Clinical Trial of AM80 in Combination With Gemcitabine, Cisplatin, and Nivolumab in Patients With Urothelial Carcinoma

Inclusion Criteria:

1. Patients who have been histologically or cytologically diagnosed with urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra based on the General Rule for Clinical and Pathological Studies on Renal Pelvic, Ureteral and Bladder Cancer, 2nd Edition that cannot be curatively resected or has recurred (diagnosis is not permitted at the site of palliative radiation)
2. Patients who have not received prior treatment for unresectable or recurrent urothelial carcinoma
3. Patients with measurable lesions according to RECIST version 1.1 on the CT at screening
4. Patients with an ECOG PS of 0-1 at screening, who are able to take oral medication
5. Patients who will be expected to survive for 12 weeks or more from the enrollment
6. Patients whose major organ functions at screening meet the following criteria

(1)Neutrophil count: 1,500/uL or more (2)Platelet count: 100,000/uL or more (3)Hb: 9.0 g/dL or more (no red blood cell transfusion within 14 days prior to screening examination) (4)T-Bil: 1.5 times or less than 1.5 times the upper limit of the facility standard value (less than 3.0 mg/dL in the case of Gilbert syndrome) (5)AST and ALT: 3 times or less than 3 times the upper limit of the facility standard value (6)CrCl 50 mL/min or more 7.Patients who have given consent to be treated if any of the following applies:

1. Female patients of childbearing potential who can prevent contraception for 30 days prior to enrollment and for 2 years after the end of AM80 treatment
2. Male patients with partners of childbearing potential, who can use contraception from the start of AM80 administration until 7 months after the end of administration and refrain from donating sperm during the above period 8.Patients aged 18-79 years at the time of consent (regardless of sex) 9.Patients who have received a thorough explanation of this clinical trial and have voluntarily given their written informed consent

Exclusion Criteria:

1. Patients who have previously been treated with drugs such as antibodies targeting PD-1, PD-L1, PD-L2, CTLA-4, OX-40, or CD137
2. Patients who have received any of the following t reatments for urothelial carcinoma:

(1)Perioperative adjuvant therapy for curative resection completed less than 12 months prior to enrollment (2)Intravesical therapy within 28 days prior to enrollment (3)Palliative radiation therapy for measurable lesions within 14 days prior to enrollment 3.Patients who have not recovered from toxicity (Grade 1 or 0 or at baseline) from prior treatment at the time of enrollment; however, enrollment is permitted for those with \<= Grade 2 fatigue and alopecia 4.Patients who have participated in other clinical trials within 28 days prior to enrollment (enrollment is permitted if the drug or medical device used in the clinical trial are similar to approved indications, dosage, and administration and do not affect the evalu ation) and who have received their last dose of a drug or other substance used in the current clinical research within the last 28 days 5.Patients with metastasis to the central nervous system or a history or complication of carcinomatous meningitis 6.Patients with multiple cancers whose disease-free interval at the time of registration is less than 3 years (excluding gastrointestinal cancer that was completely resected via endoscopic mucosal resection, completely resected intraepithelial neoplasia of the cervix, localized or presumably cured prostate cancer, completely resected basal/squamous cell carcinoma of the skin, and solid cancers similar to these that have undergone curative treatment and are presumed to be cured) 7.Patients who are taking vitamin A agents or vitam in A-containing supplements at the time of enrollment 8.Patients who have undergone surgery under general anesthesia (excluding diagnostic biopsies) or severe trauma within 28 days prior to enrollment 9.Patients known to have a bleeding tendency or coagulation disorder (e.g., patients with significant in tratumoral bleeding, thromboembolism, or a history or comorbidity of bleeding disorders), and those who require administration of anticoagulants or antiplatelet drugs 10.Patients with active infections requiring systemic administration of antibiotics, antifungals, or antivirals 11.Patients who test positive for hepatitis B surface (HBs) antigen, hepatitis C virus (HCV) antibody and RNA, or HIV antigen or antibody. However, even if the patient is negative to HBs antigen, if the patient is positive to HBs antibody or hepatitis B core (HBc) antibody, the possibility of inclusion should be considered in consultation with a gastroenterologist, if necessary, based on Document 3 of the latest Hepatitis B Treatment Guidelines.

12.Patients with a history of or comorbidity of interstitial lung disease evident on imaging, or those with active non-infectious pneumonitis 13.Patients with autoimmune disease, a history of chronic or recurrent autoimmune disease, or those who have required high-dose systemic corticosteroids (prednisolone equivalent of more than 10 mg/day) or immunosuppressants within 14 days prior to enrollment 14.Patients who require treatment for tuberculosis 15.Patients with clinical symptoms or findings indicating intestinal obstruction requiring intravenous or total parenteral nutrition, and those with risk factors for intestinal perforation (e.g., acute diverticulitis, in traperitoneal abscess, gastrointestinal obstruction, history of abdominal tumor, etc.).

16.Patients with gastrointestinal disorders that may affect the absorption of AM80 17.Patients with a history of severe hypersensitivity or anaphylactic reactions to components of the drugs used in the clinical trial or antibody preparations 18.Patients who received live or attenuated vaccines within 30 days prior to enrollment 19.Patients with serious complications (liver disease , kidney disease, heart disease, lung disease, blood disease, brain disease, etc.) 20.Patients with uncontrolled adrenal insufficiency, Grade 2 or higher hearing impairment, or Grade 2 or higher neuropathy 21.Patients with hypervitaminosis A 22.Lactating female patients (excluding those who agreed to discontinue breastfeeding during the study period and for 6 months after the final dose of A M80) 23.Female patients who are pregnant or have positive pregnancy test results (female patients who have had a period within 12 months prior to enrollment and may be pregnant will be subjected to a pregnancy test. Female patients who have not had a period within 12 months but whose pregnancy cannot be ruled out due to reasons such as chemical menopause will also be subjected to a pregnancy test) 24.Patients who are otherwise deemed inappropriate for participation in this clinical trial by the principal investigator or sub-investigator