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.
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.
Male or female participants aged ≥18 years.
Histologic or cytologic confirmation of locally advanced or metastatic urothelial carcinoma.
The participant's most recent standard therapy must have failed, and disease progression during or after treatment must be radiographically confirmed.
The prior malignancy was treated with potentially curative therapy and there has been no evidence of disease for 5 years.
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.
Prior allogeneic stem-cell or solid-organ transplantation.
Current or prior congenital or acquired immunodeficiency disorder.
Single group
Rimegepant
DrugRimegepant will be administered orally in a dose-escalation design. At dose level 1, participants will receive rimegepant 75 mg every other day. If dose level 1 is considered tolerable according to the prespecified dose-limiting toxicity criteria, dose escalation will proceed to dose level 2, in which participants will receive rimegepant 75 mg once daily. Rimegepant will be administered in combination with toripalimab.
Toripalimab
Biological/VaccineToripalimab will be administered by intravenous infusion at a dose of 3.0 mg/kg every 2 weeks.
Incidence of dose-limiting toxicities (DLTs)
Occurrence of toxicity meeting the prespecified DLT criteria during the DLT observation period;
Recommended Phase 2 dose (RP2D) of rimegepant in combination with toripalimab
The recommended Phase 2 dose (RP2D) of rimegepant in combination with toripalimab will be determined based primarily on the occurrence of dose-limiting toxicities (DLTs), together with the overall safety and tolerability of the evaluated dose levels.
Incidence and severity of adverse events and serious adverse events
Number and proportion of participants experiencing adverse events (AEs) and serious adverse events (SAEs), including events leading to dose modification or treatment discontinuation. Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 6.0 (NCI CTCAE v6.0).
Radiographic progression-free survival (rPFS)
Radiographic progression-free survival (rPFS): the time from the date of enrollment to radiographically confirmed disease progression or death from any cause, whichever occurs first. Radiographic disease progression will be determined by the investigator according to RECIST v1.1 based on assessment of the primary lesion, regional lymph node involvement, soft tissue metastases, and bone metastases.
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