Maintenance treatment in patients with locally advanced/metastatic urothelial carcinoma. MedDRA version: 21.0 Level: LLT Classification code 10046721 Term: Urothelial carcinoma bladder stage III System Organ Class: 100000004864 MedDRA version: 21.0 Level: LLT Classification code 10046722 Term: Urothelial carcinoma bladder stage IV System Organ Class: 100000004864
Conditions
Interventions
Trade Name: BAVENCIO
Product Name: Avelumab
Product Code: MSB0010718C
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: AVELUMAB
CAS Number: 1537032-82
Current Sponsor co
Sponsors
Centre François Baclesse
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Patient =18 years at the day of consenting to the study - Provision of informed consent prior to any study specific procedures - Histologically confirmed diagnosis of urothelial carcinoma of the renal pelvis, ureter (upper urinary tract), bladder or urethra. Both transitional cell and mixed transitional/non-transitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology. - Documented Stage IV disease (T4b, N0, M0; any T, N1–N3, M0; any T, any N, M1) not candidate to a curative treatment with surgery or radiotherapy at the start of first-line platinum-based chemotherapy. - Patient must have completed prior to inclusion a platinum-based (cisplatin or carboplatin) polychemotherapy for at least 4 cycles of chemotherapy (until 6 cycles maximum) and have a stable disease or a partial response (PR) or a complete response (CR) from the chemotherapy according to RECIST 1.1 criteria - A minimum dose of 55 mg/m² of cisplatin is required in order to count for 1 cycle. - A minimum dose of carboplatin AUC 4.5 is required in order to count for 1 cycle - Eligibility based on this criterion will be established locally by the investigator by examining pre and post-chemotherapy radiological assessments (CT/MRI) - Neoadjuvant or adjuvant chemotherapy is allowed (with a delay of at least 12 months between the last dose of neoadjuvant or adjuvant chemotherapy and the relapse) - Patient must be enrolled within 8 weeks after the last dose of chemotherapy. - Eastern Cooperative Oncology Group (ECOG) performance status = 2; - Normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below: -Hemoglobin = 10.0 g/dL (patient may have been transfused before inclusion) - Absolute neutrophil count (ANC) =1.5 x 109/L -Platelet count =100 G/l - Total bilirubin =1.5 x institutional upper limit of normal (ULN) -Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) =2.5 x ULN unless liver metastases are present in which case they must be =5x ULN -Patient must have creatinine clearance estimated using the CKD equation of = 40 mL/min - Able to swallow and retain oral drug - Life expectancy > 12 weeks - Serum pregnancy test (for females of childbearing potential) negative at screening - Male patient able to father children and female patient of childbearing potential and at risk for pregnancy must agree to use 2 highly effective methods of contraception throughout the study and for at least 60 days after the last dose of treatments -Patient affiliated to a French Social Security System or a beneficiary of such a system - Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations - Optional: provision of a recent formalin-fixed, paraffin-embedded (FFPE) tumor tissue block (or subsection thereof) from the most recent primary or metastatic tumor biopsy 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 50 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 50
Exclusion criteria
Exclusion criteria: -Patient who has never received chemotherapy with a platinum salt (cisplatin or carboplatin) for advanced/metastatic urothelial carcinoma -Patient who has previously received more than one line of chemotherapy for advanced/metastatic urothelial carcinoma -Patient whose disease has progressed according to RECIST v1.1 criteria after the first line platinum-based chemotherapy for urothelial carcinoma. The cancer must not be in the progression phase at inclusion -Patient with known CNS metastases and/or carcinomatous meningitis -Other malignancy within the last 3 years except: adequately treated non-melanoma, skin cancer curatively treated, in situ cancer of the cervix, ductal carcinoma in situ (DCIS), localized prostate carcinoma without PSA relapse -Patient with myelodysplastic syndrome/acute myeloid leukemia history or with features suggestive of MDS/AML -Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patient with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) are allowed.Current treatment with an immunosuppressant medicinal product or treatment within 7 days prior to inclusion, EXCEPT: oIntra-nasal, inhaled or local steroids or local steroid injections (such as intra-articular injections) oSystemic corticosteroids at physiological doses of = 10 mg/day of prednisone or equivalent oSteroids as premedication for hypersensitivity reactions (such as CT scan premedication) -Major surgery within 4 weeks or major radiotherapy within to starting experimental treatment. Previous palliative radiotherapy (= 10 fractions) for metastatic lesions is permitted provided that this has been completed at least one week prior to starting Talazoparib and Avelumab -Active viral infection (HIV, Hepatitis B/C) or known history of positive test for HIV -Any previous treatment with PARP inhibitor or any immunotherapy (e.g. anti-CTLA-4 or anti-PDL1/ PD1) -Concomitant treatment with any drug on the prohibited medication list such as live vaccines, concomitant use of strong P-gp inhibitors (cf section “Prohibited concomitant treatments”) or systemic corticoids at dose > 10 mg/day prednisone or equivalent. Live vaccines administered more than 30 days before study entry are permitted - Clinically significant (e.g. active) cardiovascular disease cerebral vascular accident/stroke in the 3 months prior to enrollment: myocardial infarction, severe/unstable angina, symptomatic congestive heart failure (= New York Heart Association Classification Class II), serious cardiac arrhythmia requiring medication, uncontrolled high blood pressure, cerebrovascular accident, transient ischaemic attack -Patient considered at poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease or any psychiatric disorder that prohibits obtaining informed consent -Pulmonary embolism or deep vein thrombosis within 3 months prior to inclusion (unless if stable, asymptomatic and treated with a low molecular heparin for at lea
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine the efficacy of a maintenance treatment combining Talazoparib and Avelumab after platinum-based chemotherapy in patients with locally advanced/metastatic urothelial carcinoma. Efficacy will be evaluated through progression-free survival (PFS). ;Secondary Objective: To determine the safety profile of Talazoparib plus Avelumab in maintenance treatment of urothelial carcinoma To assess the efficacy of the combination, for whole study population, and according to the response to the initial chemotherapy, through: •Overall Survival •Duration of tumoral response •Objective response rate •Disease control rate •Duration of treatment by Talazoparib plus Avelumab taken together and separately •Time to subsequent therapy (TST) To assess Quality of life (QoL) of patients under Talazoparib plus Avelumab treatment (time to QoL deterioration TTD) To constitute a blood and tumor banking for further ancillary biological explorations. These translational researches may include the determination of the patients’ and disease’s characteristics of tumors according to the alteration of genes involved in DNA repair HRD and PD-L1 status. ;Primary end point(s): Progression-Free Survival (PFS) defined as the time from initiation of Talazoparib plus Avelumab treatment to the first documented disease progression per RECIST 1.1 criteria based on investigator’s assessment, or death due to any cause, whichever occurs first.;Timepoint(s) of evaluation of this end point: Progression of disease | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Toxicities of the combination of Avelumab plus Talazoparib according to NCI CTCAE v 5.0 criteria • Overall survival defined as the time from talazoparib + avelumab initiation to death whatever cause. • Duration of tumoral response defined as the time elapsed between first date of objective response (complete or partial response) and date of first documented disease progression according to RECIST 1.1 criteria or date of death, due to any cause, whichever occurs first. • Proportion of patients with partial or complete response, according to RECIST 1.1 criteria • Proportion of patients with stable disease, partial or complete response, according to RECIST 1.1 criteria • Duration of treatment defined as the time elapsed between the first dose of treatment and the date of permanent discontinuation of Talazoparib and/or Avelumab regardless of cause. Patients still on treatment with any study drug at the time of database lock will be censored • Time elapsed between the date of initiation of Talazoparib plus Avelumab and the date of initiation of subsequent systemic therapy, respectively. Patients who did not receive any subsequent treatment or who have died prior to receiving subsequent treatment will be censored • Scores of quality of life assessed through the French version of the self-administered standardized questionnaire EORTC QLQ-C30 and EUROQOL EQ-5D • Survival without deterioration in QoL as assessed using the QLQ-C30 questionnaire and defined as the time interval between the date of initiation of Talazoparib plus Avelumab treatment and date of the first deterioration. Deterioration from baseline is defined as a “minimal clinically important difference” (MCID) of > 10-point out of 100. Deterioration will be considered in = 1 of the following dimensions: global health-related QoL, and fatigue, without significant clinical improvement subsequently or death, regardless of cause. ;Timepoint(s) of evaluation of this end point: - su | — |
Countries
France
Contacts
Public ContactElodie COQUAN
Centre François Baclesse
Outcome results
None listed