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Home , Fulvestrant, Tamoxifen

ANTICANCER RESEARCH 24: 1275-1280 (2004)

Fulvestrant for the Treatment of Advanced in Postmenopausal Women: A Japanese Study

TORU WATANABE1, MUNEAKI SANO2, SHINJI OHNO3, HIDEO INAJI4, REIKI NISHIMURA5, EISEI SHIN6, YASUO NOMURA7 and CHARLES MORRIS8

1National Cancer Centre Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo; 2Niigata Cancer Centre Hospital, 2-15-3, Kawagishi-cho, Niigata; 3National Kyushu Cancer Centre, 3-1-1, Notame, Minami-ku, Fukuokashi, Fukuoka; 4Osaka Medical Centre for Cancer and Cardiovascular Diseases, 1-3-3, Nakamichi, Higashinari-ku, Osaka; 5Kumamoto City Hospital, 1-1-60 Koto, Kumamoto City, Kumamoto; 6Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka; 7Oikawa Hospital, 2-21-16, Hirao, Chuo-ku, Fukuoka, Japan; 8AstraZeneca, Room E1443, 1800 Concord Pike, Wilmington, DE 19850, U.S.A.

Abstract. Background: (‘Faslodex’) is a new type of progesterone receptor (PgR) expression. Fulvestrant blocks oestrogen receptor (ER) antagonist that down-regulates the ER the trophic effects of oestrogen but, unlike , has no and has no known effects. Patients and Methods: In this known agonist effects (1-5). The effects of open-label, Phase II trial, 30 postmenopausal Japanese women tamoxifen are associated with a slightly increased risk of with hormone-sensitive advanced , who had and stimulation of recurrent disease (6). progressed on tamoxifen/ following an initial response, Despite the development of third-generation, non-steroidal received fulvestrant (250 mg; once-monthly intramuscular aromatase inhibitors (AIs), such as and , injection). Primary endpoints were objective tumour response rate which provide an alternative hormonal approach, there (complete or partial response) and assessment of tolerability; remains a need for additional effective and well-tolerated secondary endpoints included clinical benefit (objective response, therapeutic agents for the sequential treatment of advanced or stable disease ≥ 24 weeks), duration of response and breast cancer (2). pharmacokinetic analysis. Results: The objective response rate Fulvestrant demonstrated clear efficacy in a Phase II trial was 23.3% and 60.0% of patients experienced clinical benefit. in postmenopausal women with advanced breast cancer Adverse events were generally mild; the most common were resistant to tamoxifen (7-9). Following on from these pharyngitis (26.7%), headache (23.3%) and nausea (20.0%). encouraging results were two large, multicentre, randomised Pharmacokinetic data were similar to a Western study of Phase III trials (trial 0020 performed in Europe, Australia and postmenopausal patients. Conclusion: Fulvestrant 250 mg/month South Africa; trial 0021 performed in North America) which is effective and well-tolerated in Japanese patients who have compared fulvestrant (250 mg once monthly, via relapsed after one prior endocrine treatment. intramuscular [i.m.] injection) with anastrozole (1 mg once daily, orally). These trials recruited postmenopausal women Fulvestrant (‘Faslodex’) is a new type of antioestrogen, an with hormone-sensitive advanced breast cancer that had oestrogen receptor (ER) antagonist that down-regulates the progressed on prior endocrine therapy (mostly tamoxifen) (10, ER. Binding of fulvestrant to the ER reduces ER 11). The primary endpoint of both trials was time to dimerisation and leads to rapid degradation and loss of ER progression and, for this endpoint, median values for protein, with a subsequent reduction in ER-dependent fulvestrant vs anastrozole were 5.5 vs 5.1 months (hazard ratio [HR]: 0.98; 95.14% confidence intervals [CI] 0.80, 1.21; p=0.84) in trial 0020 and 5.4 vs 3.4 months (HR: 0.92, 95.14% CI 0.74, 1.14; p=0.43) in trial 0021. In both trials no significant Correspondence to: Dr Toru Watanabe, 8-5-35 Akasaka, Minato- difference in efficacy was detected between the two agents, ku, Tokyo, Japan. Tel: +81-3-3402-5581, Fax: +81-3-3402-5529, e- leading to the conclusion that fulvestrant is at least as effective mail: [email protected] as anastrozole in this setting. Both fulvestrant and anastrozole Key Words: Fulvestrant, ‘Faslodex’, breast cancer, ER antagonist, were well-tolerated; the only significant difference in antioestrogen. tolerability was a lower incidence of joint disorders

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(arthralgia) in the fulvestrant-treated group, arthralgia being the case of depot formulation); treatment with a non-approved or an effect common to the non-steroidal AIs. investigational drug within 12 weeks; history of bleeding diathesis or The present study was conducted to investigate the long-term therapy (other than antiplatelet therapy). efficacy, safety and of fulvestrant in postmenopausal Japanese women with relapsed or advanced Treatment. Fulvestrant (250 mg) was administered slowly as a single 5-ml i.m. injection into the buttock. This was given once breast cancer who had progressed on tamoxifen/toremifene monthly, defined as every 28 (± 3) days, during the 6-month following an initial response. study treatment period. Treatment continued until withdrawal due to disease progression, an unacceptable adverse event (AE), Patients and Methods non-compliance, withdrawal of consent, or until the 6-month study treatment period was complete. At 6 months, responding Trial design. This was a Japanese open-label, Phase II study patients continued treatment on a compassionate use conducted at 13 centres. The primary objectives of this trial were to programme. investigate the efficacy and safety of fulvestrant in postmenopausal women with hormone-sensitive advanced breast cancer who had Efficacy. Objective tumour assessments were performed at relapsed or progressed after initially responding to tamoxifen or screening (within 4 weeks before registration) and were repeated toremifene therapy. The secondary objective was to determine the every 12 weeks during the study treatment period. Skin or soft pharmacokinetic profile of fulvestrant after repeated administration. tissue lesions were also clinically assessed by physical examination The study was conducted in accordance with good clinical practice every 4 weeks for the first 12 weeks. Tumour response was and the Declaration of Helsinki, and all eligible patients had to assessed as CR, PR, SD ≥ 24 weeks or disease progression (PD) provide written informed consent. in accordance with the Union Internationale Contre Le Cancer (UICC) criteria. Inclusion criteria. The patient population comprised postmenopausal The primary efficacy endpoint of this trial was the objective women with histologically or cytologically confirmed hormone- tumour response rate, which was defined as the proportion of sensitive breast cancer who had progressed on tamoxifen/toremifene patients with a best overall tumour assessment of CR or PR. following an initial response. Response to prior treatment for Secondary efficacy endpoints included clinical benefit rate advanced disease was defined as a complete response (CR), partial (proportion of patients with an objective tumour response or SD response (PR), or stable disease (SD) ≥ 24 weeks. In addition, ≥ 24 weeks), duration of response, duration of clinical benefit, patients were also eligible if they had responded to adjuvant time to progression and time to response. The duration of tamoxifen or toremifene after surgery, providing they remained response was calculated (in patients with CR or PR) as the time disease-free for at least 2 years during therapy, prior to relapse. from the first day of study treatment until disease progression Women were considered postmenopausal if they fulfilled any one was first observed. The same criteria were used to calculate the of the following criteria: ≥ 60 years of age; ≥ 45 years of age with duration of clinical benefit (in patients with CR or PR or SD ≥ at least 12 months amenorrhoea and no hysterectomy; follicle- 24 weeks). Objective response and clinical benefit rates were stimulating hormone levels within postmenopausal range; or having also calculated by subpopulation, with patients stratified undergone a bilateral oophorectomy. In addition, patients were according to: prior tamoxifen or toremifene treatment for required to have at least one measurable or evaluable advanced disease or as adjuvant therapy, hormone receptor (nonmeasurable) lesion for inclusion in the trial. status, or site of lesion. Statistical analysis of efficacy endpoints was performed for Exclusion criteria. Patients were excluded from the trial if they had a patients who fulfilled all entry requirements of the trial and who World Health Organisation (WHO) performance status of 3 or 4, or received study treatment at least once. All endpoints were life expectancy < 3 months from the start of the study. Additional calculated with 95% CIs and those involving median times or exclusion criteria included: life-threatening metastatic visceral durations were calculated using the Kaplan-Meier method. disease (defined as extensive hepatic involvement, any degree of or leptomeningeal involvement, or symptomatic pulmonary Safety. Adverse events (AEs) were defined as any deterioration in lymphangitic spread); platelet count <100 x 109/L; total bilirubin a patient’s condition that was not unequivocally due to disease >1.5 times the upper limit of the reference range (ULRR); progression. These were monitored during study treatment and aminotransferase or aspartate aminotransferase >2.5 times the the 8-week follow-up period following the last i.m. injection. AEs ULRR in the absence of any metastases, or >5 times the were grouped according to the FDA Coding Symbols for ULRR if liver metastases were present; any evidence of severe or Thesaurus of Adverse Reaction Terms (COSTART) classification uncontrolled systemic disease or concomitant condition that would and were classified as mild, moderate or severe in intensity. make it undesirable for the patient to participate in the study; Patients were also monitored for clinical and laboratory systemic chemotherapy or radiotherapy within the previous 4 weeks; throughout the treatment period. any prior treatment with fulvestrant or other endocrine therapies (except tamoxifen or toremifene); history of systemic malignancy Pharmacokinetics. Blood samples for plasma concentration within the previous 3 years (other than breast cancer and adequately assessment were collected every 4 weeks for the first 24 weeks, up treated in situ carcinoma of the cervix, uteri, or basal or squamous to the sixth administration of fulvestrant. These samples were carcinoma of the skin); history of luteinising hormone-releasing collected immediately before injection of fulvestrant in order to hormone (LHRH) analogue treatment for breast cancer, or, if not determine the minimum plasma concentrations after repeated given for breast cancer, treatment within 3 months (or 4 months in administration and the data was used to estimate the time to reach

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Table I. Patient demography. Table II. Best objective tumour responses.

Characteristic No. of patients (%) Best response No. of patients (%) (n=30) [n=30]

Age (years) Complete response (CR) 0 (0.0) Median 61.0 Partial response (PR) 7 (23.3) Range 44–82 Stable disease (SD) ≥24 weeks 11 (36.7) Age distribution SD <24 weeks 6 (20.0) <65 years 20 (66.7) Progression (PD) 6 (20.0) ≥65 years 10 (33.3) Objective response Weight (kg)a [95% CI] 7 (23.3) Median 50.0 [9.9, 42.3] Range 40.0–69.0 Clinical benefit Inclusion criteriab [95% CI] 18 (60.0) 1 17 (56.7) [40.6, 77.3] 2 13 (43.3) WHO performance status Objective response, CR + PR; Clinical benefit, CR +PR + SD ≥24 0 21 (70.0) weeks. 1 8 (26.7) 2 1 (3.3) Previous treatment for breast cancer Surgery for primary breast cancer 27 (91) Chemotherapy 19 (63.3) remaining 13 patients (43.3%) had been disease-free for at Radiotherapy for primary breast cancer 5 (16.7) least 2 years while receiving tamoxifen or toremifene as Radiotherapy for metastatic disease 2 (6.7) adjuvant treatment, but had either relapsed during therapy Endocrine treatment for advanced or or within 12 months after adjuvant therapy. relapsed breast cancer 18c (60) Adjuvant endocrine treatment 20d (66.7) Tumour hormone receptor status Primary endpoints. Of the 30 patients included in this study, ER+ and/or PgR+ 28 (93.3) there were no patients with a CR, while seven patients ER+ and PgR+ 21 (70.0) experienced a PR, producing an objective response rate of ER+ and PgR- 6 (20.0) 23.3% (95% CI 9.9, 42.3). The efficacy results are ER- and PgR+ 1 (3.3) ER unknown and PgR- 2 (6.7) summarised in Table II. adata only available for 29 patients; b1: Patients with CR, PR, SD ≥ Secondary endpoints. In addition to the observed objective 24 weeks with tamoxifen or toremifene therapy for advanced or responses, 11 patients had SD ≥ 24 weeks (Table II). relapsed disease and then had disease progression, 2: Patients who Therefore, the proportion of patients with clinical benefit (CR were disease-free for at least 2 years following tamoxifen or toremifene treatment as adjuvant therapy and relapsed for the first time during + PR + SD ≥ 24 weeks) was 60.0% (95% CI 40.6, 77.3). therapy or within 12 months after therapy; cSeventeen patients Analysis of objective response rate within patient received tamoxifen, one patient received toremifene; dSeventeen subpopulations showed that there was no difference in patients received tamoxifen, two patients received toremifene and one response rate or clinical benefit rate in patients stratified patient received both tamoxifen and toremifene. according to previous breast cancer treatment or hormone receptor status (Table III). In patients with lesions in soft tissues (breast, skin/soft tissue, or lymph nodes) only the steady-state levels. The geometric mean (Gmean), response rate was 33.3%, while in patients with lesions in Gmean±standard deviation, coefficient of variation (CV), only or bone and soft tissue only, the response rate was 11.1%. minimum and maximum were calculated for the minimum plasma The median duration of response was 8.3 months (95% concentration data at each assessment. CI 6.3, 11.7) and the mean duration of clinical benefit was 9.8 months (95% CI 8.7, 10.8); both ranged from 5.6 to 13.0 Results months or longer (fewer than 50% of patients had disease progression, therefore the median duration of clinical Patient demography. A total of 30 Japanese patients of benefit was not calculable by the Kaplan-Meier method) median age 61.0 years (range 44 to 82 years) were enrolled (Figure 1). The median time to progression, calculated for in this study; demographic data are summarised in Table I. all treated patients, was 8.3 months (95% CI 6.4, 8.8), Seventeen patients (56.7%) had previously received ranging from 1.9 to 13.0 months (Figure 2). Time to tamoxifen or toremifene therapy for advanced disease and response ranged from 1.0 to 5.9 months, the median being initially responded but then had confirmed progression. The 2.8 months, (95% CI 1.8, 5.5).

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Table III. Objective response and clinical benefit rates by subpopulation.

n Objective Clinical response (%) benefit (%)

Inclusion criteriaa 1 17 5 (29.4) 10 (58.8) 2 13 2 (15.4) 8 (61.5)

Hormone receptor status ER+ or PgR+ 28 6 (21.4) 17 (60.7) ER+ and PgR+ 21 4 (19.0) 14 (66.7)

Sites of lesion Soft tissueb only 62 (33.3) 3 (50.0) Bone only or bone 9 1 (11.1) 5 (55.6) and soft tissue only Visceral involvement 15 4 (26.7) 10 (66.7) Figure 1. Kaplan-Meier plot showing duration of clinical benefit. ( or liver) a1: Patients with CR, PR, or SD ≥ 24 weeks with tamoxifen or toremifene therapy for advanced or relapsed disease and then had disease progression; 2: Patients who were disease-free for at least 2 years following tamoxifen or toremifene treatment as adjuvant therapy (six patients, 20.0%) and vomiting (five patients, 16.7%). and relapsed for the first time during therapy or within 12 months after AEs were observed in 28 of the 30 patients treated with therapy; bbreast, skin/soft tissue, or lymph nodes. Objective response, fulvestrant; the majority of patients (24 patients) only CR + PR; Clinical benefit, CR +PR + SD ≥24 weeks. experienced mild AEs, three patients experienced moderate AEs and one patient experienced a severe AE Table IV. Drug-related adverse events observed in > 5% of patients. (pathological fracture). Nineteen of the 30 patients (63.3%) experienced drug- Adverse eventa No. of patients (%) related AEs but with one exception, these events were all mild (Table IV). Injection-site pain (four patients, 13.3.%) Whole body and hyperglycaemia (three patients, 10.0%) were the only Headache 2 (6.7) Injection site pain 4 (13.3) drug-related AEs reported by three (10.0%) or more Urogenital system patients. Other AEs relating to the site of i.m. injection Leukorrhoea 2 (6.7) were injection-site reaction and inflammation, each Vaginal haemorrhage 2 (6.7) reported once by only one patient (3.3%), and all of the Metabolic and nutritional disorders AEs relating to the injection site were of mild intensity. Alkaline phosphatase increased 2 (6.7) Hypercholesterolaemia 2 (6.7) During the study a total of 255 injections were administered, Hyperglycaemia 3 (10.0) of which seven (2.7%) resulted in an injection-site reaction. Hyperlipidaemia 2 (6.7) Drug-related AEs of the digestive system included Hyperphosphataemia 2 (6.7) diarrhoea, nausea, vomiting and abnormal liver function, Lactate dehydrogenase increased 2 (6.7) being each observed in one patient (3.3%). Similarly, a aAll drug-related adverse events in >5% of patients were reported as drug-related AE of hot flushes (vasodilation) was seen in mild (observed from initial administration up to end of follow-up only one patient (3.3%). period [8 weeks after last injection]). Only one patient experienced a severe AE, a pathological fracture of lumbar vertebrae due to . This patient had osteoporosis before the study began and had also previously experienced a fracture of thoracic vertebrae. The possibility that the lumbar vertebrae fracture was due to the study treatment was low. However, as this possibility Safety. Fulvestrant was administered to all 30 patients who could not be completely excluded by the investigator, the enrolled in the study, with patients receiving 8.5 i.m. AE was classified as drug-related. injections on average. The median duration of treatment Of the 30 patients who received fulvestrant, 18 (60.0%) was 8.3 months, ranging from 2.8 to 12.9 months. were withdrawn due to objective disease progression while The most common AEs included pharyngitis (eight 12 (40%) completed the 6-month study treatment period. patients, 26.7%), headache (seven patients, 23.3%), nausea No patients were withdrawn due to AEs.

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Figure 2. Kaplan-Meier plot showing time to progression. Figure 3. Geometric mean minimum plasma concentration-time profile from this Japanese study and from a Western study.

Pharmacokinetics. Gmean minimum plasma concentrations Fulvestrant was well-tolerated in this population, with no increased steadily from 3.55 ng/ml at 4 weeks after the first patients withdrawing due to AEs and the majority of patients dose to 6.80 ng/ml at 4 weeks after the fifth dose (Figure 3). only experiencing mild AEs. The only drug-related AEs At the final measurement, 4 weeks after the sixth dose, the reported by three (10.0%) or more patients were injection- Gmean minimum plasma concentration was 6.95 ng/ml and site pain (four patients, 13.3.%) and hyperglycaemia (three it was estimated that steady-state levels were reached at 4 patients, 10.0%). weeks after the fifth or sixth dose. The accumulation ratio Pharmacokinetic results were consistent with those was approximately 2.0. from a Western study (11, 12), in which steady-state levels were reached at 4 weeks after the sixth dose, the Discussion accumulation ratio was approximately 2.3 and the Gmean minimum plasma concentration-time profile was similar Fulvestrant is currently approved in the USA and Brazil for (Figure 3). Therefore, based on the results of this trial, the treatment of postmenopausal women with ER-positive ethnicity does not appear to affect the pharmacokinetics who have disease progression of fulvestrant. following prior antioestrogen therapy. Two large Phase III Fulvestrant is an effective and well-tolerated treatment trials showed that fulvestrant is at least as effective as for Japanese postmenopausal women with relapsed or anastrozole in treating postmenopausal women with advanced advanced breast cancer who have initially responded to, but breast cancer resistant to prior antioestrogen therapy (10, 11). later progressed on, prior tamoxifen or toremifene therapy. This trial assessed the efficacy, safety and pharmacokinetics of fulvestrant (250 mg) in 30 postmenopausal Japanese Appendix women with advanced breast cancer who had previously received and responded to tamoxifen or toremifene therapy. Study Institutions: Niigata Cancer Centre Hospital, Niigata; Fulvestrant demonstrated anti-tumour activity, with an National Cancer Centre Hospital, Tokyo; St Luke’s objective response rate of 23.3% and a clinical benefit rate of International Hospital, Tokyo; Saitama Cancer Centre 60.0%. These data are in line with previous Phase III trials, in Hospital, Saitama; Aichi Cancer Centre, Aichi; Nagoya City which fulvestrant demonstrated objective response rates of University Medical School, Aichi; Osaka Medical Centre for 17.5–20.7% and clinical benefit rates of 42.2–44.6% (10, 11). Cancer and Cardiovascular Diseases, Osaka; Osaka University Twelve patients who received clinical benefit with fulvestrant Medical School, Osaka; Osaka National Hospital, Osaka; continued to receive treatment on a compassionate use basis National Shikoku Cancer Centre Hospital, Ehime; National after the completion of the trial. Treatment is still ongoing for Kyushu Cancer Centre, Fukuoka; KitaKyushu Municipal four of these patients, who have all now received fulvestrant Medical Centre, Fukuoka; Kumamoto City Hospital, for longer than 3 years without PD. Kumamoto, Japan.

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References 9 Robertson JFR, Howell A, De Friend DJ, Blamey RW and Walton P: Duration of remission to ICI 182,780 compared to 1 Howell A, Downey S and Anderson E: New endocrine in tamoxifen resistant breast cancer. The therapies for breast cancer. Eur J Cancer 32A: 576-588, 1996. Breast 6: 186-189, 1997. 2 Fisher B, Costantino JP, Wickerham DL, Redmond CK, 10 Howell A, Robertson JFR, Quaresma Albano J, Aschermannova Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, A, Mauriac L, Kleeberg UR, Vergote I, Erikstein B, Webster A Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L and Wolmark and Morris C: Fulvestrant, formerly ICI 182,780, is as effective N: Tamoxifen for prevention of breast cancer: report of the as anastrozole in postmenopausal women with advanced breast National Surgical Adjuvant Breast and Bowel Project P-1 Study. cancer progressing after prior endocrine treatment. J Clin Oncol J Natl Cancer Inst 90: 1371-1388, 1998. 20: 3396-3403, 2002. 3 Howell A, Osborne CK, Morris C and Wakeling AE: ICI 182,780 11 Osborne CK, Pippen J, Jones SE, Parker LM, Ellis M, Come S, (Faslodex): development of a novel, "pure" . Cancer Gertler SZ, May JT, Burton G, Dimery I, Webster A, Morris 89: 817-825, 2000. C, Elledge R and Buzdar A: Double-blind, randomized trial 4 Robertson JF, Nicholson RI, Bundred NJ, Anderson E, Rayter Z, comparing the efficacy and tolerability of fulvestrant versus Dowsett M, Fox JN, Gee JM, Webster A, Wakeling AE, Morris C anastrozole in postmenopausal women with advanced breast and Dixon M: Comparison of the short-term biological effects of cancer progressing on prior endocrine therapy: results of a 7alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, North American trial. J Clin Oncol 20: 3386-3395, 2002. (10)-triene-3,17beta-diol (Faslodex) versus tamoxifen in 12 Watanabe T, Sano M, Ohno S, Inaji H, Nishimura R, Shin E, postmenopausal women with primary breast cancer. Cancer Res Nomura C and Morris C: Fulvestrant provides clinical benefit 61: 6739-6746, 2001. to postmenopausal women with metastic breast cancer who 5 Wakeling AE, Dukes M and Bowler J: A potent specific pure have relapsed on prior antiestrogen therapy: A Japanese study. antiestrogen with clinical potential. Cancer Res 51: 3867-3873, Proc Am Soc Clin Oncol 22: 69, 2003 (abstract 274). 1991. 6 Jaiyesimi IA, Buzdar AU, Decker DA and Hortobagyi GN: Use of tamoxifen for breast cancer: twenty-eight years later. J Clin Oncol 13: 513-529, 1995. 7 Howell A and Robertson J: Response to a specific antioestrogen (ICI 182780) in tamoxifen-resistant breast cancer. Lancet 345: 989-990, 1995. 8 Howell A, DeFriend DJ, Robertson JF, Blamey RW, Anderson L, Anderson E, Sutcliffe FA and Walton P: Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti- oestrogen ICI 182780 in women with advanced breast cancer. Received December 30, 2003 Br J Cancer 74: 300-308, 1996. Accepted February 25, 2004

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