The study aims to evaluate the activity of cisplatin based neoadjuvant chemotherapy compared with the combination of durvalumab and tremelimumab to T2-T4a bladder cancer patients according to the pro-inflammatory signature. MedDRA version: 20.0 Level: PT Classification code 10005003 Term: Bladder cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Fundación CRIS contra el cancer
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1 Male and female subjects; age = 18 years at the time of study entry. 2 Subjects must provide written informed consent prior to performance of any protocol-related procedures, including screening evaluations and must be willing to comply with treatment and follow up. Informed consent may be obtained prior to start of the 28-day screening window. 3 Subjects must have histologic documentation of transitional cell carcinoma of the urothelium (including the urinary bladder, ureter, urethra and renal pelvis) of the urinary tract (cystoscopy and biopsy or positive cytology). 4 Patients must have confirmed cT2-T4 N0-1 M0 (TNM classification). 5 Archival tumour samples for biomarker research in formalin-fixed and paraffin-embedded blocks. 6 Body weight >30kg 7 ECOG performance status of 0 or 1. 8 Life expectancy of at least 12 weeks 9 Absolute neutrophil count (ANC) = 1500/mm3 (= 1.5 GI/L); Platelets =100,000/mm3 (= 100 GI/L); Hemoglobin = 9 g/dL (= 90 g/L) 10 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =2.5 x upper limit of normal unless liver metastases are present, in which case it must be =5x ULN; Total bilirubin = 1.5 × the upper limit of normal. For subjects with Gilbert’s disease = 3 mg/dL (= 51.3 µmol/L). 11 Calculated CrCl or 24-hour urine CrCl>40 mL/min or Calculated creatinine clearance CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance 12 Fasting serum triglycerides = 2.5 × upper limit of normal AND total cholesterol = 300 mg/dL (= 7.75 mmol/L). Lipid-lowering medication is allowed. 13 HbA1c = 8%. 14 Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. 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 40 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 59
Exclusion criteria
Exclusion criteria: 1 Histology of pure adenocarcinoma, pure squamous cell carcinoma, or predominant small cell carcinoma or sarcomatoid features in the tumor sample. 2 Evidence of any metastatic lesion outside the primary tumour site identified in the radiological evaluation. 3 Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. . The following are exceptions to this criterion: -Intranasal,- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent -Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication). 4 Previous therapy with PD-1, PD-L1 or CTLA-4 inhibitors, including durvalumab and tremelimumab. 5 Any concurrent chemotherapy, IMT, or biologic or hormonal therapy for cancer treatment. Concurrent use of hormones for non-cancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable. 6 History of severe allergic reactions to any unknown allergens or any components of the study drug formulations. 7 Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease diverticulitis , systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome. 8 Major surgery within 4 weeks of study randomization. 9 Prior high-dose chemotherapy requiring hematopoietic stem cell rescue. 10 Prior radiation therapy to >25% of the bone marrow. 11 Current treatment on another clinical trial. 12 Diagnosis of any second malignancy within the last 3 years, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix. 13 Any of the following within the 12 months prior to starting study treatment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, cerebrovascular accident including transient ischemic attack, or pulmonary embolus. 14 Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) 15 Any unresolved toxicity NCI CTCAE Grade =2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria 16 Hypertension that cannot be controlled by medications 17 Current treatment with therapeutic doses of Coumadin (low dose Coumadin up to 2 mg PO daily for deep vein thrombosis prophylaxis is allowed). 18 History of active primary immunodeficiency 19 Active infection including tuberculosis, hepatitis B surface antigen (HBsAg), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 20 Known positive for human immunodeficiency virus (HIV), chronic or active hepatitis B or C or active hepatitis A. 21 Receipt of live, attenuated vaccine within 30 days prior to the first dose of investigational products (NOTE: Subjects, if enrolled, should not receive live vaccine during the study and 30 days after the last dose of investigational products). 22 Pregnancy or breastfeeding. 23 Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administrat
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the antitumor activity measured as pT0 rate of durvalumab plus tremelimumab in comparison with the activity shown by standard chemo-based approach in selected patients with locally advanced urothelial bladder tumors with a pro-inflammatory composite biomarker selection.;Secondary Objective: - To assess the antitumor activity measured as pT0 rate of standard chemo-based approach in selected patients with locally advanced urothelial tumors lacking a pro-inflammatory composite biomarker. - To assess the difference in Objective Response Rate according to RECIST v1.1 criteria. - To assess the difference in Disease Free Survival of durvalumab plus tremelimumab in comparison with standard chemo-based approach in selected patients with locally advanced urothelial bladder cancer tumors with a pro-inflammatory composite biomarker selection. - To assess the difference in Overall Survival of durvalumab plus tremelimumab in comparison with standard chemo-based approach in selected patients with locally advanced urothelial bladder cancer tumors with a pro-inflammatory composite biomarker selection. - To compare the toxicity among patients treated with durvalumab plus tremelimumab in comparison with those treated with standard chemo-based approach.;Primary end point(s): - No evidence of residual disease based on pathological review of the surgical specimen;Timepoint(s) of evaluation of this end point: At the cystectomy | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - pT0 rate - Percentage of patients in whom a complete response (CR) or a partial response (PR) according to RECIST criteria is confirmed - Disease Free Survival measured from the start of treatment with durvalumab and tremelimumab or cisplatin-based chemotherapy until the documentation of disease recurrence according to RECIST v1.1 or death due to any cause, whichever occurs first - OS will be measured as the time from the start of treatment with the combination of durvalumab and tremelimumab or cisplatin-based chemotherapy until death due to any cause. - Safety will be assessed on the basis of the reports of adverse events, the frequency of discontinuation of treatment due to adverse events, analytical or ECG assessments;Timepoint(s) of evaluation of this end point: - At cystectomy - At 12 weeks of treatment - every 12 weeks - every 12 weeks - every 4 weeks | — |
Countries
Spain
Contacts
Public ContactClinical Operations Department
APICES SOLUCIONES S.L.
Outcome results
None listed