Overview

This multicenter, open-label, single-arm exploratory study will evaluate the safety, tolerability, and preliminary antitumor activity of rimegepant in combination with toripalimab in patients with locally advanced or metastatic urothelial carcinoma after failure of prior standard therapy. Approximately 6 to 12 participants will be enrolled. The primary objectives are to assess dose-limiting toxicities and other safety outcomes and to determine the recommended Phase 2 dose (RP2D) of rimegepant when combined with toripalimab. The study will also explore preliminary antitumor activity and selected biomarkers, including changes in the tumor immune microenvironment and circulating tumor DNA. The study is designed to determine whether targeting calcitonin gene-related peptide (CGRP) signaling with rimegepant can be safely combined with programmed cell death protein 1 (PD-1) blockade using toripalimab and whether this combination shows evidence of antitumor activity in patients with advanced urothelial carcinoma who have progressed after standard treatment.

Eligibility

Inclusion criteria:

1. The participant voluntarily agrees to participate in this study, provides written informed consent, and is willing and able to comply with all study visits and the treatment plan.
2. Male or female participants aged ≥18 years.
3. Histologic or cytologic confirmation of locally advanced or metastatic urothelial carcinoma.
4. The participant's most recent standard therapy must have failed, and disease progression during or after treatment must be radiographically confirmed.
   1. Standard therapies include, but are not limited to, platinum-containing chemotherapy regimens; programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitor monotherapy; or a PD-1/PD-L1 inhibitor in combination with chemotherapy or an antibody-drug conjugate (ADC).
   2. Participants previously treated with a PD-1/PD-L1 inhibitor may be enrolled, except those who permanently discontinued such treatment because of an immune-related adverse event.
5. At least one measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
6. The most recent adequate archival tumor tissue specimen obtained within the previous 12 months must be provided as a formalin-fixed, paraffin-embedded block or serial unstained sections. Fresh tumor biopsies at baseline and at disease progression for exploratory biomarker research are strongly recommended but not required; a participant's decision whether to undergo biopsy will not affect eligibility for the main part of this clinical trial.
7. Estimated life expectancy of at least 6 months.
8. Eastern Cooperative Oncology Group (ECOG) score (PS) of 0 or 1.
9. Adequate major-organ function.

Exclusion criteria:

1. History of a malignancy other than urothelial carcinoma, except in either of the following circumstances:
   1. The prior malignancy was treated with potentially curative therapy and there has been no evidence of disease for 5 years.
   2. Successfully resected basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, cervical carcinoma in situ, or another carcinoma in situ.
2. Prior allogeneic stem-cell or solid-organ transplantation.
3. Current or prior congenital or acquired immunodeficiency disorder.
4. Known or suspected allergy to an anti-programmed cell death protein 1 (anti-PD-1) agent, history of hypersensitivity to chimeric or humanized antibodies or fusion proteins, or allergy to any excipient of either investigational product.
5. Other clinically significant abnormalities in clinical status or laboratory test results that, in the investigator's opinion, may affect the safety assessment, such as uncontrolled diabetes mellitus, chronic kidney disease, Grade 2 or higher peripheral neuropathy according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 6.0 (NCI CTCAE v6.0), or thyroid dysfunction.
6. An active or poorly controlled serious infection, including any of the following:
   1. Positive for antibodies to human immunodeficiency virus type 1 or 2 (HIV-1/2).
   2. Active hepatitis B, defined as hepatitis B surface antigen (HBsAg) positivity or hepatitis B virus (HBV) DNA \>2,000 IU/mL accompanied by abnormal liver function.
   3. Active hepatitis C, defined as hepatitis C virus (HCV) antibody positivity or HCV RNA ≥10³ copies/mL accompanied by abnormal liver function.
   4. Active tuberculosis.
   5. Any other uncontrolled active infection of Grade 3 or higher according to NCI CTCAE v6.0.
7. Failure to recover from surgery, such as the presence of an unhealed incision or serious postoperative complications.
8. Participants who are pregnant or breastfeeding, or female or male participants of reproductive potential who are unwilling or unable to use effective contraception.
9. Any other circumstance that the investigator considers unsuitable for enrollment.