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Phase 3 Study of trastuzumab brengitecan versus platinum‑based chemotherapy in adults with HER2‑positive metastatic urothelial cancer after anti‑PD‑(L)1 therapy

Verified siteRegistered drugNo placebo
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What is this trial about?

A plain-language summary of the goals, design and what participants do

The study focuses on adults with metastatic urothelial cancer that shows the HER2-positive marker and that has grown despite treatment that blocks PD-(L)1 proteins. The experimental medication is T-bren (BL-M07D1), a version of trastuzumab brengitecan given by IV infusion. The comparison treatment consists of standard platinum‑based chemotherapy using drugs such as cisplatin, gemcitabine and carboplatin.

The purpose of the trial is to determine whether the experimental medication can keep the cancer from growing longer than the standard chemotherapy. Participants are randomly assigned to receive either the experimental drug or the standard chemotherapy, and the study is open‑label, meaning the treatment each person receives is known to the doctors and participants. Treatment cycles are given every few weeks for several months, with regular clinic visits to check the disease, record any side effects, and perform routine laboratory tests.

Disease status is evaluated with imaging scans such as CT that create pictures of the inside of the body, and the main outcome measured is progression-free survival, the time before the cancer shows signs of growth or new symptoms appear. Additional assessments include overall survival, response rates, and questionnaires that capture the participants’ quality of life. Safety is continuously monitored throughout the study.

The research process

The trial runs in 8 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Randomization to Treatment Group

    After joining the study, you will be randomly assigned to receive either the investigational drug trastuzumab brengitecan (referred to as T‑bren) or a standard platinum‑based chemotherapy regimen.

    The randomization process ensures that the assignment is unbiased and based solely on chance.

  2. Step 2

    Baseline Assessments

    Before the first infusion, baseline medical tests will be performed, including blood work and imaging studies, to document the current status of your disease.

    These assessments provide reference points for later comparisons.

  3. Step 3

    First Infusion of Assigned Medication

    If you are assigned to the investigational arm, you will receive trastuzumab brengitecan by IV infusion at a dose of 4.4 mg per kilogram of body weight.

    If you are assigned to the comparator arm, you will receive a combination of cisplatin (70 mg per square meter), gemcitabine (1000 mg per square meter), and carboplatin (dose 5 as defined by the protocol), each administered by IV infusion.

  4. Step 4

    Repeated Treatment Cycles

    The infusion(s) will be repeated in cycles according to the study schedule. Each cycle includes the same medication(s) and dose as described for the first infusion.

    The exact interval between cycles (for example, every 3 weeks) follows the protocol and will be explained by the study team.

  5. Step 5

    Safety Monitoring During Treatment

    At each treatment visit, you will undergo safety monitoring, which includes laboratory tests (blood counts, kidney and liver function) and evaluation for any adverse events.

    Any side effects that are serious or intolerable may lead to dose adjustments or discontinuation, as determined by the investigators.

  6. Step 6

    Imaging Assessments for Disease Evaluation

    Periodic imaging studies (such as CT or MRI scans) will be performed to assess tumor response.

    These scans help determine whether the disease is stable, improving, or progressing, which is essential for measuring progression‑free survival.

  7. Step 7

    Continuation or Discontinuation of Therapy

    Treatment will continue until one of the following occurs: documented disease progression, occurrence of unacceptable toxicity, or completion of the planned number of cycles.

    If treatment is stopped, you will be informed of the reason and next steps.

  8. Step 8

    Post‑Treatment Follow‑Up

    After discontinuation of the study medication, you will enter a follow‑up period during which additional safety checks and imaging may be performed.

    The follow‑up continues for a defined period to monitor long‑term outcomes and any delayed side effects.

Who can join the trial?

24 criteria

  • Informed consent: Sign the consent form voluntarily and agree to follow the study requirements.
  • Disease progression: Cancer must have gotten worse on imaging scans after the most recent treatment.
  • Toxicity recovery: Any side effects from previous cancer medicines must be back to normal or only mild (grade 1), except mild nerve problems or lab changes that are not a safety risk.
  • Platinum eligibility: Must be able to receive carboplatin or cisplatin with gemcitabine. If platinum chemotherapy was given before, at least 12 months must have passed since the last dose and the cancer must not have progressed or stayed stable for less than 6 months as the best response.
  • Measurable lesion: Have at least one tumor that can be measured on imaging (RECIST criteria). Bone‑only disease is allowed if it has a soft‑tissue part that can be measured. Treated lesions must show growth to be counted. If only one measurable lesion, a scan must be done at least 14 days after any biopsy. If brain metastases are known or suspected, an MRI of the brain (or CT if MRI is not possible) must be done within 28 days before randomization.
  • ECOG performance status: Score of 0 or 1 (fully active or able to walk and do light work).
  • Organ function:
    • Bone marrow: White blood cells (ANC) ≥1.5 × 10⁹/L, platelets ≥100 × 10⁹/L, hemoglobin ≥9.0 g/dL (no transfusions or growth‑factor drugs in the week before screening).
    • Liver: Total bilirubin ≤1.5 × normal; AST and ALT ≤3 × normal if no liver metastases, or ≤5 × normal if liver metastases are present (higher allowed for Gilbert’s syndrome).
    • Kidneys: Creatinine clearance ≥30 mL/min (or ≥60 mL/min if planned to receive cisplatin) using the Cockcroft‑Gault formula.
    • Coagulation: INR ≤1.5 × normal and aPTT ≤1.5 × normal, unless the patient is on blood thinners with levels in the therapeutic range.
    • Childbearing potential: Must use highly effective birth control during the study and for 6 months after the last dose for men or 7 months for women; a second method such as condoms is recommended.
    • Pregnancy test: Must have a negative serum pregnancy test at screening and must not be breastfeeding.
    • Women’s fertility status: Considered able to become pregnant unless permanently sterilized, post‑menopausal (no periods for 12 months at age > 45), or have a follicle‑stimulating hormone (FSH) level >40 mIU/mL confirming menopause.
    • G‑CSF: Must be willing to receive prophylactic G‑CSF (a drug that helps white blood cells recover) with no contraindication.
    • Age: 18 years or older.
    • Life expectancy: Expected to live at least 3 months.
    • Diagnosis: Confirmed metastatic or unresectable transitional cell carcinoma (urothelial cancer) of the bladder, ureter, renal pelvis, or urethra, as shown by pathology.
    • Prior immunotherapy: Cancer must have progressed after treatment with anti‑PD‑1/PD‑L1 therapy, alone or with other systemic therapy.
    • Prior platinum therapy: If platinum chemotherapy was given first, the patient must also have received enfortumab vedotin (EV) before enrollment, unless EV is unavailable or not suitable.
    • FGFR3 status: If the tumor has a FGFR3 genetic alteration and erdafitinib is approved locally, the patient should have received erdafitinib before enrollment (not required if unavailable or contraindicated).
    • Prior treatment lines: No more than two previous lines of systemic chemotherapy or similar treatment for advanced disease (treatments given before count as a line if cancer returned within 12 months after surgery‑related therapy).
    • Enfortumab vedotin/pembrolizumab: Patients who only received these drugs around surgery may still enroll if a repeat of those drugs is not considered standard care by the investigator.
    • Biopsy requirement: Must agree to provide a fresh tumor biopsy or allow use of archived tumor tissue.
    • HER2 expression: Must have HER2 protein level of IHC 1+ to 3+ confirmed by a central laboratory test (a separate consent for this test will be signed).

Who cannot join the trial?

29 criteria

  • No chemotherapy, biological therapy, immunotherapy, radical radiotherapy, targeted therapy, or any other anti‑cancer treatment within 4 weeks (or five drug half‑lives, whichever is shorter) before the first dose; also no major surgery within 4 weeks, no mitomycin or nitrosoureas within 6 weeks, and no phenytoin for at least 14 days before and during the study.
  • No known blood disorders that could affect the bone marrow’s ability to make cells, such as myelodysplastic syndrome, unexplained anemia (low red blood cells), unexplained low platelets, or a history of immune‑related low platelets.
  • No history of serious bleeding or a perforation (hole) in the gastrointestinal tract within the past 6 months.
  • No active autoimmune or inflammatory diseases such as lupus, psoriasis that needs systemic medication, rheumatoid arthritis, or inflammatory bowel disease. Skin conditions that do not need systemic treatment, well‑controlled type 1 diabetes, or hypothyroidism are allowed.
  • No uncontrolled high blood pressure, defined as repeated readings above 150 mmHg systolic or 100 mmHg diastolic despite medication.
  • No past or current non‑infectious lung disease called interstitial lung disease (ILD) or pneumonitis that required steroids, and none that cannot be ruled out by imaging tests.
  • No serious lung problems such as poorly controlled chronic obstructive pulmonary disease (COPD), severe asthma, restrictive lung disease, or pulmonary hypertension within the past 6 months.
  • No stroke or transient ischemic attack (TIA) within the past 6 months.
  • No history of severe allergic reaction (anaphylaxis) to humanized or chimeric antibodies or any component of the study drug.
  • No history of organ transplantation or allogeneic stem‑cell transplantation.
  • No use of systemic glucocorticoids (steroid pills) higher than 10 mg/day of prednisone equivalent, except for certain lung or infusion‑related uses; low‑dose steroids are allowed.
  • No prior treatment with a topoisomerase inhibitor‑based antibody‑drug conjugate (ADC) therapy.
  • People with HIV are excluded unless they have an undetectable viral load, a CD4 count of at least 350 cells/µL, no AIDS‑defining infections in the past year, and have been on stable antiretroviral therapy for at least 4 weeks.
  • Active hepatitis B infection (positive surface antigen) excludes participation; inactive chronic hepatitis B is allowed only if viral load is ≤500 IU/mL, liver enzymes are normal (or only mildly elevated if liver metastases are present), and the person is on antiviral treatment if needed.
  • Active hepatitis C infection (positive antibody with detectable RNA) excludes participation; only those with a negative RNA test are allowed.
  • Active or latent tuberculosis excludes participation.
  • Active infections that need intravenous antibiotics, antivirals, or antifungals (such as severe pneumonia, bloodstream infection, or sepsis) within 2 weeks before the first dose exclude participation; stable oral antibiotics without signs of active infection are allowed.
  • No investigational drug use within 4 weeks before screening.
  • Pregnant, breastfeeding, or planning to become pregnant during the study are excluded.
  • History of a life‑threatening drug allergy (anaphylaxis) to any part of the study drug, including its antibody or linked chemotherapy (e.g., irinotecan).
  • Allergy or hypersensitivity to cisplatin, carboplatin, or gemcitabine (common chemotherapy drugs) excludes participation.
  • Any other condition that the investigator or sponsor believes makes participation unsuitable.
  • Primary brain tumors, active or untreated brain metastases, or cancer spreading to the lining of the brain (carcinomatous meningitis) exclude participation; previously treated brain metastases are allowed if stable.
  • Bladder cancers with small‑cell histology are excluded.
  • Other recent cancers are excluded, except for certain skin cancers, low‑grade prostate cancer, or cancers treated curatively with at least a 3‑year disease‑free interval.
  • Severe heart disease such as symptomatic congestive heart failure grade 2 or higher, New York Heart Association (NYHA) class 2 or higher, recent heart attack, or unstable chest pain within the past 6 months excludes participation.
  • Abnormal heart rhythm measures such as a corrected QT interval (QTcF) >470 ms, complete left bundle branch block, grade 3 atrioventricular block, or any risk factors for Torsades de Pointes (e.g., long QT syndrome, low potassium) exclude participation.
  • Blood clot events (deep vein thrombosis or pulmonary embolism) within the past 6 months exclude participation, unless the clot is stable and the person has been on adequate anticoagulant therapy for at least 3 weeks.
  • Known coagulation (blood‑clotting) disorders such as hemophilia, von Willebrand disease, or other clotting disorders that affect blood clotting exclude participation.
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Investigated drugs

  • Trastuzumab brengitecan

    is an antibody‑drug conjugate designed to find and bind to HER2 proteins that are present on the surface of certain cancer cells. Once attached, it delivers a chemotherapy agent directly into the cancer cell, helping to stop the cell from growing and causing it to die. In this study it is given through an IV infusion.

  • Cisplatin

    is a chemotherapy medicine that contains platinum. It works by damaging the DNA inside cancer cells, which makes it hard for the cells to multiply. It is given by IV infusion and is commonly used for many types of solid tumors.

  • Gemcitabine

    is a chemotherapy drug that stops cancer cells from making new DNA, which slows or stops their growth. It is often used together with other chemotherapy agents and is administered through an IV infusion.

  • Carboplatin

    is another platinum‑based chemotherapy. Like cisplatin, it damages the DNA of cancer cells, but it tends to have a different side‑effect profile that some patients tolerate better. It is also given by IV infusion.

What is already known about the treatment

  • Trastuzumab brengitecan

    This medication is given as an IV infusion after reconstituting a powder for solution. It is an investigational antibody‑drug conjugate that is currently being studied in clinical trials for HER2‑positive metastatic urothelial cancer. The drug works by using an antibody that binds to HER2 on cancer cells and then delivers a chemotherapy payload that blocks DNA replication, leading to cell death. It is classified as a targeted antibody‑drug conjugate therapy.

  • Cisplatin

    Cisplatin is administered by IV infusion of a clear solution. It is a long‑standing, FDA‑approved chemotherapy used for many solid tumors, including bladder and other urothelial cancers. The drug creates strong links between DNA strands, which prevents the cancer cells from copying their DNA and makes them die. It belongs to the class of platinum‑based cytotoxic chemotherapy agents.

  • Gemcitabine

    Gemcitabine is given as an IV infusion of a sterile solution. It is an approved chemotherapeutic drug widely used for cancers such as bladder, pancreatic, and lung cancer. The medication mimics a building block of DNA, gets incorporated into the DNA chain, and stops the cancer cell from making new DNA, causing cell death. It is classified as an antimetabolite, specifically a nucleoside analog.

  • Carboplatin

    Carboplatin is delivered by IV infusion of a ready‑to‑use solution. It is an established, FDA‑approved chemotherapy for a range of solid tumors, including urothelial carcinoma. Like other platinum drugs, it forms bonds with DNA that block the DNA from being copied, which leads to cancer cell death. It is categorized as a platinum‑based cytotoxic chemotherapy agent.

Investigated diseases

Metastatic urothelial carcinoma - A cancer that begins in the lining of the urinary tract, most often in the bladder, and later spreads to distant organs such as lymph nodes, bones, or lungs. The tumor initially grows locally, causing symptoms like blood in the urine or frequent urination. As cancer cells break away, they travel through the bloodstream or lymphatic system to form new growths elsewhere. These secondary tumors can enlarge and affect the function of the organs they invade. The disease often progresses in stages, with each new site of spread adding to the overall burden.
Trial detailsLast updated 8 Nov 2026
Age18+ yearsPhasePhase IIITrial ID2026-527617-29-00Protocol codeBL-M07D1-UC-301Estimated enrolment423 patientsSponsorSystimmune Inc.

sourced from the EU Clinical Trials Register and site verification

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