This is a global, multicenter, randomized, open-label, Phase 2/3 study of Dato-DXd plus carboplatin or cisplatin versus gemcitabine plus carboplatin or cisplatin in participants with la/mUC who progressed during or after EV plus pembrolizumab combination treatment.
This trial will start with part A, Phase 2. During part A, Phase 2, preliminary efficacy and safety will be assessed, and the recommended Phase 3 dose (RP3D) will be identified when the data allow sufficient assessment of activity, safety, and tolerability. The Phase 3 part will start contingent upon the assessment in the Phase 2 part, taking into consideration the totality of information.
Adult ≥18 years at the time the ICF is signed (if the legal age of consent is > 18 years old, then follow the local regulatory requirements).
Histologically or cytologically confirmed unresectable or locally advanced (T4b, any N; or any T, N 2-3) or metastatic (any T, any N, M1) urothelial carcinoma of the bladder, renal pelvis, ureter, or urethra. Participants with urothelial carcinoma (transitional cell) with squamous differentiation or mixed cell types are eligible if the histology is predominantly urothelial as specified in the protocol.
Must provide tumor tissue sample from archival tissue or newly obtained pretreatment biopsy for exploratory biomarker testing. Tumor tissue sample should not be collected from a lesion that was irradiated unless documentation can be provided confirming that the tumor tissue was collected at least 3 months after radiation and the lesion increased/appeared since radiation occurred. Tumor tissue must be of sufficient quantity (as defined in the Laboratory Manual).
Archival tissue collected after the most recent anticancer treatment and within 12 months before the informed consent date is preferred.
Has had prior systemic therapy other than the combination of EV and pembrolizumab for la/mUC. The following participants may be considered eligible after approval by the Sponsor's Medical Monitor or Sponsor's designee.
Participant who progressed during or after treatments with assets that include either anti-Nectin 4 or vedotin payload (MMAE or other microtubule inhibitors) combined with PD1/PD-L1 inhibitors in 1L la/mUC.
History of an allogeneic bone marrow or solid organ transplant.
Concomitant treatment with any prohibited medications in this protocol.
Sequential
Dato-DXd
DrugDato-DXd will be administered as an intravenous (IV) infusion every three weeks (Q3W) at a dose of 4 mg/kg or 6 mg/kg in Part A or RP3D in Part B
Carboplatin
DrugCarboplatin will be administered as an intravenous (IV) infusion every three weeks (Q3W) at a dose of AUC 4.5 or 5.0 mg•min/mL
Cisplatin
DrugCisplatin will be administered as an intravenous (IV) infusion every three weeks (Q3W) at a dose of 70 mg/m\^2 (Phase 2) or 70 mg/m\^2 on Day 1 or 35 mg/m\^2 on Day 1 and Day 8 each 21- day cycle (Phase 3)
Gemcitabine
DrugGemcitabine will be administered as an IV infusion at a dose of 1000 mg/m\^2 on Day 1 and 8 of every 3 week cycle.
Overall Response Rate - Part A (Phase 2)
Overall Response Rate (ORR) is defined as the proportion of participants with a Best Overall Response (BOR) of confirmed Complete Response (CR) or confirmed Partial Response (PR). As assessed by investigator per RECIST v1.1
Progression Free Survival as Assessed by Blinded Independent Central Review (BICR) - Part B (Phase 3)
Progression Free Survival (PFS) is defined as the time from randomization to the first documented radiographic disease progression or death due to any cause, whichever occurs first. As assessed by BICR per RECIST v1.1
Overall Survival - Part B (Phase 3)
Overall Survival (OS) is defined as the time from randomization to death due to any cause.
Duration of Response - Part A (Phase 2)
Duration of Response (DoR) is defined as the time from the date of first documentation of objective tumor response (confirmed CR or confirmed PR) to the date of the first documented radiographic disease progression or death due to any cause, whichever occurs first in responding participants. As assessed by investigator per RECIST v1.1
Progression Free Survival as Assessed by Investigator - Part B (Phase 3)
PFS is defined as the time interval from the date of randomization to the first documented radiographic disease progression or death due to any cause, whichever occurs first. As assessed by investigator per RECIST v1.1
Overall Response Rate - Part B (Phase 3)
ORR is defined as the proportion of participants with a BOR of confirmed CR or confirmed PR. As assessed by BICR and investigator per RECIST V1.1
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Daiichi Sankyo
Lead sponsor
AstraZeneca
Collaborator
