survival rate of young rats.

A two-year carcinogenicity study in rats. At the highest dose (10 mg / kg / day), the incidence of hepatocellular adenomas in male and female rats and mesenteric lymph node angiosarcoma in female rats were: A slight increase, but a statistically significant increase. Hepatocellular adenoma was also observed in another 2-year carcinogenicity study of mice, showing the incidence of male mice at a dose of 50 mg / kg / day and at a maximum dose of 90 mg / kg / day At the time (reduced from 125 mg / kg / day to this dose from week 22), the incidence of both female and male mice increased slightly. The results for female mice were statistically significant, but not for males. The clinical relevance of these findings is unknown.

Iressa Pharmacokinetics

After intravenous administration, gefitinib was rapidly cleared and widely distributed, with an average clearance half-life of 48 hours. Cancer patients have slower absorption after oral administration, with an average terminal half-life of 41 hours. Gefitinib showed 2-8 times accumulation once a day, and reached a steady state after 7-10 doses. After reaching steady state, the drug is administered at 24-hour intervals, and the ratio of the highest and lowest plasma drug concentration is generally maintained between 2-3 times.

absorb

After oral administration of this product, the peak plasma concentration of gefitinib appeared 3 to 7 hours after administration. The average absolute bioavailability of cancer patients is 59%. The effect of eating on gefitinib absorption was not significant.

distributed

The average distribution volume of gefitinib at steady state is 1400L, indicating that it is widely distributed in tissues. The plasma protein binding rate is about 90%. Gefitinib binds to serum albumin and 1-acid glycoprotein.

metabolism

Data from in vitro studies indicate that the P450 isoenzyme involved in the oxidative metabolism of gefitinib is mainly CYP3A4.

In vitro studies have shown that gefitinib has limited inhibition of CYP2D6 (see Drug Interactions).

Gefitinib has not shown enzyme induction in animal studies, and has no obvious inhibitory effect on other cytochrome P450 enzymes in vitro.

Three biotransformation sites have been identified in the metabolism of gefitinib: the metabolism of N-propylmorpholine groups, the demethylation of methoxy substituents on quinazoline, and Oxidative defluorination. Five metabolites have been fully identified in the stool, and the main metabolite is O-desmethylgefitinib, although it only accounts for 14% of the dose.

Eight human metabolites were fully identified in human plasma, and the main metabolite was O-desmethylgefitinib. Its inhibitory effect on EGFR-stimulated cell growth is 14 times weaker than that of gefitinib, and it has no inhibitory effect on tumor cell growth in mice. It is therefore unlikely to have an effect on the clinical activity of gefitinib.

In vitro studies have shown that CYP2D6 is involved in the production of O-desmethylgefitinib. The role of CYP2D6 in the elimination of gefitinib metabolism has been evaluated in clinical studies of healthy volunteers typed with CYP2D6 status. No measurable levels of O-desmethylgefitinib were produced in slow metabolizers. The range of gefitinib exposure is very large and overlaps in the fast and slow metabolizing populations, but the average exposure of gefitinib in slow metabolizing populations is 2 times higher than that of fast metabolizing populations. Since adverse reactions are related to dose and exposure, the high average exposure achieved in individuals lacking active CYP2D6 may be clinically relevant.

eliminate

Gefitinib has a total plasma clearance of approximately 500 mL / min. Excretion is mainly through feces, and less than 4% is cleared by the kidneys in the form of prototypes and metabolites.

Special population

Crowd dynamics

In population-based data analysis performed by cancer patients, no relationship was found between expected steady-state plasma concentration and patient age, weight, gender, ethnicity, or creatinine clearance.

Liver function impairment

In a phase I open-label study, a single dose of 250 mg gefitinib was used in patients with mild, moderate, or severe liver impairment caused by cirrhosis (based on the Child-Pugh classification) compared to healthy controls , Exposure levels increased in all groups. In patients with moderate to severe hepatic impairment, gefitinib exposure levels increased by an average of 3.1 times. None of these patients had cancer, but all had cirrhosis and some had hepatitis. Because adverse reactions are related to the dose and exposure of gefitinib, this increase in exposure may be clinically relevant.

In a clinical study of 41 patients with solid tumors (14 with normal liver function, 13 with moderate liver damage, and 4 with severe liver damage due to liver metastases) Fentinib was evaluated for pharmacokinetics. Studies have shown that the time to reach steady state, the total plasma clearance rate and steady state value (Cmaxss, AUC24ss) of 250 mg daily product is similar between normal liver function group and moderate liver function impairment group after 28 days. Four patients with severe liver damage due to liver metastasis had similar steady-state values to those with normal liver function.

Iressa storage

Store below 30 ° C.

Iressa Packaging

PVC / aluminum foil blister pack.

10 pieces / box

Iressa Validity Period

24 months

Iressa implementation standards

Import drug registration standard JX20030224

Iressa Approval Number

National Medicine Standard J20070047

Iressa production company

AstraZeneca UK Limited

Iressa Packaging Enterprise

AstraZeneca Pharmaceuticals

Iressa Approval Date

October 23, 2006

Iressa revision date

November 30, 2006 May 24, 2007 October 19, 2007