Urothelial carcinoma requiring radical cystectomy with bilateral pelvic lymph node dissection MedDRA version: 20.0 Level: LLT Classification code 10046714 Term: Urothelial carcinoma bladder System Organ Class: 100000004864
Conditions
Interventions
Product Name: Bintrafusp alfa
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: BINTRAFUSP ALFA
Other descriptive name: M7824
Concentration unit: mg/ml milligram(s)/milli
Sponsors
Queen Mary University of London
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Willing and able to provide written informed consent 2. Ability to comply with the protocol 3. Age = 18 years 4. Histopathologically confirmed urothelial carcinoma (T2-T4aN0-1M0) of the bladder where radical cystectomy with bilateral pelvic lymph node dissection is indicated. Patients with “variant histology” such as micropapillary, plasmocytoid, nested, sarcomatoid, microcystic, squamous and adeno variants of urothelial carcinoma are required to have more than 50% of tumor tissue with transitional cell pattern. 5. Residual disease after TURBT or endoscopy (surgical opinion, cystoscopy or radiological presence). 6. Fit and planned for surgery (according to local guidelines). 7. N0-1 and M0 disease CT or MRI (within 4 weeks of enrolment). Patients with N2 disease on cross sectional imaging are excluded from the study. 8. Representative formalin-fixed paraffin embedded (FFPE) tumour samples with an associated pathology report that are determined to be available and sufficient for central testing. 9. Patients who will not receive neoadjuvant cisplatin based chemotherapy, refuse neoadjuvant cisplatin-based chemotherapy or in whom neoadjuvant cisplatin-based therapy is not appropriate. 10.Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 11.Negative serum pregnancy test within 14 days of Day 1 Cycle 1 for female patients of childbearing potential. 12.Highly effective method of contraception throughout the study until 2 months after the last dose of bintrafusp alfa for female patients of childbearing potential and 4 months after the last dose of bintrafusp alfa for male patients. Refer to section 6.11.1.1 for further details. 13.Adequate haematologic and end-organ function within 4 weeks prior to the first study treatment defined by the following: a. ANC = 1500 cells/µL (without granulocyte colony-stimulating factor support within 14 days prior to Cycle 1, Day 1) b. WBC counts > 2500/µL c. Lymphocyte count = 500/µL d. Platelet count = 100,000/µL (without transfusion within 14 days prior to Cycle 1, Day 1) e. Haemoglobin = 9.0 g/dL (patients may be transfused or receive erythropoietic treatment to meet this criterion). f. AST or ALT, and alkaline phosphatase = 1.5 times the institutional upper limit of normal (ULN) and serum bilirubin = 1.5 times the institutional ULN (patients with known Gilbert disease who have serum bilirubin level = 3 × the institutional ULN may be enrolled). g. INR and aPTT = 1.5 × the institutional ULN. This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose. h. Calculated creatinine clearance = 30 mL/min (Cockcroft-Gault formula) Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 19 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 30
Exclusion criteria
Exclusion criteria: 1. Pregnant and lactating female patients. 2. Major surgical procedure within 4 weeks prior to enrolment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis. 3. Previous intravenous chemotherapy or immune therapy for bladder cancer. 4. Patients with prior allogeneic stem cell or solid organ transplantation. 5. Prior treatment with CD137 agonists, anti-CTLA-4, anti-programmed death-1 (PD-1), or anti-PD-L1 therapeutic antibody or pathway-targeting agents. 6. Has received any prior radiotherapy to the bladder. 7. Patients must not have had oral or intravenous (IV) steroids for 14 days prior to Cycle 1 Day 1. 8. Received therapeutic IV antibiotics within 14 days prior to enrolment. 9. Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study. 10. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin [IL]-2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment. 11. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to enrolment. 12. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results. 13. Malignancies other than urothelial carcinoma of the bladder within 3 years prior to enrolment 14. Severe infections within 4 weeks prior to enrolment. 15. Significant cardiovascular disease. 16. History of idiopathic pulmonary fibrosis. 17. Patients with uncontrolled Type 1 diabetes mellitus. 18. Patients with active hepatitis infection. 19. Positive test for HIV. 20. Patients with active tuberculosis. 21. History of autoimmune disease. 22. History of bleeding diathesis or recent major bleeding events. 23. Has a diagnosis of immunodeficiency. 24. Receiving chronic systemic steroid therapy. 25. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins. 26. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the bintrafusp alfa formulation. 27. Serious non-healing wound/ulcer/bone fracture.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the efficacy of bintrafusp alfa before undergoing radical cystectomy with bilateral pelvic lymph node dissection with respect to pathological complete response rate (pCRR) in patients with T2-T4aN0-1M0 urothelial carcinoma of the bladder;Secondary Objective: 1. To assess the effect of 4 x doses of bintrafusp alfa at 14 day intervals before undergoing surgery on immune parameters (dynamic changes in TGFb, T-effector signatures and CD8 count) in patients with T2-T4aN0-1M0 urothelial carcinoma of the bladder. 2. To evaluate the safety and tolerability of bintrafusp alfa before undergoing surgery. 3. To assess the efficacy of bintrafusp alfa given before undergoing surgery with respect to anti-tumour effects based on DFS. 4. To assess the efficacy of bintrafusp alfa given before undergoing surgery with respect to overall survival (OS).;Primary end point(s): pCRR defined as no microscopic evidence (pT0/Tis/Cis) of residual disease in the bladder based on histological evaluation of the resected bladder specimen collected during radical surgery (post–treatment).;Timepoint(s) of evaluation of this end point: After surgery | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Dynamic changes in TGFb, T-effector signatures and CD8 count measured in tumour samples collected pre- and post-treatment. 2. Incidence, nature and severity of adverse events (AE) graded according to NCI-CTCAE v5.0 collected during treatment and up to 24 weeks post cystectomy. Surgical complications as assessed by the Clavien-Dindo scoring system. 3. DFS defined as time between the date of enrolment to first evidence of relapse based on local investigator assessments or death, whichever occurs first. 4. OS defined as the time between the date of enrolment and death due to any cause.;Timepoint(s) of evaluation of this end point: 1. At the start and the end of treatment. 2 During treatment and up to 24 weeks post surgery. 12 weeks post surgery 3. Until disease progression. 4. Since diagnosis until death | — |
Countries
France, Spain, United Kingdom
Contacts
Public ContactClinical Operations Department
APICES SOLUCIONES S.L
Outcome results
None listed