Informations générales (source: ClinicalTrials.gov)
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)
Interventional
Phase 2/Phase 3
Daiichi Sankyo (Voir sur ClinicalTrials)
septembre 2025
janvier 2030
17 juin 2026
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.
Etablissements
| Les établissements d'Île-de-France ayant mis à jour leurs données Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CLCC INSTITUT GUSTAVE ROUSSY | Yohann LORIOT | 20/04/2026 16:15:07 | Contacter | ||
Critères
Tous
- 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:
1. Participant does not have radiological metastasis of a proven prostate cancer.
2. 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.
3. 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:
1. 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.
Key Exclusion Criteria:
- 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.
a. 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.
- Treatment with any of the following:
1. History of an allogeneic bone marrow or solid organ transplant.
2. Concomitant treatment with any prohibited medications in this protocol.
3. Prior TROP2 directed ADC therapy.
- Uncontrolled or significant cardiovascular disease, including:
1. QTcF interval >470 ms based on the average of triplicate 12-lead (ECG per local
read) at screening.
2. Myocardial infarction within 6 months prior to randomization.
3. Uncontrolled angina pectoris within 6 months prior to randomization.
4. NYHA Class 3 or 4 congestive heart failure at screening.
5. Uncontrolled hypertension (resting systolic blood pressure >160 mmHg or
diastolic blood pressure >100 mmHg within 28 days before randomization that is
not resolved despite maximal medical therapy).
- Has a history of non-infectious ILD/pneumonitis including radiation pneumonitis that
required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis
that cannot be ruled out by imaging at Screening.
- Has clinically severe pulmonary compromise as judged by the investigator resulting
from intercurrent pulmonary illnesses including, but not limited to, any underlying
pulmonary disorder (eg, severe asthma, severe chronic obstructive pulmonary disease,
restrictive lung disease, pleural effusion, etc.) or any autoimmune, connective
tissue, or inflammatory disorders with pulmonary involvement (eg, rheumatoid
arthritis, Sjögren's syndrome, sarcoidosis, etc.), or prior complete pneumonectomy.
- Toxicities from previous anticancer therapy, defined as toxicities (other than
alopecia) not yet improved to NCI-CTCAE version 5.0 Grade ≤1 or baseline. Note:
Participants may be enrolled with chronic, stable Grade 2 toxicities (defined as no
worsening to Grade >2 for at least 3 months prior to randomization and managed with
standard of care treatment) which the investigator deems related to previous
anticancer therapy, comprised of (including but not limited to):
1. Anticancer therapy-induced neuropathy
2. Residual toxicities from prior immunotherapy treatment: Grade 1 or Grade 2
endocrinopathies which may include:
- Hypothyroidism/ hyperthyroidism
- Type I diabetes
- Hyperglycemia
- Adrenal insufficiency
- Adrenalitis c. Skin hypopigmentation (vitiligo)