Avelumab for Urothelial carcinoma

Inclusion criteria

• {"criterion_text":"- 1.\tWilling and able to provide written informed consent."}
• {"criterion_text":"- 10.\tAgreement to use adequate contraceptive measures (Refer to section 11.30 for full details)."}
• {"criterion_text":"- FRANCE SPECIFIC CRITERIA: 11.\tPatients affiliated to the social security system."}
• {"criterion_text":"- 2.\tAbility to comply with the protocol, including but not limited to, the repeated completion of the EORTC QLQ-C30 questionnaires."}
• {"criterion_text":"- 3.\tAge ≥ 18 years."}
• {"criterion_text":"- 4.\tHistologically confirmed, unresectable locally advanced or metastatic urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Patients with squamous or sarcomatoid differentiation or mixed cell types are eligible but a component of urothelial cancer is required."}
• {"criterion_text":"- 5.\tMeasurable disease by RECIST v1.1."}
• {"criterion_text":"- 6.\tEligible for gemcitabine/ cisplatin or gemcitabine/carboplatin. Patients meeting any of the following criteria or considered ineligible for cisplatin as per investigator discretion, should be considered for gemcitabine/carboplatin (as per local standard practice): a.\tGFR <60 mL/min (measured by the Cockcroft-Gault formula or by local accepted standards). Subjects with a GFR ≥50 mL/min and no other cisplatin ineligibility criteria may be considered cisplatin-eligible based on the investigator’s clinical judgement. Subjects are required to have a GFR ≥30 mL/min (measured by the Cockcroft-Gault formula or by local accepted standards) to receive carboplatin. b.\tECOG or WHO performance status of 2. c.\tNCI CTCAE Grade ≥2 audiometric hearing loss. d.\tNYHA Class III heart failure."}
• {"criterion_text":"- 7.\tEastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2."}
• {"criterion_text":"- 8.\tAdequate haematologic and organ function as defined below: a.\tHaemoglobin ≥ 9.0g/dL b.\tAbsolute neutrophil count (ANC) ≥1.5 x 109/L (≥1500/μL) without growth factor support c.\tPlatelet count ≥ 100 x 109 /L (≥100,000/μL) d.\tTotal serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (this will not apply to subjects with confirmed Gilbert’s syndrome [persistent or recurrent hyperbilirubinaemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology], who will be allowed only in consultation with their physician. e.\tSerum transaminases (AST/ALT) ≤ 2.5 x the institutional ULN with the following exception in patients with documented liver metastases: AST and/or ALT ≤5 × ULN f.\tGFR ≥30mL/min measured by Cockcroft-Gault formula, or locally accepted standards."}
• {"criterion_text":"- 9.\tNegative serum or urine pregnancy test within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential only. Non-childbearing potential is defined as either: a.\tPostmenopausal ≥ 50 years of age and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments OR b.\tDocumented irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation OR c.\t<50 years of age who have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels within local institution postmenopausal ranges"}

Exclusion criteria

• {"criterion_text":"- 1.\tPrior treatment with a PD-(L)-1 inhibitor for any advanced malignancy. Treatment with PD-(L)-1 inhibitors in the neoadjuvant or adjuvant setting for UC are permitted."}
• {"criterion_text":"- 10.\tMalignancies other than urothelial carcinoma within 3 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason score ≤ 3 + 4 and PSA < 10 ng/mL undergoing active surveillance and treatment naive)."}
• {"criterion_text":"- 11.\tSignificant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction or cerebral vascular accident/stroke within 6 months prior to enrolment, unstable arrhythmias, or unstable angina."}
• {"criterion_text":"- 12.\tRadiotherapy within 2 weeks prior to C1D1. Patients must have recovered adequately from toxicities resulting from the intervention prior to starting study treatment."}
• {"criterion_text":"- 13.\tMajor surgery (defined as requiring general anaesthesia and >24-hour inpatient hospitalization) within 4 weeks prior to randomisation. Patients must have recovered adequately from complications from the intervention prior to starting study treatment."}
• {"criterion_text":"- 14.\tHistory of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan (History of radiation pneumonitis in the radiation field (fibrosis) is permitted)."}
• {"criterion_text":"- 15.\tActive hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible."}
• {"criterion_text":"- 16.\tPositive HIV test."}
• {"criterion_text":"- 17.\tActive tuberculosis."}
• {"criterion_text":"- 18.\tActive autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis."}
• {"criterion_text":"- 19.\tHistory of autoimmune-related hypothyroidism, unless on a stable dose of thyroid replacement hormone."}
• {"criterion_text":"- 2.\tPrior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions: a platinum containing regimen (cisplatin or carboplatin) in the neoadjuvant or adjuvant setting if more than 6 months since last cycle have occurred. Patients who received adjuvant or neoadjuvant immune therapy for muscle invasive or non-muscle invasive disease are eligible."}
• {"criterion_text":"- 20.\tHistory of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies."}
• {"criterion_text":"- 21.\tKnown hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of avelumab."}
• {"criterion_text":"- 22.\tActive infection requiring systemic therapy."}
• {"criterion_text":"- 23.\tPersisting toxicity related to prior therapy (NCI CTCAE Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator’s judgment are acceptable."}
• {"criterion_text":"- 24.\tAny condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results"}
• {"criterion_text":"- 25.\tParticipants with previous or known history of allergic reaction to cisplatin, gemcitabine, carboplatin or other platinum containing compounds, or any component of the chemotherapy formulations."}
• {"criterion_text":"- 26.\tPatients with bleeding tumours"}
• {"criterion_text":"- 27.\tAny other contraindication for gemcitabine/ cisplatin or gemcitabine/carboplatin treatment as per SmPC."}
• {"criterion_text":"- France Specific Criteria: 28.\tPerson deprived of their liberty or under protective custody or guardianship."}
• {"criterion_text":"- 3.\tPregnant and lactating female patients."}
• {"criterion_text":"- 4.\tKnown history of active CNS metastases. Patients with treated CNS metastases are permitted on the study if all of the following are true: a.\tCNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis; b.\tthe subject is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks prior to C1D1 (if requiring steroid treatment); c.\tsubject does not have leptomeningeal disease."}
• {"criterion_text":"- 5.\tPrior allogeneic stem cell or solid organ transplantation."}
• {"criterion_text":"- 6.\tAdministration 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."}
• {"criterion_text":"- 7.\tTreatment 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 (see section 11.26)."}
• {"criterion_text":"- 8.\tConcurrent treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to enrolment."}
• {"criterion_text":"- 9.\tEvidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome)."}

Primary endpoints

• {"endpoint_text":"- Change in GHS/QoL scale scores from baseline to completion of 6 cycles of treatment. Patients who withdraw from treatment between Cycles 4 and 6 will be included, provided an EORTC QLQ-C30 questionnaire is completed within 14 days from the date of withdrawal.","definition_or_measurement_approach":"Measured as change in Global Health Status/Quality of Life (GHS/QoL) scale scores using the EORTC QLQ-C30 from baseline to completion of 6 cycles; includes patients who withdraw between Cycles 4 and 6 if an EORTC QLQ-C30 is completed within 14 days of withdrawal."}

Secondary endpoints

• {"endpoint_text":"- \tQuality of Life assessment from baseline to the completion of 10 Cycles of treatment using the GHS/QOL scale score, as per the primary endpoint methodology.","definition_or_measurement_approach":"GHS/QoL measured by EORTC QLQ-C30 from baseline to completion of 10 cycles using the same methodology as primary endpoint."}
• {"endpoint_text":"- \tQuality of Life assessment from the beginning of cycle 5 to the completion of 10 Cycles of treatment using the GHS/QOL scale score, as per the primary endpoint methodology.","definition_or_measurement_approach":"GHS/QoL measured by EORTC QLQ-C30 from cycle 5 start to completion of 10 cycles as per primary methodology."}
• {"endpoint_text":"- \tChange in GHS/QOL scale scores from baseline to the end of assessment (wk54), as per the primary endpoint methodology.","definition_or_measurement_approach":"Change in GHS/QoL by EORTC QLQ-C30 from baseline to week 54 (end of assessment) using primary endpoint methodology."}
• {"endpoint_text":"- \tGHS/QoL scale score time to deterioration (TTD), where deterioration in the GHS/QoL scale score is defined as a decrease by ≥10 points at any time point after baseline with no subsequent observations with a <10 point decrease from baseline.","definition_or_measurement_approach":"Time to deterioration defined as first occurrence of ≥ 10-point decrease in GHS/QoL from baseline with no subsequent improvement (<10-point decrease)."}
• {"endpoint_text":"- \tChange in the GHS/QOL scale score from baseline as per the primary endpoint, but adjusted for baseline imbalances in GHS/QOL scale scores.","definition_or_measurement_approach":"Adjusted change in GHS/QoL from baseline accounting for baseline imbalances."}
• {"endpoint_text":"- Performance status as measured by the Karnofsky Scale on completion of 6 cycles of treatment.","definition_or_measurement_approach":"Karnofsky Performance Status measured at completion of 6 cycles."}
• {"endpoint_text":"- \tIncidence, nature and severity of adverse events graded according to NCI-CTCAE v5.0 at the following timepoints: o\tThroughout treatment o\tOn completion of Cycle 6 of treatment o\tBetween Cycle 4 and the completion of Cycle 10. •\tTreatment discontinuation rate due to AEs.","definition_or_measurement_approach":"Safety assessed by incidence, nature and severity of AEs per NCI-CTCAE v5.0 at specified timepoints; also treatment discontinuation rate due to AEs."}
• {"endpoint_text":"- Overall response rate in each randomised treatment arm defined as the proportion of patients who achieved complete response (CR) or partial response (PR) according to RECIST v1.1 recorded from randomisation until week 20. (investigator assessed unconfirmed best response)","definition_or_measurement_approach":"ORR per RECIST v1.1 (CR or PR) from randomisation until week 20 (investigator-assessed, unconfirmed)."}
• {"endpoint_text":"- Progression free survival rate at 20 weeks post randomisation (PFS rate) in each treatment arm defined as the proportion of patients who did not experience disease progression or death from any cause according to RECIST v1.1 recorded from randomisation until week 20.","definition_or_measurement_approach":"PFS rate at 20 weeks: proportion without progression or death per RECIST v1.1 from randomisation to week 20."}
• {"endpoint_text":"- Duration of response defined as the time from first documentation of CR or PR to disease progression (RECIST v1.1) or death from any cause, whichever occurs first.","definition_or_measurement_approach":"Time from first documented CR/PR to progression (RECIST v1.1) or death."}
• {"endpoint_text":"- Overall survival (OS), defined as the time between the date of randomisation and death due to any cause.","definition_or_measurement_approach":"Time from randomisation to death from any cause."}

France

Earliest CTIS Part Ii Submission Date

22-11-2024

Latest Decision Or Authorization Date

19-06-2025

Processing Time Days

209

Number Of Sites

12

Number Of Participants

35

Spain

Earliest CTIS Part Ii Submission Date

22-11-2024

Latest Decision Or Authorization Date

20-11-2025

Processing Time Days

363

Number Of Sites

19

Number Of Participants

158

Primary sponsor

Full Name

Queen Mary University Of London

Organisation Type

Educational Institution

Country Of Registered Address

United Kingdom

Third parties

• {"country":"","full_name":"Merck Healthcare KGaA","duties_or_roles":"Source of monetary support","organisation_type":"Pharmaceutical company"}