WO1998047500A1 - Utilisation de l'acetyldinaline pour fabriquer un medicament destine au traitement du nephrocarcinome - Google Patents

Utilisation de l'acetyldinaline pour fabriquer un medicament destine au traitement du nephrocarcinome Download PDF

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Publication number
WO1998047500A1
WO1998047500A1 PCT/US1998/006484 US9806484W WO9847500A1 WO 1998047500 A1 WO1998047500 A1 WO 1998047500A1 US 9806484 W US9806484 W US 9806484W WO 9847500 A1 WO9847500 A1 WO 9847500A1
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study
dose
patients
treatment
grade
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PCT/US1998/006484
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English (en)
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William Richard Grove
Wilbur Richard Leopold
Patricia Lorusso
Mark Bradley Meyer
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Warner-Lambert Company
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Priority to AU68781/98A priority Critical patent/AU6878198A/en
Publication of WO1998047500A1 publication Critical patent/WO1998047500A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol

Definitions

  • This invention concerns treatment of renal cell carcinoma utilizing acetyldinaline.
  • Acetyldinaline is effective for treating renal cell cancer.
  • Acetyldinaline is 4-acetylamino-N-(2'-aminophenyl)-benzamide. It is also known as CI-994. It is described in U.S. 5,137,918, which is incorporated herein by reference for its teaching of how to make acetyldinaline and how to formulate it into dosage forms.
  • This invention provides a method for treating renal cell carcinoma comprising administering to a patient suffering therefrom and in need of treatment an effective amount of acetyldinaline.
  • All that is required to practice this invention is to administer an effective amount of acetyldinaline to a patient suffering from renal cell carcinoma and in need of treatment.
  • An effective amount is that quantity of acetyldinaline which exhibits a positive therapeutic effect on the renal cell cancer.
  • Such effective amount will be from about 10 to about 300 mg, and especially from about 20 to 50 mg, administered orally or parenterally.
  • CI-994 is a substituted benzamide derivative that has demonstrated significant growth inhibitory activity against several murine and human tumor models in vitro and in vivo. Its mechanism of action is unknown but appears novel compared to existing anticancer drugs. This section presents an overview of the preclinical pharmacology, pharmacokinetics, and toxicology studies conducted with CI-994.
  • CI-994 exhibited cytostatic and cytotoxic activity in vitro in several murine and 'human tumor cell lines with IC 50 values generally in the low micromolar range with continuous drug exposure. Exposures of less than 8 to 10 hours did not result in significant growth inhibitory activity. Growth inhibition was characterized by accumulation of cells in G j . At higher concentrations, accumulation of cells at G 2 fM also was observed. Human and murine CFU-GM marrow progenitor cells were equally sensitive to CI-994 mediated cytotoxicity, and showed no differential sensitivity compared to tumor cells.
  • CI-994 The growth inhibitory activity of CI-994 was confirmed in vivo. Sensitive models included transplanted mouse and rat tumors, human tumor xenografts, and carcinogen- induced autochthonous mammary and colon carcinomas in rats. The activity of CI-994 was unusual in that tumors such as human colon carcinoma xenograft HCT-8 and mammary adenocarcinoma 25, which normally are refractory to anticancer agents, were among those most sensitive to CI-994. In most of the sensitive solid tumor models, CI-994 was predominately cytostatic. Tumor regression was noted in the Brown Norway Myelogenous Leukemia (BNML) model in which short duration dosing regimens consistently reduced the surviving fraction of leukemia cells to less than 1 x 10 "6 .
  • BNML Brown Norway Myelogenous Leukemia
  • Oral and intraperitoneal dosing regimens were equally efficacious and essentially equipotent. Efficacy was largely proportional to the duration of therapy for most tumor models. Acute dosing regimens were uniformly ineffective for all models except the BNML model. For dosing regimens longer than 7 days, efficacy in the mammary adenocarcinoma 25 model was not significantly affected by the dose fractionation scheme used. The maximum tolerated daily dose, the highest dose that produced less than 10% lethality, was generally between 60 and 90 mg/kg for regimens >7 days and was not a function of treatment duration. These doses were tolerated for extended periods without significant effects on body weight or other signs of toxicity.
  • CI-994 does not directly cause DNA damage, specifically inhibit synthesis of macromolecules (DNA, RNA, protein), or significantly alter precursor pools for these processes. Interference with mitochondrial function, lipid metabolism, and microtubule function also are not primary effects of CI-994.
  • the earliest known effect of exposure to growth inhibitory concentrations of CI-994 is the loss of a 16kD nuclear phosphoprotein recently identified as Histone 2 A. The loss of this protein precedes cessation of growth, and upon removal of CI-994 from the medium, reexpression of Histone 2A occurs before growth resumes.
  • CI-994 Binding of CI-994 to mouse, rat, dog, and human plasma proteins is concentration dependent, ranging from 54.1% bound at 0.05 ⁇ g/mL to 24.5% bound at 50 ⁇ g/mL. Interspecies differences in CI-994 plasma protein binding are minimal. CI-994 appears to be stable in mouse, rat, dog, and human plasma for at least 28 days at -20°C and for 8 hours at 37°C.
  • CI-994 is rapidly absorbed with maximum plasma concentrations occurring approximately 1 hour postdose in rats, dogs, and monkeys. Absolute oral bioavailability ranges from essentially 100% in rats receiving a 10-mg/kg solution dose to 77.1% in dogs receiving a 2-mg/kg suspension dose. Oral absorption of a 5-mg/kg [ 14 C]CI-994 solution dose in monkeys was at least 56.0% based on urinary 14 C excretion data. CI-994 oral pharmacokinetics are dose proportional for single 2-, 10-, and 50-mg/kg doses in rats and single 0.5-, 2-, and 7-mg kg doses in dogs.
  • CI-994 IV pharmacokinetics following single 0.5- and 2-mg/kg doses in dogs were .. linear. Elimination half-life values following oral administration ranged from 4 to 5 hours in rats, 2.6 to 7.3 hours in dogs, and 4.0 to 5.8 hours in monkeys.
  • CI-994 is not extensively metabolized in rats and monkeys. Unchanged CI-994 accounts for 66% of total radioactivity excreted in rat urine and 80% of total radioactivity in 0- to 24-hour monkey urine. Several minor unidentified radioactive peaks occur in rat (7 peaks) and monkey (at least 4 peaks). Unchanged drug, is the major constituent in 2-hour monkey plasma samples, accounting for 92.7% of total radioactivity.
  • Urinary excretion is the major elimination pathway in rats and monkeys. Combined urinary and fecal recovery of 1 C averaged 92.2% of the radioactive dose administered to rats.
  • mice were administered single oral doses ranging from 200 to 1400 mg/kg (600 to 4200 mg/m 2 ) or repeated daily doses of 100 to 250 mg/kg (300 to 750 mg/m ) for 5 days. Severe signs of toxicity were generally noted beginning at 500 mg/kg in the single-dose study and at 140 mg/kg in the repeated-dose study.
  • the combined-sex single-dose 29-day LD 10 , LD 50 , and LD 90 values in mice were 452, 747, and 1234 mg/kg (1357, 2242, and 3704 mg/m 2 ), respectively.
  • the combined-sex 33-day LD 10 , LD 50 , and LD 90 values were 104, 139, and 184 mg/kg (313, 416, and 551 mg/m 2 ), respectively.
  • Rats were given single oral doses ranging from 2.5 to 380 mg/kg (15 to 2280 mg/m 2 ) and dogs were administered single oral doses from 0.7 to 70 mg kg (14 to 1400 mg/m ).
  • Clinical signs of toxicity were noted beginning at 115 mg/kg in rats and at 7 and 70 mg/kg in dogs.
  • Myelosuppression was first noted at 23 mg/kg in rats and at 2 mg/kg in dogs.
  • Thrombocytopenia also occurred beginning in rats at 23 mg/kg and in dogs at 70 mg/kg.
  • Lymphoid tissue, bone marrow, intestinal tract, and testes were target organs in both species; epithelial cells of various organs were additional targets in rats.
  • the minimal-effect dose in rats was 2.5 mg/kg (15 mg/m ), and the no-effect dose in dogs was 0.7 mg/kg (14 mg/m ). With the exception of testicular effects, all changes were reversible within the recovery periods of 4 weeks in rats and 9 weeks in dogs.
  • rats were administered daily doses of 1.5, 5, or 15 mg/kg (9, 30, and 90 mg/m ) and dogs were given daily doses of 0.5, 2, and 5 mg/kg (10, 40, and 100 mg/m ).
  • Clinical signs similar to those in single-dose studies were observed in rats at 15 mg/kg and in dogs beginning at 2 mg/kg.
  • Neutropenia, lymphope ' nia, and thrombocytopenia were observed in rats beginning at 5 mg/kg and in dogs beginning at 2 mg/kg.
  • Reduced erythrocyte counts also were noted at the highest doses in both species. Bone marrow, lymphoid organs/tissues, and testes were target organs in both species.
  • Epithelial cells of various tissues in rats and small intestine in dogs were additional targets.
  • the minimal effect dose was 1.5 mg/kg (9 mg/m 2 ) in rats and 0.5 mg/kg (10 mg/m ) in dogs.
  • All changes were reversible within the recovery periods of 4 weeks in rats and 9 to 10 weeks in dogs.
  • mean maximum plasma drug concentration and area under the plasma drug concentration-time curves were similar in both sexes and increased proportionally with dose. Repeated daily dosing did not alter plasma CI-994 elimination.
  • a recently completed 13-week dog study evaluated 3 dose levels of CI-994 including 0.1, 0.5, and 2 mg/kg (corresponding to 2, 10, and 40 mg/m 2 , respectively). There were no bone marrow affects at the lower doses and only minimal bone marrow suppression affecting primarily lymphocytes at the highest dose level with full recovery following withdrawal of drug.
  • CI-994 exhibits cytostatic and cytotoxic activity in vitro and in vivo in several tumor models. Bioavailability ranged from 77% to 100% in rats and dogs, and linear pharmacokinetics are observed following single or repeated doses. CI-994 produced clinical and hematological effects and target organ toxicity expected of anticancer drugs that affect rapidly proliferating cells. Dose-related myelosuppression, lymphoid depletion, testicular degeneration, and gastrointestinal effects were similar among species. These findings were not observed or were minimal in rats and dogs given single or repeated doses at approximately 10 mg/m , equivalent to the starting dose proposed for initial clinical trials. With the exception of testicular effects, all changes were reversible. Reversal of testicular effects would not be expected due to the limited duration of the recovery period.
  • Tlie MTDfor CI-994 has been determined to be 8 mg/m /day for 8 weeks. Further dose escalation will be attempted by giving patients weekends off from dosing. The starting dose will now be increased to 6.5 mg/m /day and, if adequately tolerated, will be increased sequentially to 12.5 mg and 15 mg/m /day.
  • the goal of this Phase 1 study will be to determine the maximum tolerated dose of CI-994 administered daily for 5 days of each week for 8 consecutive weeks.
  • Cohorts of 3 patients each will be studied at increasing dose levels starting with 10 mg/m /day followed by 12.5 and 15 mg/m /day as tolerated Dosage adjustments for toxicity may occur at any time during the treatment course (see Dosage Adjustments, Page 14) and patients may receive additional courses of treatment following a 2-week "rest" from dosing.
  • the investigator is responsible for the retention of the patient log and patient records as detailed in Appendix E.
  • This study is a single center, Phase 1, dose-seeking study of CI-994 in patients with solid tumors for which no proven effective therapy exists. Dose escalations will be determined by clinical tolerance.
  • Pretreatment evaluation will include a history and physical exam, baseline hematologies, laboratory chemistries (SMA-12, electrolytes, PT, PIT) chest x-ray, EKG, and urinalysis (see Appendices A.1, A.4).
  • the Clinical Trials office will register every patient with Parke-Davis Research prior to initiation of CI-994 treatment. Patients must be registered by calling Mark Meyer, Senior Clinical Engineer or other designated clinical monitor at (313) 996-7465 during Parke-Davis Research hours of operation (8 AM to 5 PM). Eligibility information from the Prescreen Form will be reviewed at the time of registration and a patient number will be assigned. No patient may be entered on study or started on treatment before being registered and having an accession number assigned. When possible, patients entering this study will be admitted to the Clinical Pharmacology Unit at 4-Center in Harper Hospital for appropriate monitoring.
  • CHG Patients will receive a single oral dose of CI-994 daily for 5 days of each week for 8 weeks with subsequent courses of treatment to be repeated after a 2-week drug holiday (see 7.2, Study Treatment).
  • the primary efficacy parameter will be rate of response (complete, partial, stable disease, progressive disease) (see Appendix B.l).
  • CI-994 All patients receiving one or more doses of CI-994 will be evaluated for safety.
  • the safety parameters of interest include all laboratory and hematologic abnormalities, physical exam findings, as well as spontaneous reports of adverse events by patients. All adverse events will be graded for intensity according to the Common Toxicity Criteria in Appendix B.2.
  • CI-994 may be withheld or discontinued and the patient treated at the discretion of the physician investigator.
  • CI-994 will be provided by Parke-Davis Pharmaceutical Research in 2.5-, 5-, 25-, 100-, and 250-mg gelatin capsules for oral administration.
  • Excipients include lactose, corn starch, and talc or Polyethylene Glycol 6000 as a lubricant.
  • a course of CI-994 treatment will consist of daily oral administration, Monday through Friday each week for 8 weeks to be repeated after a 2-week drug holiday. •Calculated doses (based upon body surface area) will be in the 10 to 20 mg range and will be rounded off to the nearest 2.5 mg.
  • the dosing strategy for chronic CI-994 therapy will be to maintain platelet and_ granulocyte counts at or above 40 x l ⁇ /L and 1.0 x 10 L, respectively. If counts decrease below these levels or if nonhematologic toxicity exceeds Grade 2 severity, the dosage will be reduced according to Table 1, below.
  • the dose should be decreased by 25%
  • the MTD will be that dose level that produces drug-attributable, dose-limiting toxicity in at least half of a minimum of 6 patients receiving either their first or second course of CI-994.
  • Dose-limiting toxicity is defined as any of the following: ⁇ Grade 3 nonhematologic toxicity (excluding alopecia, nausea, and vomiting), Grade 2 neurologic, renal, or cardiac toxicity or Grade 4 hematologic toxicity. Patients receiving more than 1 course of treatment will contribute data from their first 2 courses only toward determination of MTD.
  • the MTD is sufficiently well- tolerated to be declared the recommended Phase 2 starting dose, in which case no further patients will be enrolled. If the recommended Phase 2 starting dose is to be lower than the MTD (generally approximately 75% of the MTD) a total of 6 patients will be enrolled at this dose level.
  • Data analysis and summary will be prepared by the Parke-Davis Research Biometrics, Clinical Communications, Clinical Research, and Clinical Data Management Departments. The demographic and disease characteristics of the patient population will be described. Detailed tabulations of the adverse event data and clinical laboratory data will be prepared. Data summary will be the responsibility of the Biometrics Department.
  • Pharmacokinetic parameters such as Cmin, Cmax, tmax, AUC, and tY. will be determined from plasma CI-994 concentration-time data using established methods for the 2 patients who undergo the 24-hour sampling. Descriptive statistics, such as mean, standard deviation, and percent relative standard deviation (coefficient of variation), will be derived by dose level.
  • Safety will be assessed on the basis of frequency and intensity of adverse events. Data for all patients who received CI-994 will be analyzed, regardless of evaluability. Detailed tabulations of adverse events both by investigator term and Costart term will be displayed with onset and duration, intensity (grade), drug association, and clinical outcome (reversibility) information.
  • Radiographic studies including chest x-ray and other appropriate ! scans for determination of tumor size, or physical assessments as deemed necessary to evaluate disease (See Appendix A.3). All a asssseessssmmeernts to be repeated monthly except for radiographic studies which will be performed every 2 months.
  • CR Complete Response
  • Partial Response A decrease of >50% in the sum of the products of the perpendicular diameters of all measured lesions and no new lesions for at least 4 weeks.
  • Stable Disease Decreases in tumor size from 0% to 50% are to be labeled stable disease lasting at least 4 weeks or a steady state not qualifying for increasing disease of at least 8 weeks of duration. There must be no appearance of new lesions.
  • PD Progressive Disease
  • Lymphocytes ⁇ 2.0 1.5-1.9 1.0-1.4 0.5-0.9 ⁇ 0.5
  • Diarrhea none increase of 2-3 increase of 4-6 increase of 7-9 increase of stools per day stools per day of stools per day, ⁇ 10 stools per over predose nocturnal stools, or incontinence day, or grossly or moderate or severe bloody diarrhea, cramping cramping or need for parenteral support
  • Stomatitis none painless ulcers, painful painful requires erythema, or erythema, erythema, parenteral or mild soreness edema, or edema, or ulcers, cnteral support ulcers, but can and cannot eat eat APPENDLX B.2
  • Cardiac dysrhythmias none asymptomatic, recurrent or requires requires transient, persistent, no treatment monitoring or requiring no therapy required hypotension, or therapy ventricular tachycardia, or fibrillation
  • Cardiac function none asymptomatic, asymptomatic mild CHF, severe or decline of decline of responsive to refractory CHF resting ejection resting ejection therapy fraction by fraction by
  • Cardiac ischemia none nonspecific asymptomatic. angina without acute myocardial
  • Hypertension none or asymptomatic. recurrent or requires therapy hypertension no change transient persistent crisis increase increase
  • Neurosensory none or mild mild or severe objective no change paresthesias, loss moderate sensory loss or of deep tendon objective paresthesias that reflexes sensory loss; interfere with moderate function paresthesias
  • Neurologic continuously Neurocortical mild somnolence moderate severe coma, seizures, or agitation somnolence or somnolence, toxic psychosis agitation agitation, confusion, disorientation, or hallucinations
  • Neuromood no change mild anxiety or moderate severe anxiety or suicidal ideation depression anxiety or depression depression
  • Weight Gain/Loss ⁇ 5.0% 5.0%-9.9% 10.0%-19.9% ⁇ 20.0% -
  • CI-994 capsules must be swallowed intact with 8 oz of water at approximately the same time each day. Because the influence of food and dietary fat, in particular on
  • CHG absorption is unknown, it is important that food not be eaten for 2 hours before or at least 1 hour after dosing (except for Days 1 and 8 when the food effect pharmacokinetic sampling is to be carried out - see below). Because the morning is a common time CI-994 is taken, breakfast foods containing high fat (eg, bacon, sausage, eggs, butter) should be avoided. Recommended alternatives include juice, toast, cold cereals, or oatmeal.
  • high fat eg, bacon, sausage, eggs, butter
  • CHG Day 1 except that a breakfast consisting of cereal, 8 oz of low-fat (2%) milk, 2 eggs scrambled without fat, and 2 slices of white toast with 2 teaspoons of margarine will be served Four ounces of the low-fat milk will be used to administer the CI-994 capsule(s).
  • the breakfast must be finished within 30 minutes and CI-994 will be administered 15 minutes after beginning to eat the breakfast
  • no food shall be administered until 4 hours have elapsed since taking CI-994 and an 8 ounce glass of unsweetened fruit juice can again be offered after the 2-hour blood sample.
  • the lunch served at 4 hours should be as similar as possible to the lunch served following the first day of sampling and, in general, the meals consumed during the 2- to 48-hour sampling periods should be as similar as possible.
  • the 8-week course of treatment with CI-994 may begin any time following withdrawal of the second 48-hour blood sample on Day 10 (or later).
  • a free-flowing intravenous line attached to a cannula dedicated to pharmacokinetic sampling shall be placed.
  • a heparin lock may replace the IV line.
  • Blood samples will be 5 mL in volume and will be collected in polypropylene tubes containing heparin according to the schedule in the following table. Blood samples will be
  • CHG collected predose (0 hour), and at 0.5, 1, 2, 4, 8, 12, 24, 36 and 48 hours postdose on both days.
  • Plasma will be immediately isolated by centrifugation and samples stored at -20°C in an upright position. Each tube should be labeled with protocol number, patient identification, dose, date, and sampling time. Patients will continue to have a trough sample withdrawn weekly (Weeks 3-9 beginning from the Day 1 dose) to study the potential for drug accumulation.
  • CI994 (4-acetyla ino-N-(2'aminophenyI)-benzamide; acetyldinaline) is a novel, water insoluble, antitumor agent with a unique mechanism of action.
  • this compound was active against several solid tumors of mouse and human origin. Based on preclinical data, we embarked on an oral (po) trial attempting both duration of administration and dose escalation. A total of 19 patients have been registered. Tumor types include: colorectal(13), NSCLCa(2), melanoma(l), renal cell(2) and mesothelioma. Median age was 65 years(42-83). Median PS was 0(0-1). The majority of patients were heavily pretreated.
  • the dose imiting toxicities were neutropenia and thrombocytopenia. Other toxicities included: leukopenia, nausea, vomiting, diarrhea, fatigue, and anorexia.
  • Patients with colorectai carcinoma tolerated less CI994 than other tumor types.
  • Preclinical in vitro myelotoxicity assays demonstrated significantly greater sensitivity of human vs mouse marrow. There was an "adaptation" phenomena of the platelets at a certain dose allowing for continued dosing despite Grade HI toxicity.

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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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Abstract

L'acétyldinaline est efficace pour traiter le néphrocarcinome.
PCT/US1998/006484 1997-04-24 1998-04-02 Utilisation de l'acetyldinaline pour fabriquer un medicament destine au traitement du nephrocarcinome WO1998047500A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU68781/98A AU6878198A (en) 1997-04-24 1998-04-02 Use of acetyldinaline for the manufacture of a medicament for the treatment of renal cell carcinoma

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US4411097P 1997-04-24 1997-04-24
US60/044,110 1997-04-24

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000018393A1 (fr) * 1998-09-25 2000-04-06 Warner-Lambert Company Chimiotherapie contre le cancer, dans laquelle de l'acetyldinaline combinee a de la gemcitabine, de la capecitabine ou du cisplatine sont utilises
KR20030015829A (ko) * 2001-07-02 2003-02-25 워너-램버트 캄파니 배합 화학요법

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5137918A (en) * 1986-04-22 1992-08-11 Goedecke Aktiengesellschaft N-(2'-aminophenyl)-benzamide derivatives process for the preparation thereof and pharmaceutical compositions containing them

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5137918A (en) * 1986-04-22 1992-08-11 Goedecke Aktiengesellschaft N-(2'-aminophenyl)-benzamide derivatives process for the preparation thereof and pharmaceutical compositions containing them

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
P.M.LORUSSO ET AL.: "Phase I clinical trial of CI994", PROC ANNU MEET AM SOC CLIN ONCOL, vol. 16, May 1977 (1977-05-01), pages 213a, XP002071742 *
P.M.LORUSSO ET AL.: "Preclinical activity of CI-994", INVESTIGATIONAL NEW DRUGS, vol. 14, no. 4, 1996, pages 349 - 356, XP002071743 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000018393A1 (fr) * 1998-09-25 2000-04-06 Warner-Lambert Company Chimiotherapie contre le cancer, dans laquelle de l'acetyldinaline combinee a de la gemcitabine, de la capecitabine ou du cisplatine sont utilises
US6469058B1 (en) 1998-09-25 2002-10-22 Warner-Lambert Company Chemotherapy of cancer with actyldinaline in combination with gemcitabine capecitabine or cisplatin
KR20030015829A (ko) * 2001-07-02 2003-02-25 워너-램버트 캄파니 배합 화학요법

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ZA983455B (en) 1998-10-29

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