A Randomized, Open-Label, Phase 2/3 Study of Datopotamab Deruxtecan (Dato-DXd) Plus Carboplatin or Cisplatin Versus Gemcitabine Plus Carboplatin or Cisplatin in Participants With Locally Advanced or Metastatic Urothelial Carcinoma (la/mUC) Who Progressed During or After Enfortumab Vedotin (EV) Plus Pembrolizumab Combination Treatment TROPION-Urothelial03 (TU03)
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 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.
⁃ \> Note 1: Urachal, small cell, and adenocarcinoma histology is not permitted.
• Note 2: Participants with la/mUC and a history of nonclinically active prostate cancer are allowed into the trial if:
∙ Participant does not have radiological metastasis of a proven prostate cancer.
‣ Participant with nonmetastatic prostate cancer do not have rising PSA (as determined using local testing by a validated or approved test method) defined as follows:
• Increase in PSA within 2 consecutive measurements separated by at least 1 week (completed within 4 weeks prior to consent or within Screening) and neither of the measurements with an absolute value above 2 ng/mL.
‣ Participant does not currently receive androgen deprivation therapy for the treatment of prostate cancer.
• Note 3: Participant with MIBC (T2-T4aN0M0 or T1-T4aN1M0) who received EV (or other agents with a vedotin payload) plus pembrolizumab (or other PD-1/PD-L1 inhibitors) as neoadjuvant/adjuvant therapy and progressed during treatment or within 12 months of treatment completion may be considered for enrollment, with approval from the Sponsor's Medical Monitor or designee.
‣ 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).
‣ a. Archival tissue collected after the most recent anticancer treatment and within 12 months before the informed consent date is preferred.
⁃ Must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigator's judgment. Participants eligible for cisplatin will receive cisplatin. If a participant received gemcitabine, carboplatin, or cisplatin for early UC in the adjuvant/neoadjuvant setting, the decision to rechallenge the participant with platinum therapy will be at the discretion of the investigator. Participants only receive carboplatin if they are ineligible for cisplatin. Participants are cisplatin-ineligible if they meet any of the following criteria:
• GFR \<60 mL/min (GFR may be estimated by calculated CrCl using the Cockcroft-Gault formula, Modification of Diet in Renal Disease, or 24-hour urine)
⁃ For Phase 2 part:
• Participants with a GFR \<60 mL/min but ≥50 mL/min but have no other cisplatin ineligibility criteria (items b, c, and d) may be considered cisplatin-eligible based on the investigator's clinical judgment.
⁃ For Phase 3 Part:
• Participants with borderline renal function CrCl ≥40 mL/min to \<60 mL/min who have no other cisplatin ineligibility criteria (items b, c, and d) may receive cisplatin using a split-dose regimen, administered as cisplatin 35 mg/m2 on Days 1 and 8 of each 21-day cycle, for a maximum of 4 to 6 cycles.
• In participants with CrCl ≥50 mL/min to \<60 mL/min, full-dose cisplatin may also be administered at the investigator's discretion, based on the overall clinical assessment.
⁃ The dosing schedule and dose level for Dato-DXd or gemcitabine are not altered when combined with either split-dose or full-dose cisplatin.
⁃ For both Phase 2 and Phase 3:
⁃ b. NCI-CTCAE Grade ≥2 audiometric hearing loss c. NCI-CTCAE Grade ≥2 peripheral neuropathy d. NYHA Class III heart failure
⁃ • Must have experienced radiographic progression or relapse during or after 1L of EV (or other agents with a vedotin payload) and pembrolizumab (or other PD-1/PD-L1 inhibitors).
⁃ Participants who discontinued EV (or other agents with a vedotin payload) and pembrolizumab (or other PD-1/PD-L1 inhibitors) in 1L due to toxicity are eligible if they have experienced disease progression following discontinuation. Participant who received EV (or other agents with a vedotin payload) plus pembrolizumab (or other PD-1/PD-L1) inhibitors in a neoadjuvant/adjuvant setting and progressed during treatment or within 12 months of treatment completion will also be considered for enrollment, after approval by the Sponsor's Medical Monitor or Sponsor's designee.