| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| High-risk non-muscle invasive bladder cancer (NMIBC) after transurethral resection of the bladder (TURBT) and pathological assessment. |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 efficacy of atezolizumab in association with BCG versus BCG alone in patients with high-risk NMIBC as measured by event-free survival. |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of atezolizumab in association with BCG versus BCG alone as measured by:
•high-grade recurrence free survival,
•progression free survival,
•disease-specific survival,
• overall survival,
•To evaluate disease worsening in each arm,
•To evaluate complete response rate and duration of response among patients with CIS tumor with or without papillary disease associated, in each arm,
•To evaluate complete response rate and duration of response among patient with CIS.
Safety and patient self-reported treatment tolerance objectives
•To evaluate the safety and tolerability of atezolizumab in association with BCG versus BCG alone,
•To assess quality of life in patient treated by atezolizumab in association with BCG versus BCG alone as measured by the EORTC QLQ-C30.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| •To identify predictive and prognostic biomarkers of recurrence and bladder cancer detection in tumor tissue, blood and urine. |
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| E.3 | Principal inclusion criteria |
1. Signed informed consent form after the last endoscopic surgery (TURBT)
2. Adult man and women ( age ≥ 18 years)
3. Any high risk non muscle invasive urothelial carcinoma histologically confirmed (mixed histology tumors allowed if urothelial carcinoma histology is predominant) defined on the TURBT as any of the following
T1 tumor and/or
High grade (WHO 2004) and/or
Grade 3 (WHO 1973) and/or
Carcinoma in situ (CIS)
4. Tumor tissue available from the surgery for central confirmation of the diagnosis and analysis the expression of PD-L1. In case of a second TURBT performed, as per Belgian guidelines, the tumour tissue from the TURBT procedure that supports the primary diagnosis for study eligibility should be the tumour tissue used for the PD-L1 expression testing (applicable only in Belgium).
5. At least one additional (second) resection of the primary tumor has been performed in any of the following cases [without upstaging toward MIBC (EAU guidelines, 2017)] :
- T1 tumors at physician’s discretion,
- incomplete initial TURBT,
- no muscle in the specimen (can be omitted if TaLG/G1 tumors or primary CIS only was found).
As per Belgian guidelines,the second TUBRT should be performed equal or more than 4 weeks and equal or less to 13 weeks prior to Day 1 of cycle 1 of treatment.
6. Absence of metastasis in the pelvis, abdomen, or chest, as confirmed by a negative baseline computed tomography (CT) or magnetic resonance imaging (MRI) scan no more than 90 days prior to the first study treatment
7. ECOG performance status of ≤ 2
8. Life expectancy ≥ 12 weeks
9. Systolic blood pressure (BP) <160 mmHg and diastolic BP <95 mmHg, as documented within 7 days prior to the first study treatment (hypertension allowed provided it is controlled)
10. Adequate hematologic and end-organ function, as defined by the following laboratory results obtained within 7 days prior to the first study treatment:
ANC ≥ 1500 cells/μL
WBC counts > 2500/μL
Lymphocyte count ≥ 300/μL
Platelet count ≥ 100,000/μL
Hemoglobin ≥ 9.0 g/dL
ASAT, ALAT, and alkaline phosphatase ≤ 2.5 × the upper limit of normal (ULN)
Serum bilirubin ≤ 1.0 ×ULN
Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled.
Partial thromboplastin time (PTT)/Prothrombin Time (PT) ≤ 1.5 × ULN or INR < 1.7 × ULN
Calculated creatinine clearance ≥ 20 mL/min (Cockcroft-Gault formula)
11. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 5 months after the last dose of atezolizumab
12. Patients affiliated to the social security system
13. Patient is willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up
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| E.4 | Principal exclusion criteria |
1. Patient having received previous BCG therapy for bladder cancer. In addition, for Belgium, patients who have received prior radiation therapy will not be eligible
2. Any approved anti-cancer therapy, including systemic chemotherapy, or hormonal therapy within 3 weeks prior to initiation of study treatment. Hormone-replacement therapy or oral contraceptives are allowed
3. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days or five half-lives of the drug, whichever is longer, prior to day 1 of study treatment
4. Malignancies other than UC within 5 years prior to Day 1 of cycle 1 of treatment
5. Pregnancy or breastfeeding
6. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
7. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
8. History of autoimmune disease or history of immunosuppression, or conditions associated with congenital or acquired immune deficiency , 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
9. Serum albumin < 2.5 g/dL
10. Known HIV infection
11. Patients with active hepatitis B virus (HBV; chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test prior to randomization) or hepatitis C.
12. Known active tuberculosis
13. Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.
14. Signs or symptoms of urinary infection and/or other signs and symptoms > grade 1 (NCI CTCAE v5.0) within 2 weeks prior to Cycle 1, Day 1.
Patients receiving therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1 are not eligible. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible.
15. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 3 months before Cycle 1, Day 1, unstable arrhythmias, or unstable angina.
16. Major surgical procedure other than for diagnosis within 4 weeks prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure during the course of the study
17. Prior allogeneic stem cell or solid organ transplant
18. Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation if such a live, attenuated vaccine will be required during the study
19. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
20. Prior treatment with CD137 agonists or immune checkpoint−blockade therapies, including anti-CD40, anti−CTLA-4, anti−PD-1, and anti−PD-L1 therapeutic antibodies
21. Treatment with systemic immunostimulatory agents (including but not limited to interferons, IL-2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1
22. Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemic immunosuppressive medications during the trial
23. For France and Belgium, person deprived of their liberty or under protective custody or guardianship
24. For France: Patients who have previously experienced a pericardial disorder on prior treatment with other immune-stimulartory anticancer agents
25. For Belgium, any contra-indications for the adjuvant intravesical BCG treatment (please refer to the SMPCs to the different strains of BCG)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Event-free survival defined as the time from randomization to the time of first EFS event.
EFS events are :
• High grade or low grade Ta tumor at any time after the start of therapy
• T1 tumor and higher (e.g .T2) at any time after the start of therapy
• CIS tumor at least 6 months after the start of therapy (Persistent CIS without papillary tumor at 3 months without any other event for EFS will
not be an event)
• Any UTUC after NMIBC
• Any N+ at any time after the start of therapy
• Any M+ at any time after the start of therapy
• Death whatever the cause |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Event free survival (EFS) at 3 years after inclusion of the first patient (144 events expected) |
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| E.5.2 | Secondary end point(s) |
Efficacy:
• High-grade recurrence-free survival is defined by reappearance of high risk disease (high grade, T1 or CIS) (Persistent CIS without papillary tumor at 3 months will not be considered as an event for RFS);
• Progression-free survival is defined as the time from randomization to the date of progression or death. Progression defined as increase of stage from Ta
to T1 or from CIS to T1; progression to MIBC (T≥ 2) or to lymph node N+ or to distant disease M+;
• Disease-specific survival defined as the time from randomization to the date of death from bladder cancer;
• Overall Survival, defined as the time from randomization to the date of death from any cause;
• Disease worsening, defined as cystectomy or indicative change in therapy, including systemic chemotherapy or radiation therapy. The date
of diagnosis (cystoscopy or CT) leading to cystectomy or chemotherapy/radiotherapy will be considered as the time of disease worsening.
• Complete response will be measured among patients with CIS disease with or without papillary tumor at diagnosis, Week 12, Week 51, and 2
years after randomization. It will be defined by normal cystoscopy and normal cytology.
•Duration of response (DOR) is defined as the interval
from response initiation (when either complete or partial response is first determined) to progression or death, whichever occurs first.
Complete response and DOR will be measured among patients with pure in situ carcinoma (without papillary tumor) with the same timeline
Safety and patient self-reported treatment tolerance:
• Frequency, nature, and severity of adverse events graded according to NCI CTCAE v5.0 and immune-related event (irAE)
• Quality of life will be measured using EORTC QLQ-C30 assessed at baseline and then every 12 weeks for year 1-2 then every 24 weeks for year 3-5
Exploratory endpoints:
• Status of tumor immune-related biomarkers in archival and /or freshly obtained tissues;
• Status of exploratory biomarkers in urine, plasma, whole blood collected before and during treatment with atezolizumab or at recurrence and association with outcome.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Specific, overall and progression free survival: 1-year and 2-year specific, overall and progression free survival rates, as well as disease
worsening rates, will be determined 3 years after the inclusion of the first patient.
Other late endpoints (namely 3 and 5-year rates and median times) will be determined at the end of the trial. |
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| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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