Sponsor: BicycleTx Limited (industry)
Phase: 2/3
Start date: Jan. 24, 2024
Planned enrollment: 956
Zelenectide pevedotin (BT8009; BCY8245) is an investigational Bicycle Toxin Conjugate targeting Nectin‑4, a cell-adhesion molecule overexpressed in several epithelial cancers, notably urothelial carcinoma. Early-phase clinical data show antitumor activity as monotherapy in metastatic urothelial cancer (mUC) pretreated with platinum and PD‑(L)1 therapy and in combination with pembrolizumab in cisplatin‑ineligible, treatment‑naive mUC. A randomized phase 2/3 program (Duravelo‑2) is ongoing. (aacrjournals.org)
Monotherapy (EV‑naive, previously treated mUC; RP2D 5 mg/m² weekly)
- ESMO 2024 update (Duravelo‑1): among 38 efficacy‑evaluable patients, ORR 45% (1 CR, 16 PR; 13 confirmed), disease control included durable stable disease ≥16 weeks in 9 patients; median duration of response 11.1 months (95% CI 3.9, not reached). (oncologypro.esmo.org)
Combination with pembrolizumab (first‑line, cisplatin‑ineligible mUC)
- ASCO 2025 presentation/topline update (Duravelo‑1): among 20 efficacy‑evaluable patients, ORR 65% with 25% CR; confirmed responses in 50% (10/20); median DOR not yet mature at the January 3, 2025 cutoff. (onclive.com)
Note: These are early, non-comparative cohorts; confirmatory randomized data are pending from Duravelo‑2. (ascopubs.org)
Monotherapy at RP2D in EV‑naive mUC (N=45):
- Any‑grade treatment‑emergent AEs 93%; grade ≥3 TEAEs 53%. Common treatment‑related AEs (≥15%): nausea (33%), asthenia (22%), fatigue (20%), pyrexia (20%), diarrhea (18%), appetite decreased (16%), alopecia (16%). Notably, no grade ≥3 treatment‑related neuropathy, skin reactions, or eye disorders were reported. Dose reductions 27%; interruptions 53%; discontinuations 4%. (oncologypro.esmo.org)
Phase 1 dose‑escalation experience across tumor types:
- Generally gastrointestinal AEs and fatigue predominated; low incidence of skin/ocular events and peripheral neuropathy relative to antibody‑drug conjugates; most common grade ≥3 TRAE was neutropenia (14% across all doses), with serious drug‑related AEs in 6% and none in the 5 mg/m² cohort. (investors.bicycletherapeutics.com)
Combination with pembrolizumab (first‑line cisplatin‑ineligible mUC):
- Topline update described a safety/tolerability profile consistent with monotherapy; peripheral neuropathy, skin reactions, and eye disorders were primarily low grade; grade 3 TRAEs of clinical interest were reversible; no grade 4–5 TRAEs reported. (biospace.com)
ClinicalTrials.gov entries
- Duravelo‑1 (NCT04561362). (mycancergenome.org)
- Duravelo‑2 (NCT06225596). (yalemedicine.org)
Abbreviations: ADC, antibody‑drug conjugate; AE, adverse event; CR, complete response; DOR, duration of response; EV, enfortumab vedotin; mUC, metastatic urothelial carcinoma; ORR, objective response rate; PR, partial response; RP2D, recommended phase 2 dose; TEAE/TRAE, treatment‑emergent/treatment‑related adverse event.
Last updated: Oct 2025
Goal: Evaluate the efficacy and safety of BT8009 (zelenectide pevedotin), a Nectin-4–targeting Bicycle Toxin Conjugate, as monotherapy and in combination with pembrolizumab versus standard platinum-based chemotherapy (with optional avelumab maintenance) in locally advanced or metastatic urothelial cancer, using an adaptive phase 2/3 design with dose selection followed by expansion.
Patients: Adults with histologically/cytologically confirmed, unresectable locally advanced or metastatic urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra, measurable disease by RECIST 1.1, and life expectancy ≥12 weeks. Cohort 1 includes previously untreated patients eligible for cisplatin- or carboplatin-based chemotherapy. Cohort 2 includes patients previously treated with ≥1 systemic regimen with progression/recurrence after the most recent therapy; prior enfortumab vedotin or other MMAE-based therapy is excluded in Cohort 2. Key exclusions include active corneal disease, need for strong CYP3A/P-gp modifiers, high-dose steroids, hypersensitivity to study components/MMAE, recent major surgery not recovered, and recent live vaccines.
Design: Global, multicenter, randomized, open-label, adaptive phase 2/3 trial with an initial dose-selection phase followed by continuation. Two parallel cohorts: first-line platinum-eligible and previously treated. Blinded independent central review is used for key efficacy endpoints.
Treatments: Cohort 1: BT8009 plus pembrolizumab (two experimental arms reflecting dose/schedule selection) versus standard platinum-based combination chemotherapy (gemcitabine with cisplatin or carboplatin) with optional avelumab maintenance per contemporary standard. Cohort 2: BT8009 monotherapy (two experimental arms reflecting dose/schedule selection); an earlier BT8009 plus pembrolizumab arm is not recruiting. BT8009 is a small-molecule Bicycle Toxin Conjugate targeting Nectin-4, linked to monomethyl auristatin E via a cleavable valine–citrulline linker. Its small size and short plasma half-life are designed to enhance tumor penetration and reduce normal tissue exposure compared with larger antibody–drug conjugates. Early phase 1/2 data in previously treated urothelial cancer reported an objective response rate of approximately 45% at the recommended phase 2 dose with a median duration of response around 11 months and a generally manageable safety profile characterized mainly by low-grade gastrointestinal and constitutional adverse events, with limited high-grade neuropathy, dermatologic, or ocular toxicity at the RP2D. Pembrolizumab and platinum-based chemotherapy with avelumab maintenance represent approved standard regimens in the studied settings.
Outcomes: Primary endpoints: Cohort 1 progression-free survival by BICR per RECIST 1.1; Cohort 2 objective response rate by BICR per RECIST 1.1. Key secondary endpoints across cohorts include ORR (BICR and investigator), PFS (BICR and investigator), duration of response, disease control rate, overall survival, safety (AEs/SAEs and laboratory, ECG, and vitals changes), and patient-reported outcomes (EQ-5D and EORTC QLQ-C30).
Burden on patient: Moderate. As a randomized phase 2/3 oncology study, patients should expect regular imaging for RECIST assessment, safety labs, vitals, and ECGs similar to standard of care. Additional requirements include provision of archival or fresh tumor tissue, which may necessitate a biopsy if archival tissue is inadequate. Combination arms involve intravenous administrations on standard schedules, implying frequent clinic visits. Although extensive pharmacokinetics sampling is not specified, early-phase dose selection components and ongoing safety monitoring may increase visit frequency early in treatment. Quality-of-life questionnaires add minor time. Overall, visit and monitoring intensity are greater than routine practice but typical for pivotal oncology trials.
Last updated: Oct 2025
Key Inclusion Criteria:
* Life expectancy ≥ 12 weeks.
* Measurable disease as defined by RECIST v1.1.
* Histologically or cytologically confirmed locally advanced (unresectable) or metastatic UC of the renal pelvis, ureter, bladder, or urethra.
* Archival or fresh tumor tissue comprising muscle-invasive UC or locally advanced or metastatic UC should be available for submission to central laboratory.
* Negative pregnancy test for women of childbearing potential (WOCBP) (negative serum test at Screening and negative urine or serum test within 72 hours prior to the first dose).
* Cohort 1: Previously Untreated: Eligible to receive platinum-based chemotherapy (either cisplatin- or carboplatin-based chemotherapy based on Investigator decision.
* Cohort 1: Participants must not have received prior systemic therapy for locally advanced or metastatic UC with the following exceptions:
1. Prior local intravesical chemotherapy, local surgery when full resection is not achieved, local immunotherapy, and radiotherapy are permitted if completed at least 4 weeks prior to the initiation of study treatment and all acute toxicities have resolved.
2. Prior neoadjuvant/adjuvant chemotherapy or monomethyl auristatin E (MMAE)-based therapy with recurrence \>12 months from completion of therapy.
3. Prior neoadjuvant/adjuvant immune checkpoint inhibitor therapy with recurrence \>12 months from completion of therapy.
* Cohort 2: Previously Treated: Participants must have received ≥ 1 prior systemic treatment for locally advanced or metastatic UC. This includes neoadjuvant/adjuvant platinum-based chemotherapy if recurrence occurred within 12 months of completing therapy.
* Cohort 2: Progression or recurrence of UC during or following receipt of most recent therapy.
Key Exclusion Criteria:
* Active keratitis or corneal ulcerations.
* Requirement, while on study, for treatment with strong inhibitors or strong inducers of human cytochrome P450 3A (CYP3A) or inhibitors of P-glycoprotein (P-gp) including herbal- or food-based inhibitors.
* Any condition requiring current treatment with high dose corticosteroids (\> 10 mg daily prednisone or equivalent).
* Known hypersensitivity or allergy to any of the ingredients of any of the study interventions, or to MMAE.
* Has not adequately recovered from recent major surgery (excluding placement of vascular access).
* Receipt of live or attenuated vaccine within 30 days of first dose.
* Cohort 1: Previously Untreated: Prior treatment with a checkpoint inhibitor (CPI) for any other malignancy within the last 12 months.
* Cohort 2: Previously Treated: Received more than 1 prior platinum-based chemotherapy regimen for locally advanced or metastatic UC. This includes neoadjuvant/adjuvant platinum-based chemotherapy if recurrence occurred within 12 months of completing therapy.
* Cohort 2: Prior treatment with enfortumab vedotin or any other MMAE-based therapy
Viedma, 8500, Argentina
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Santa Fe, S2000KZE, Argentina
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Pergamino, B2700CPM, Argentina
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La Rioja, 5300, Argentina
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Córdoba, X5008HHW, Argentina
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Cipolletti, R8324, Argentina
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Buenos Aires, C1426ANZ, Argentina
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Buenos Aires, C1419AHN, Argentina
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Buenos Aires, C1280AEB, Argentina
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Buenos Aires, C1120AAT, Argentina
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Adelaide, 5000, Australia
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Brisbane, 4101, Australia
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Douglas, 4814, Australia
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Woolloongabba, 4102, Australia
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Geelong, 3220, Australia
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Hunter, 2310, Australia
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Nedlands, 6009, Australia
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New South Wales, 2148, Australia
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Randwick, 2031, Australia
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South Brisbane, 4066, Australia
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Southport, 4215, Australia
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Vienna, 1020, Austria
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Vienna, 1090, Austria
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Linz, 4020, Austria
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Charleroi, 6060, Belgium
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Ghent, 9000, Belgium
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Ghent, 9000, Belgium
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Leuven, 3000, Belgium
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Barretos, 14784-400, Brazil
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Florianópolis, 88020-210, Brazil
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Ijuí, 98700-000, Brazil
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Porto Alegre, 90110-270, Brazil
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Porto Alegre, 90610-000, Brazil
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São Paulo, 01327-001, Brazil
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São Paulo, 01509-010, Brazil
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Kelowna, V1Y 5L3, Canada
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Québec, H4A 3J1, Canada
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Toronto, M5G 2M9, Canada
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Winnipeg, R3E 0V9, Canada
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Santiago, 7500921, Chile
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Santiago, 8420000, Chile
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Viña del Mar, 2520598, Chile
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Aalborg, 9000, Denmark
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Bordeaux, 33000, France
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Besançon, 25000, France
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Bordeaux, 33076, France
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Le Mans, 72000, France
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Limoges, 87042, France
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Lyon, 69008, France
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Marseille, 13273, France
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Montpellier, 34298, France
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Nancy, 54100, France
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Nice, 06189, France
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Paris, 75014, France
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Paris, 75015, France
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Pierre-Bénite, 69495, France
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Poitiers, 86000, France
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Villejuif, 94805, France
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Tbilisi, 0159, Georgia
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Tbilisi, 0186, Georgia
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Batumi, 6000, Georgia
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Tbilisi, 0141, Georgia
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Göttingen, 37075, Germany
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Freiburg im Breisgau, 79110, Germany
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Freiburg im Breisgau, 49013, Germany
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Frankfurt, 60590, Germany
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Frankfurt, 60488, Germany
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Essen, 45147, Germany
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Dresden, 01307, Germany
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Münster, 48149, Germany
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Tübingen, 72076, Germany
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Nürtingen, D-72622, Germany
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Herne, 44625, Germany
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Mannheim, 68167, Germany
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Budapest, H-1145, Hungary
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Kaposvár, 7400, Hungary
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Kecskemét, H-6000, Hungary
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Budapest, H-1122, Hungary
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Jerusalem, 9112001, Israel
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Be’er Ya‘aqov, 7030001, Israel
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Haifa, 3109601, Israel
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Kfar Saba, 4428164, Israel
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Petah Tikva, 4941492, Israel
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Tel Aviv, 6423906, Israel
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Genova, 16132, Italy
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Aviano, 33081, Italy
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Milan, 20141, Italy
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Terni, 5100, Italy
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Napoli, 80131, Italy
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Gdynia, 81-519, Poland
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Wieliszew, 05-135, Poland
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Krakow, 31-559, Poland
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Gdansk, 80-210, Poland
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Belgrade, 11000, Serbia
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Singapore, 119228, Singapore
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Singapore, 168583, Singapore
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Seoul, 02841, South Korea
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Goyang, 10408, South Korea
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Daejeon, 35015, South Korea
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Seoul, 3722, South Korea
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Seoul, 06351, South Korea
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Seoul, 05505, South Korea
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Seoul, 03080, South Korea
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Gwangju, 58128, South Korea
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Valencia, 46009, Spain
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Barcelona, 08026, Spain
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Barcelona, 08036, Spain
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Barcelona, 08908, Spain
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Las Palmas de Gran Canaria, 35016, Spain
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Madrid, 28007, Spain
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Madrid, 28027, Spain
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Madrid, 28040, Spain
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Madrid, 28041, Spain
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Madrid, 28046, Spain
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Pamplona, 31008, Spain
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San Sebastián, 20014, Spain
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Santander, 39008, Spain
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Santiago de Compostela, 15706, Spain
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Taichung, 40447, Taiwan
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Taoyuan, 333, Taiwan
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Taipei, 10002, Taiwan
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Tainan City, 710, Taiwan
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Tainan City, 704, Taiwan
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Kaohsiung City, 807, Taiwan
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Istanbul, 34000, Turkey (Türkiye)
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Ankara, 06680, Turkey (Türkiye)
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Edirne, 22030, Turkey (Türkiye)
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Kocaeli, 41380, Turkey (Türkiye)
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Izmir, 35575, Turkey (Türkiye)
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Istanbul, 34899, Turkey (Türkiye)
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Sutton, SM2 5PT, United Kingdom
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Bristol, BS2 8ED, United Kingdom
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Cambridge, CB2 0QQ, United Kingdom
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London, EC1A 7BE, United Kingdom
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London, NW1 2PG, United Kingdom
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London, NW3 2QG, United Kingdom
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London, W6 8RF, United Kingdom
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Manchester, M20 4BX, United Kingdom
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Plymouth, PL6 8DH, United Kingdom
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Little Rock, Arkansas, 72205, United States
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Orange, California, 92868, United States
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Fullerton, California, 92835, United States
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St. Helena, California, 94574, United States
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San Francisco, California, 94158, United States
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Denver, Colorado, 80218, United States
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New Haven, Connecticut, 06520-8028, United States
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Newark, Delaware, 19713, United States
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Jacksonville, Florida, 32266, United States
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Miami, Florida, 33165, United States
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Miami Beach, Florida, 33140, United States
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Tampa, Florida, 33612, United States
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Miami, Florida, 33136, United States
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Springfield, Illinois, 62702, United States
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Des Moines, Iowa, 50309, United States
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Westwood, Kansas, 66205, United States
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Louisville, Kentucky, 40202, United States
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Baton Rouge, Louisiana, 70809, United States
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Grand Rapids, Michigan, 49503, United States
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Omaha, Nebraska, 68130, United States
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Omaha, Nebraska, 68130, United States
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Voorhees Township, New Jersey, 01009, United States
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East Brunswick, New Jersey, 08816, United States
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Voorhees Township, New Jersey, 08043, United States
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The Bronx, New York, 10461, United States
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New York, New York, 10032, United States
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Cleveland, Ohio, 44106, United States
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Myrtle Beach, South Carolina, 29572, United States
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Charleston, South Carolina, 29425, United States
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Nashville, Tennessee, 37203, United States
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San Antonio, Texas, 78229, United States
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Fort Worth, Texas, 76104, United States
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Houston, Texas, 77030, United States
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