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

NCT06983210 | Recruiting Phase 2

• 1 other identifier: MIKE-1(362003)
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

Brief Summary

【Treatment of Urothelial Carcinoma】 Treatment for urothelial carcinoma includes surgery, chemotherapy (anticancer drugs), and radiation therapy. Chemotherapy is generally used when metastasis has already occurred at diagnosis and surgery is not curative (metastatic urothelial carcinoma) or when the cancer recurs after local therapy such as surgery or radiation therapy (recurrent urothelial carcinoma). Although there are several recommended treatments for urothelial carcinoma, the options are often limited by side effects and other factors, and these treatments may not be fully effective. Therefore, the development of safer and more effective treatments is desired. 【About the Drugs to be Used in this Clinical Trial】 In this clinical trial, the investigational drug MIKE-1 will be used in combination with nivolumab plus GC (cisplatin gemcitabine), one of the recommended chemotherapy regimens, and subsequently with nivolumab monotherapy for patients with unresectable metastatic or recurrent urothelial cancer. Nivolumab, cisplatin, and gemcitabine are injectable (intravenous infusion), while MIKE-1 is oral. 【Purpose of the Clinical Trial】 The purpose of this clinical trial is to evaluate the efficacy (how much the cancer shrinks or slows down) and safety of the investigational drug MIKE-1 in combination with nivolumab and gemcitabine and cisplatin therapy in patients with untreated unresectable or recurrent urothelial cancer.

Conditions

Urothelial Carcinoma Bladder; Urothelial Carcinoma of the Renal Pelvis and Ureter; Urothelial Carcinoma Urethra; Urothelial Carcinoma Recurrent

Keywords

urothelial carcinoma; Gemcitabine, Cisplatin and Nivolumab; bladder cancer; renal pelvis cancer; ureteral cancer; urethral cancer

Outcome Measures

Primary Outcomes (1)

• Response rate (RR)

  Response rate (RR): determined by the investigator or sub-investigator at the site. Tumor shrinkage by the best overall response based on the RECIST criteria will be determined by CT scan at each time point. For the same subject, the same imaging method used to evaluate measurable lesions at screening (e.g., the same contrast method) will be used during the study period in principle. The evaluation on each visit day should be performed by the same evaluator as much as possible to ensure internal consistency between each visit day. The response rate is calculated as the ratio of the total number of subjects with complete response (CR) and partial response (PR). CR or PR shall require "confirmation of efficacy".

  Time from the start of treatment (day 1) to the confirmation of complete response (CR: complete disappearance of tumor) or partial response (PR: reduction of tumor by a certain percentage or more). (Average 18 weeks)

Secondary Outcomes (3)

• Overall survival

  Time from day 1 of AM80 administration to death. (Average 49 weeks)

• Progression free survival

  Time from day 1 of AM80 administration to the date of confirmed progression. (Average 49 weeks)

• Duration of Response

  Time since initiation of treatment from the time PR or CR was first identified to the date of tumor recurrence. (Average 49 weeks)

Study Arms (1)

MIKE-1

EXPERIMENTAL

A characteristic pathology of refractory cancers such as advanced urothelial carcinoma is a high proliferation of cancer-associated fibroblasts (CAFs) in the stroma and associated fibrosis. The investigators have previously identified fibroblast-specific meflin as the first functional marker of tumor suppressive CAFs. The investigators hypothesize that increasing the number of mephrin-positive tumor suppressive CAFs may increase the efficacy of ICI. The investigators investigated this in a mouse model of bladder cancer among urothelial carcinomas and confirmed that AM80 administration markedly increased the therapeutic efficacy of ICI. The investigators considered that the efficacy of ICI may be enhanced in patients with urothelial carcinoma when AM80 is administered in combination with ICI. Based on the above, The investigators will explore and evaluate the efficacy and confirm the safety of AM80 when administered in combination with nivolumab, gemcitabine, and cisplatin.

Drug: Add-on effect of adding tamivarotene (AM80) to gemcitabine, cisplatin, and nivolumab combination therapy

Interventions

Add-on effect of adding tamivarotene (AM80) to gemcitabine, cisplatin, and nivolumab combination therapy DRUG

To explore the efficacy and safety of the combination of tamivarotene (AM80), gemcitabine, cisplatin, and nivolumab in the treatment of patients with untreated unresectable or recurrent urothelial cancer

Also known as: AM80

MIKE-1

Eligibility Criteria

• Age: 18 Years - 79 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• Patients who have not received prior treatment for unresectable or recurrent urothelial carcinoma
• Patients with measurable lesions according to RECIST version 1.1 on the CT at screening
• Patients with an ECOG PS of 0-1 at screening, who are able to take oral medication
• Patients who will be expected to survive for 12 weeks or more from the enrollment
• 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:
• 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
• 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

You may not qualify if:

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

Sponsors & Collaborators

• Nagoya University: lead
• Japan Agency for Medical Research and Development: collaborator
• Kyushu University: collaborator
• Chiba University: collaborator
• University of Tsukuba: collaborator
• Kyoto University: collaborator

Study Sites (1)

Nagoya University Hospital

Nagoya, Aichi-ken, 4668560, Japan

RECRUITING

Related Publications (1)

• Owaki T, Iida T, Miyai Y, Kato K, Hase T, Ishii M, Ando R, Hinohara K, Akashi T, Mizutani Y, Ishikawa T, Mii S, Shiraki Y, Esaki N, Yamamoto M, Tsukamoto T, Nomura S, Murakami T, Takahashi M, Yuguchi Y, Maeda M, Sano T, Sassa N, Matsukawa Y, Kawashima H, Akamatsu S, Enomoto A. Synthetic retinoid-mediated preconditioning of cancer-associated fibroblasts and macrophages improves cancer response to immune checkpoint blockade. Br J Cancer. 2024 Jul;131(2):372-386. doi: 10.1038/s41416-024-02734-3. Epub 2024 Jun 7.

  PMID: 38849479 BACKGROUND

MeSH Terms

Conditions

Carcinoma, Transitional Cell; Urinary Bladder Neoplasms; Ureteral Neoplasms; Urethral Neoplasms

Interventions

tamibarotene; Cisplatin

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases; Ureteral Diseases; Urethral Diseases

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds

Study Officials

• Syusuke Akamatsu

  Nagoya University Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Tomoyasu Sano

CONTACT

+81-527441111; sano.tomoyasu.y6@f.mail.nagoya-u.ac.jp

Yuri Amano

CONTACT

+81-527442942; amano.yuri.b3@f.mail.nagoya-u.ac.jp

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Lecturer (Department of Urology)

Model Details: In this study, treatment period 1 will consist of one course of 3 weeks (21 days) in principle, and up to 6 courses will be continued. After discontinuation of Treatment Phase 1 (when gemcitabine or cisplatin cannot be continued) or termination of Treatment Phase 1, AM80 and nivolumab will be continued for one course of 4 weeks (28 days) in principle, until either the discontinuation criteria are met or the imaging evaluation at 49 weeks is completed. During the follow-up period, patients will be followed until the last patient completes the imaging evaluation at 49 weeks, with a follow-up survey every 8 weeks until 49 weeks after the first dose of AM80, and a follow-up survey every 12 weeks after 49 weeks after the first dose of AM80, as follow-up survey (1).

Study Record Dates

• First Submitted: May 2, 2025
• First Posted: May 21, 2025
• Study Start: May 1, 2025
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2029
• Last Updated: August 14, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: Beginning 3 months and ending 3 years after the publication of results.
• Access Criteria: If the principal investigator, clinical trial office, main stakeholder conclude that secondary use of individual data obtained in this clinical trial is beneficial for additional analysis, the secondary use of data excluding personal information will be acceptable after publication of results.

Locations

JP (1)