| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Muscle-invasive bladder cancer |
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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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10022877 |
| E.1.2 | Term | Invasive bladder cancer |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10022878 |
| E.1.2 | Term | Invasive bladder cancer stage II |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10022879 |
| E.1.2 | Term | Invasive bladder cancer stage III |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10022880 |
| E.1.2 | Term | Invasive bladder cancer stage IV |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 |
The primary objective of this trial is to find out whether durvalumab given after standard care improves disease-free survival in patients with T2 or more muscle-invasive bladder cancer who elect for bladder-sparing treatment.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
• To compare non muscle-invasive bladder cancer recurrence rate (< T2).
• Comparison of loco-regional control rate between treatment arms at the 12 week visit.
• To compare overall survival and bladder intact disease-free survival between treatment arms.
• Compare patterns of disease recurrence between treatment arms.
• Compare metastasis-free survival between arms.
• Compare safety between treatment arms.
• Compare quality of life between treatment arms.
• Compare cost effectiveness and health economics between treatment arms.
The tertiary objectives are:
• Exploratory analysis of disease-free and overall survival in relevant molecular subgroups.
• To perform a retrospective comparison of PD-L1 status (PD-L1 + versus PD-L1 -) and its prognostic and predictive impact on outcomes. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Histologic diagnosis of urothelial carcinoma of the bladder. Patients with mixed histology and focal differentiation are eligible but patients with pure small cell histology will be excluded.
2) Stage T2-T4a N0M0 at time of diagnosis (AJCC-TNM version 8) based on trans-urethral resection of bladder tumour (TURBT), imaging, and/or bimanual examination under anesthesia (EUA).
3) CT scan of the chest/abdomen/pelvis within 8 weeks from enrollment, showing no evidence of metastatic disease.
4) Patients must be ≥ 18 years of age.
5) Patients must have a life expectancy greater than 6 months.
6) Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (see Appendix I) and a body weight of > 30kg.
7) Patients must have adequate haematologic reserve: Platelet count ≥ 75 x 109/L, Absolute neutrophils ≥ 1.0 x 109/L. Anemia will be corrected to minimum hemoglobin of 90 g/L with red cell transfusions, if necessary.
8) Patients must have an estimated creatinine clearance (Cockcroft-Gault Equation) ≥ 30 ml/min.
9)Patients must have adequate liver function with a bilirubin ≤ 1.5 ULN (if confirmed Gilbert’s, eligible providing bilirubin ≤ 3 x UNL) and AST/ALT (SGOT/SGPT) < 2.5 x the upper normal limit.
10) All patients must have a tumour block from their primary tumour available and consent to release the block/cores/cut slides for correlative analyses and the hospital/pathologist must have agreed to the submission of the specimen(s).
11) Patients have completed prior trimodality therapy (TMT) consisting of surgery, chemotherapy and radiation therapy treatment prior to enrollment on the BL.13 study.
*Patients should begin protocol treatment within 42 days after completion of TMT.
12) Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires in either English or French. The baseline assessment must be completed within required timelines, prior to registration / randomization. Inability (lack of comprehension in English or French, or other equivalent reason such as cognitive issues or lack of competency) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible.
13) Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate.
14) Patients must be accessible for treatment and follow-up. Patients registered on this trial must be treated and followed at the participating centre. This implies there must be reasonable geographical limits (for example: 1 ½ hour's driving distance) placed on patients being considered for this trial.
15) Protocol treatment is to begin within 2 working days of patient enrollment.
16) Women/men of childbearing potential must have agreed to use a highly effective contraceptive method during and for 3 months following treatment. A woman is considered to be of “childbearing potential” if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, “effective contraception” also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or vasectomy/vasectomized partner. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures.
Women of childbearing potential will have a pregnancy test to determine eligibility as part of the Pre-Study Evaluation; this may include an ultrasound to rule-out pregnancy if a false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and partner is vasectomized, it may be associated with tumour production of hCG, as seen with some cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy.
17) Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. |
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| E.4 | Principal exclusion criteria |
1) Pre-existing medical conditions precluding treatment.
2) Pregnancy or lactating mothers.
3) Received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-PD-L1, including durvalumab anti-programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-1BB ligand, a member of the Tumour Necrosis Factor Receptor [TNFR] family), or anti-Cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
4) Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease (e.g. colitis or Crohn’s disease), diverticulitis with the exception of diverticulosis, celiac disease (controlled by diet alone) or other serious gastrointestinal chronic conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis), rheumatoid arthritis, hypophysitis, uveitis, etc., within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:
• Patients with alopecia;
• Patients with Grave’s disease, vitiligo or psoriasis not requiring systemic treatment (within the last 2 years);
• Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement;
• Any chronic skin condition that does not require systemic therapy.
5) Patients with active or uncontrolled intercurrent illness including, but not limited to:
• cardiac dysfunction (symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia);
• active peptic ulcer disease or gastritis;
• active bleeding diatheses;
• psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent;
• known history of previous clinical diagnosis of tuberculosis;
• known human immunodeficiency virus infection (positive HIV 1/2 antibodies);
• known active hepatitis B infection (positive HBV surface
antigen(HBsAg).Patients with a past or resolved HBV infection (defined as
presence of hepatitis B core antibody (anti-HBc) and absence of HBsAg) are
eligible;
• known active hepatitis C infection. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
6) History of primary immunodeficiency, history of allogenic organ transplant that requires therapeutic immunosuppression and the use of immunosuppressive agents within 28 days of randomization* or a prior history of severe (grade 3 or 4) immune mediated toxicity from other immune therapy or grade ≥ 3 infusion reaction.
* Intranasal/inhaled corticosteroids or systemic steroids that do not to exceed 10 mg/day of prednisone or equivalent dose of an alternative corticosteroid are permissible.
7) Current or prior use of immunosuppressive medication within 28 days of study entry, with the exceptions of intranasal and inhaled corticosteroids or systemic chronic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Corticosteroids used on study for anti-emetic purpose are allowed. Corticosteroids as premedication for hypersensitivity reactions (e.g. computed tomography [CT] scan premedication) are allowed.
8) Peripheral neuropathy ≥ grade 2 (CTCAE v5.0).
9) History of allergic or hypersensitivity reactions to any study drug or their excipients.
10) Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥ 470 msec in screening ECG measured using standard institutional method or history of familial long QT syndrome.
11) History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline CT scan.
12) Any active disease condition which would render the protocol treatment dangerous or impair the ability of the patient to receive protocol therapy.
13) Any condition (e.g. psychological, geographical, etc.) that does not permit compliance with the protocol.
14) Live attenuated vaccination administered within 30 days prior to randomization.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome measure is disease-free survival.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Disease-free survival, is defined as the time from the randomisation to the time of the first event that is either recurrent (local or distant) bladder cancer, a new primary bladder cancer or death from any cause. Patients who are disease free at the time of final analysis will be censored at their last disease assessment date. All randomized patients will be included in the analysis of DFS.
It is estimated that the 102 required events will be observed within the 3-year recruitment and 2-year follow up periods. |
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| E.5.2 | Secondary end point(s) |
• Muscle-invasive bladder cancer recurrence rate (< T2).
• Loco-regional control rate (LCR) between treatment arms at the 12 week visit defined as proportion of patients with a confirmed locoregional complete response at 3 months after randomization. Locoregional complete response will be ascertained on basis of a combination of follow-up CT imaging of the irradiated field (bladder, pelvic lymph nodes) and distant, cystoscopy with re-biopsy of involved areas, and urine cytology.
• Overall survival and bladder-intact disease-free survival between treatment arms.
• Disease recurrence
• Metastasis-free survival
• Safety
• Quality of life measured using FACT - BL ( Functional Assessment of Cancer Therapy-Bladder Cancer)
• Economic analyses (for Canadian patients only) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
LCR: The proportion of patients with a confirmed locoregional complete response at 3 months after randomization.
Bladder-intact Disease-Free Survival: Measured from the time of enrollment to the time of radical cystectomy.
Overall survival: Time from randomization to death from any cause.
Safety: AEs will be continuously graded from screening through to Post-treatment / surveillance Follow-Up.
QoL: Completed at baseline and week 8, 12, 24, 36 ,48 and at time of treatment/surveillance period completion.
All analyses will occur at the same time as the analysis of the primary outcome measure. |
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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 | No |
| 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 | 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 | 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 | Yes |
| E.8.2.3.1 | Comparator description |
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| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 38 |
| 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 |
| Canada |
| Spain |
| United Kingdom |
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| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
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