| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable locally advanced or metastatic urothelial carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer in the cells that line the bladder or metastatic bladder cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10046714 |
| E.1.2 | Term | Urothelial carcinoma bladder |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the effect of 3 vs 6 cycles platinum-based, front line chemotherapy followed by maintenance avelumab based on patient-reported outcomes (PROs) in the study population. |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the effect of 3 vs 6 cycles platinum-based, front line chemotherapy followed by maintenance avelumab based on additional patient-reported outcomes (PROs) in the study population.
2. To evaluate the effect of 3 vs 6 cycles platinum-based, front line chemotherapy followed by maintenance avelumab based on clinician reported outcomes.
3. To evaluate the safety and tolerability of 3 vs 6 cycles of platinum-based, front line chemotherapy followed by maintenance avelumab therapy.
4. To assess the efficacy of 3 vs 6 cycles platinum based, front line chemotherapy followed by maintenance avelumab in patients with advanced UC.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Willing and able to provide written informed consent.
2. Ability to comply with the protocol, including but not limited to, the repeated completion of the EORTC QLQ-C30 questionnaires.
3. Age ≥ 18 years.
4. Histologically 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.
5. Measurable disease by RECIST v1.1.
6. Eligible for gemcitabine/ cisplatin or gemcitabine/carboplatin. The following criteria are established for the use of carboplatin (patients not fulfilling the following carboplatin criteria should be considered for gemcitabine/ cisplatin):
a. GFR <60 mL/min but ≥30 mL/min (measured by the Cockcroft-Gault formula. 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.
b. ECOG or WHO performance status of 2.
c. NCI CTCAE Grade ≥2 audiometric hearing loss.
d. NYHA Class III heart failure.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2.
8. Adequate haematologic and organ function as defined below:
a. Haemoglobin ≥ 9.0g/dL
b. Absolute neutrophil count (ANC) ≥1.5 x 109/L (≥1500/µL) without growth factor support
c. Platelet count ≥ 100 x 109 /L (≥100,000/µL)
d. Total 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. Serum 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. GFR ≥30mL/min measured by Cockroft-Gault.
9. Negative 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. Postmenopausal ≥ 50 years of age and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments OR
b. Documented irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation OR
c. <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.
10. Agreement to use adequate contraceptive measures (Refer to section 11.30 for full details).
11. Patients affiliated to the social security system (French specificity).
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|
| E.4 | Principal exclusion criteria |
1. Prior treatment with a PD-(L)-1 inhibitor for any malignancy, including earlier stage UC
2. Prior 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
3. Pregnant and lactating female patients
4. Known history of active CNS metastases. Patients with treated CNS metastases are permitted on the study if all of the following are true:
a. CNS 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. the 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. subject does not have leptomeningeal disease
5. Prior allogeneic stem cell or solid organ transplantation
6. 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
7. 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
8. Concurrent treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to enrolment
9. Evidence 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)
10. Malignancies other than urothelial carcinoma of the bladder 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)
11. Significant 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
12. Radiotherapy within 2 weeks prior to C1D1. Patients must have recovered adequately from toxicities resulting from the intervention prior to starting study treatment
13. Major 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.
14. History 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)
15. Active 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.
16. Positive HIV test
17. Active tuberculosis
18. History of 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
19. History of autoimmune-related hypothyroidism, unless on a stable dose of thyroid replacement hormone
20. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies
21. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of avelumab
22. Active infection requiring systemic therapy
23. Persisting 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.
24. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
[...]
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 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 after the date of withdrawal. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Patient reported outcomes reported at completion of cycle 6. Patients who withdraw from treatment between Cycles 4 and 6 will be included, provided an EORTC QLQ-C30 questionnaire is completed within 14 days after the date of withdrawal. |
|
| E.5.2 | Secondary end point(s) |
1.Quality 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.
2.Quality 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.
3.Change in GHS/QOL scale scores from baseline to the end of assessment (wk54), as per the primary endpoint methodology.
4.The above endpoints will be repeated using the EORTC QLQ-C30 scale score.
5.GHS/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.
6.Change in the GHS/QOL scale score from baseline as per the primary endpoint, but adjusted for baseline imbalances in GHS/QOL scale scores.
7. Performance status as measured by the Karnofsky Scale on completion of 6 cycles of treatment.
8. Incidence, nature and severity of adverse events graded according to NCI-CTCAE v5.0 at the following timepoints:
a. Throughout treatment
b. On completion of Cycle 6 of treatment
c. Between Cycle 4 and the completion of Cycle 10.
9. Treatment discontinuation rate due to AEs.
10. 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)
11. 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.
12. 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.
13. Overall survival (OS), defined as the time between the date of randomisation and death due to any cause.
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.From baseline to the completion of 10 Cycles of treatment
2.From the beginning of cycle 5 to the completion of 10 Cycles of treatment
3.Baseline to the end of assessment (wk54)
4.As per timepoints in endpoints 1 - 3
5.From baseline until a decrease by ≥10 points at any time point after baseline with no subsequent observations with a <10 point decrease from baseline
6. From baseline as per the primary endpoint
7. Upon completion of 6 cycles of treatment
8a. Throughout treatment
8b. Upon completion of 6 cycles of treatment
8c. Between Cycle 4 and the completion of Cycle 10
9. Enrolment until 90 day safety visit
10. From randomisation until week 20
11. From randomisation until week 20
12. Enrolment until death due to any cause
13. From randomisation until death |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of trial is defined as last patient last visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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