A Phase 3 Open-Label, Randomized Controlled Trial of T-bren (BL-M07D1) vs. Platinum-based Chemotherapy in Patients with HER2-expressing metastatic urothelial cancer with disease progression on or after anti-PD-(L)1-based therapy

Prior treatment

• Chemotherapy, biological therapy, immunotherapy, radical radiotherapy, targeted therapy (including small molecule inhibitor of tyrosine kinase), and other antitumor therapy within 4 weeks or 5 half-lives (whichever is shorter) prior to the first administration; major surgery within 4 weeks prior to the first administration; mitomycin and nitrosoureas treatment within 6 weeks prior to the first administration; phenytoin will be prohibited at least 14 days prior to the first administration and throughout the trial.
• Prior history of clinically significant bleeding, or perforation of the gastrointestinal tract within 6 months of randomization.
• Participants with active autoimmune diseases and inflammatory diseases, such as systemic lupus erythematosus, psoriasis requiring systemic treatment, rheumatoid arthritis, and inflammatory bowel disease, etc. For autoimmune conditions that are active but stable on systemic therapy, discussion with the medical monitor is required prior to Screening. Participants with skin diseases that do not require systemic treatment (such as vitiligo, psoriasis), well controlled type 1 diabetes, or hypothyroidism are permitted.
• Participants who have a history of noninfectious interstitial lung disease (ILD)/pneumonitis that required treatment with steroids, have current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
• Participants with advanced/clinically significant lung disease (eg, poorly controlled chronic obstructive pulmonary disease or asthma, restrictive lung disease, or pulmonary hypertension) within 6 months prior to randomization.
• Participants with stroke or transient ischemic attack (TIA) within 6 months before Screening.
• Participants who are receiving treatment with systemic glucocorticoids >10 mg/day equivalent of prednisone, except for the treatment of chronic obstructive pulmonary disease, antiemetic, infusion reactions; however, treatment with low dose glucocorticoids (≤10 mg/day equivalent of prednisone) is permitted. The use of topical, inhaled, and locally injected steroids is permitted.
• Participants who have received prior topoisomerase inhibitor-based ADC therapy.
• Participants who have received an investigational agent within 4 weeks prior to Screening.
• Participants with primary tumors in the central nervous system (CNS), active or untreated CNS metastases, or carcinomatous meningitis should be excluded. Participants with previously treated brain metastases may participate provided they are clinically stable at baseline assessment. See SOA for required brain scans.
• Participants with other prior or concurrent malignancies except for basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or carcinoma in situ after adequate resection, low-grade prostate cancer, or other malignancy treated with curative intent with a disease-free interval of at least 3 years. Note: For prostate cancer, localized low-grade prostate cancer after prostatectomy or definitive radiation, or that does not require treatment per investigator’s assessment due to low risk of progression is allowed; any prostate cancer requiring systemic hormonal or chemotherapy treatment is not allowed. Participants with concurrent lowgrade prostate cancer require sponsor’s approval to enroll in the study.
• Subjects with history of severe heart disease, such as symptomatic congestive heart failure (CHF) ≥Grade 2 (CTCAE 6.0), New York Heart Association (NYHA) ≥Grade 2 heart failure, history of myocardial infarction, unstable angina pectoris within 6 months before Screening.
• Participants with a thromboembolic event (eg, deep vein thrombosis [DVT] or pulmonary embolism) within 6 months before Screening except for those who are clinically stable and receiving treatment with adequate anticoagulant therapy for at least 3 weeks before Screening.

Other illness

• Participants with known hematologic conditions that may affect bone marrow reserve, including but not limited to myelodysplastic syndrome, unexplained anemia, unexplained thrombocytopenia, or a history of immune thrombocytopenia.
• Participants with poorly controlled hypertension defined by recurrent or persistent readings of systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg despite antihypertensive treatment.
• Participants who have a history of anaphylaxis or severe hypersensitivity to recombinant humanized antibodies or human-mouse chimeric antibodies or any of the components of T-bren.
• Participants who have a history of being a recipient of organ transplantation or allogeneic hematopoietic stem cell transplantation.
• Participants with active hepatitis C virus (HCV) infection (HCV antibody positive and HCV RNA >the lower limit of detection). Participants with a positive anti-HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• Participants with active or latent tuberculosis.
• History of any life-threatening drug allergy (such as anaphylaxis) including history of an anaphylactic reaction to any component (eg, excipients of T-bren or related compounds), including the antibody and conjugated payload (Ed-04) or related compounds (eg, irinotecan or other topoisomerase inhibitors).
• History of allergy or hypersensitivity to cisplatin, carboplatin, or gemcitabine or related compounds.
• Participants with other conditions that the investigator or sponsor believes are not suitable for participating in this clinical trial.
• Participants with bladder cancers with small cell histology are excluded.
• Participants with known coagulation disorders, including hemophilia, von Willebrand disease, or any other coagulation disorders, that may affect blood clotting.

Lab values

• Participants with known human immunodeficiency virus infection (antibody [HIVAb] positive). Participants are allowed to participate if all of the following criteria are met: (1) Undetectable HIV RNA and CD4 count ≥350 cells/μL at Screening, (2) No AIDS defining opportunistic infection within 12 months prior to Screening, (3) On stable antiretroviral therapy (ART) for at least 4 weeks prior to Screening with projected continuation of ART as clinically indicated while on the study.
• Participants with active hepatitis B virus (HBV) infection (positive hepatitis B surface antigen [HBsAg] test). Participants with chronic inactive HBV infection are eligible if they meet all of the following criteria: 1. Have HBV DNA viral load ≤500 IU/mL 2. Have a normal AST and ALT, OR if liver metastasis is present, has AST and ALT < 3 × ULN which are not attributed to HBV infection 3. Are on antiviral treatment, as clinically indicated.
• Participants with active infections requiring IV antibiotic, antiviral, or antifungal treatment, such as severe pneumonia, bacteremia, sepsis, etc., within 2 weeks prior to first dose of study treatment. Participants on stable oral antimicrobials with no clinical or laboratory evidence of active infection are eligible.
• Participants with corrected QT interval using Fridericia’s formula (QTcF) >470 msec, complete left bundle branch block, Grade 3 atrioventricular block, or a history of additional risk factors for Torsades de Pointes (TdP), eg, symptomatic heart failure, chronic or recurrent hypokalemia that requires medical intervention, congenital long QT syndrome, family history of long QT syndrome.

Other

• Participants who are pregnant, breastfeeding, or planning to become pregnant during the study.

• Signed the informed consent form voluntarily and agreed to follow the trial requirements
• Radiographically documented disease progression on or after receiving the most recent therapy.
• Any toxicity from prior antineoplastic therapy has returned to baseline or Grade ≤1 defined by NCI-Common Terminology Criteria for Adverse Events (CTCAE) v6.0 (except for Grade 2 neuropathy or asymptomatic laboratory abnormalities and toxicities that the investigator determines to have no safety risk, for example: alopecia).
• Must be eligible to receive carboplatin or cisplatin in combination with gemcitabine. For participants who have received prior PBC to be considered eligible, participants must have a platinum-free interval of at least 12 months from the last dose of platinum therapy and must not have progressive disease or stable disease of less than 6 months as the best overall response on prior PBC.
• At least 1 measurable lesion based on RECIST v1.1. a. Bone-only disease is allowed provided it is measurable (ie, with a soft tissue component). b. Lesions that have been treated with radiotherapy must show evidence of disease progression based on RECIST v1.1 to be deemed a target lesion. c. If there is only 1 measurable lesion, if a biopsy is performed on that lesion, baseline imaging should be performed at least 14 days after the biopsy. d. Participants must have an MRI of the brain within 28 days prior to randomization if they have known or suspected brain metastases. A computed tomography (CT) scan can be used if there is a contraindication to an MRI such as a pacemaker.
• An Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1.
• Adequate organ function, before enrollment defined as: a. Marrow function: Absolute neutrophil count (ANC) ≥1.5×109/L, platelet count ≥100×109/L, hemoglobin (Hb) ≥9.0 g/dL (blood transfusion, platelet transfusion, erythropoietin [EPO], hematopoiesis agents such as thrombopoietin [TPO], and G-CSF use are not allowed 1 week prior to Screening]) b. Hepatic function: Total bilirubin (TBIL) ≤1.5×upper limit of normal (ULN);, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) without liver metastasis ≤3.0×ULN, AST and ALT with liver metastasis ≤5.0×ULN. NOTE: For participants with Gilbert’s syndrome, TBIL <3.0×ULN. c. Renal function: Creatinine clearance (CrCl) ≥30 mL/min (Cockcroft-Gault equation) (or ≥60 mL/min for those participants projected to receive cisplatin) . NOTE: For the Cockcroft-Gault formula Female CrCl= ([140-age in years] × weight in kg ×0.85) / (72 × serum creatinine in mg/dL). Male CrCl= ([140-age in years] × weight in kg ×1.00) / (72 × serum creatinine in mg/dL) NOTE: If CrCl is less than the limits specified above by the Cockcroft-Gault formula, then the site may consider a 24-hour urine collection to further reassess eligibility. If the 24-hour measured CrCl is greater than the limits specified above by the Cockcroft-Gault formula, then enrollment is permitted. NOTE: Participants with prior significant pre-existing hearing impairment, significant audiometric abnormalities or peripheral neuropathy are contraindicated for cisplatin-based therapy but may be eligible for carboplatin-based therapy.
• Coagulation parameters: International normalized ratio (INR) ≤1.5×ULN and activated partial thromboplastin time (aPTT) ≤1.5×ULN, unless receiving anticoagulation therapy with prothrombin time (PT) and aPTT levels within the intended therapeutic range.
• Individuals of childbearing potential (IOCBP) include sexually active fertile participants and their partners. IOCBP must agree to use highly effective methods of contraception during the course of the study and for 6 months for men and 7 months for women after the last dose of study treatment. An additional contraceptive method, such as a barrier method (eg, condom), is recommended.
• IOCBP must have a negative serum pregnancy test at Screening and must be nonlactating. Female participants are considered IOCBP unless one of the following criteria are met: documented permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman >45 years old in the absence of other biological or physiological causes). In addition, females <55 years old must have a serum follicle stimulating hormone (FSH) level >40 mIU/mL to confirm menopause.
• Participants must be willing to receive prophylactic G-CSF with no contraindication during their time on study. NOTE: Documentation may include review of medical records, medical examination, or medical history interview by study site staff.
• Age ≥18 years
• Life expectancy of ≥3 months
• Histologically or cytologically documented metastatic or surgically unresectable transitional cell carcinoma (TCC) of the urothelium involving the renal pelvis, ureter, bladder, or urethra. Minor histologic variants (ie, <50% overall) are acceptable, provided that TCC is the dominant histology
• Prior anticancer therapy: a. Participants must have disease progression or recurrence on or following treatment with anti-programmed cell death protein 1/programmed death-ligand 1 (anti-PD-[L]1-based therapy) in any setting, either in combination with or sequential to another systemic therapy (eg, PBC, ADC). b. If a participant has received PBC in the frontline, the participant must have received EV prior to enrolling in the study, if EV is approved and accessible as an SoC in the country/ region, unless there is a contraindication. c. For participants previously treated with platinum-based chemotherapy (including in the perioperative setting) and a checkpoint inhibitor, FGFR3 genetic alteration status is required from an available test result or by testing for it before enrollment, in countries or regions where erdafitinib is approved and accessible as a standard of care. For participants with a FGFR3 sensitizing genetic alteration, erdafitinib is recommended, but not required, prior to enrollment, if erdafitinib is approved and accessible as a SoC in the country/ region, unless there is a contraindication.
• Participants should have no more than 2 prior lines of systemic cytotoxic therapy (eg, ADC, chemotherapy) in the advanced or metastatic setting. Peri-operative systemic therapy counts as a line of therapy if disease progression occurred within 12 months of completing the therapy.
• Participants relapsed after treatment with only peri-operative enfortumab vedotin/ pembrolizumab would be allowed if re-treatment with enfortumab vedotin/ pembrolizumab is not considered SoC per investigator’s assessment or local guideline.
• Participant agrees to provide fresh biopsy or archival tumor samples.
• Documented HER2 expression (IHC 1+ to 3+) by central laboratory testing. Note: A separate informed consent for pre-screening for HER2 expression by central laboratory testing will be signed.