| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
We hypothesise that the known interaction of chemotherapy and radiotherapy are increased by the addition of further cancer therapies, specifically drugs that block immune system cells, like durvalumab. These drugs may supplement the effect of radiotherapy and chemotherapy in muscle invasive bladder cancer and thus improve local control and the spread of the disease.
The aim of RadIO is therefore to assess the safety, feasibility and efficacy of a combination of radiotherapy with durvalumab and chemotherapy in muscle invasive bladder cancer using a randomised multi-arm multi-stage design.
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| E.2.2 | Secondary objectives of the trial |
The patient experience during treatment is also important to describe in Rad-IO. A standard quality of life evaluation will therefore be performed.
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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 |
Quality of life sub-study
As cancer treatments may produce adverse effects that diminish patient Quality of Life (QoL), even when tumour regression or extended survival is achieved, the acceptance of any new treatment regimen may be critically dependent on QoL consequences. Thus a detailed assessment of QoL changes is an important aspect of this trial.
In order to assess QoL we will be using the EORTC QLQ-C30 and EORTC QLQ-BLM30 questionnaires.
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| E.3 | Principal inclusion criteria |
• Age >18 years old
• Body weight >30 kg
• Histologically proven invasive bladder carcinoma (adenocarcinoma,
transitional cell carcinoma or squamous cell carcinoma)
• Localised muscle invasive carcinoma either surgically or by imaging (T2-
T4a N0 M0)
• World Health Organisation (WHO) performance status grade 0 to 1
• Adequate normal organ and marrow function as defined below:
o Haemoglobin ≥100 g/L
o Absolute neutrophil count 1.5 x 109/L
o Platelet count ≥100 x 109/L
o Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN).
o AST or ALT ≤2.5 x institutional upper limit of normal
o Calculated creatinine clearance >40 mL/min by the Cockcroft-Gault
formula.
• Available for long-term follow-up
• Fit for a radical course of radiotherapy
• Must have a life expectancy of at least 12 weeks
• Evidence of post-menopausal status or negative urinary or serum pregnancy
test for female pre-menopausal patients. Women will be considered post-
menopausal if they have been amenorrheic for 12 months without an
alternative medical cause. The following age-specific requirements apply:
o Women <50 years of age would be considered post-menopausal if
they have been amenorrheic for 12 months or more following cessation
of exogenous hormonal treatments and if they have luteinizing hormone
and follicle-stimulating hormone levels in the post-menopausal range
for the institution or underwent surgical sterilization (bilateral
oophorectomy or hysterectomy).
o Women ≥50 years of age would be considered post-menopausal if they
have been amenorrheic for 12 months or more following cessation of all
exogenous hormonal treatments, had radiation-induced menopause with
last menses >1 year ago, had chemotherapy-induced menopause with last
menses >1 year ago, or underwent surgical sterilization (bilateral
oophorectomy, bilateral salpingectomy or hysterectomy).
• Male and female patients of childbearing age willing to use highly
effective contraception
• 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.
• Written informed consent and any locally-required authorization obtained
from the patient prior to performing any protocol-related procedures,
including screening evaluations
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| E.4 | Principal exclusion criteria |
• Uncontrolled systemic disease which would preclude the patient from
participating in the trial including severe or uncontrolled
cardiovascular disease
• Restrictive or obstructive disturbances to pulmonary ventilation, renal function or liver function
• Previous pelvic radiotherapy
• Bilateral hip replacements compromising accurate radiotherapy planning
• Evidence of significant clinical disorder, or laboratory finding which,
in the opinion of the investigator, makes it undesirable for the patient
to participate in the trial
• Widespread Carcinoma in situ (CIS), or CIS remote from the muscle
invasive tumour
• Untreated hydronephrosis. Patients with hydronephrosis can be included if
the kidney/ureter has been stented or nephrostomy has been inserted
• Prior participation in another trial (within the previous 30 days) or
concurrent enrolment in another clinical trial, unless it is an
observational (non-interventional) clinical study or during the follow-up
period of an interventional study
• Any unresolved toxicity Common Terminology Criteria for Adverse Events
(CTCAE) Grade ≥2 from previous anticancer therapy
with the exception of alopecia, vitiligo, and the laboratory values
defined in the inclusion criteria (see protocol for exceptions)
• Any previous treatment with a PD-L or PD-L1 inhibitor, including
durvalumab
• Current or prior use of immunosuppressive medication within 14 days prior
to randomisation, with the exceptions of intranasal and inhaled
corticosteroids or systemic corticosteroids at physiological doses, which
are not to exceed 10 mg/day of prednisone, or an equivalent
corticosteroid (see protocol for exceptions)
• Current use of brivudin, sorivudin, and analogues
• Patients with an active non-infective pneumonitis
• History of primary immunodeficiency
• Known history of previous clinical diagnosis of tuberculosis (TB)
• Any concurrent chemotherapy, Investigational Medicinal Product,
biologic, or hormonal therapy for cancer treatment. Concurrent use of
hormonal therapy for non-cancer-related conditions is acceptable.
• Major surgical procedure other than transurethral resection of the
bladder tumour within 30 days prior to randomisation
• History of allogenic organ transplantation
• Active or prior documented autoimmune or inflammatory disorders (see
protocol for exceptions).
• Uncontrolled intercurrent illness (see protocol for details)
• History of another primary malignancy (see protocol for details)
• Metastatic disease
• Acute, serious (e.g. Herpes zoster, chickenpox) or active infection
including TB, hepatitis B (known positive Hepatitis B, Hepatitis C, or
HIV
• Bone marrow depression after radiotherapy or treatment with other
antineoplastic agents
• Pancytopenia or isolated leucopoenia/thrombopenia or haemorrhagic
diathesis
• Receipt of live attenuated vaccine within 30 days prior to randomisation
• Serious liver impairment
• Homozygotic for diydropyrimidine or known complete absence of
dihydrophyrimidine dehydrogenase (DPD) activity
• Patients undergoing management for non-malignant disease
• Female patients who are breastfeeding
• Known allergy or hypersensitivity to any of the trial IMPs or any of the
trial drug excipients
• Judgement by the Investigator that the patient is unsuitable to
participate in the trial and the patient is unlikely to comply with trial
procedures, restrictions and requirements
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Stage 1:
Safety - Adverse Events (AEs) will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Acute toxicity defined as related AEs experienced during treatment and late toxicity defined as related AEs reported at a time more than three month’s from completion of treatment. The number of patients experiencing each event will be reported by type and severity.
Stage 2:
Disease-free survival time - Defined as the number of whole days between the date of randomisation and the earliest date of
• Diagnosis of distant metastases
• Diagnosis of loco-regional nodal disease
• Diagnosis of new muscle invasive tumour in the bladder
• Diagnosis of non-muscle invasive tumour in the bladder
• Diagnosis of upper tract urothelial cancer
• Death from bladder cancer
Stage 3:
Overall survival time - defined as the number of whole days between the date of randomisation and date of death from any cause. Patients who do not die during the course of the trial will be censored at the last date of assessment.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Stage 1 (Pilot): The first 6 patients in the Research Arm will be evaluated for feasibility and safety 3 months after randomisation. Further feasibility and safety evaluations will be carried out 3 months post randomisation on 6 patients who had prior chemotherapy and for 6 patients with no prior chemotherapy. Recruitment will continue while safety and feasibility data is collected. There are no pre-defined stopping rules for stage 1.
Stage 2 (Efficacy): The analysis will be conducted once 70 events have been observed.
Stage 3 (Efficacy)
The results of Stage 2 will inform the timing of the analysis for Stage 3. |
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| E.5.2 | Secondary end point(s) |
Stage 1:
Feasibility - defined as the impact on radiotherapy treatment and assessed by days delay to start of radiotherapy, days extension in length of planned radiotherapy and stopping radiotherapy early.
Stage 2:
Toxicity - will be graded as per the safety outcome in the pilot stage. Rate of occurrences of AEs of Grade 3 or higher will be reported along with all Adverse Events of Special Interest (AESI).
Delivery of core target therapy (chemoradiotherapy)- defined as the impact on radiotherapy treatment and assessed by days delay to start of radiotherapy, days extension in length of planned radiotherapy and stopping radiotherapy early.
Time to local muscle invasive progression - defined as the number of whole days between the date of randomisation and the date of detection of local muscle invasive bladder cancer or death from bladder cancer, whichever occurs first. Patients with no evidence of local muscle invasive disease will be censored at the last date of assessment or date of death if death is not attributed to bladder cancer.
Time to local non-muscle invasive progression - defined as the number of whole days between the date of randomisation and the date of detection of local non-muscle invasive bladder cancer or death from bladder cancer, whichever occurs first. Patients with no evidence of local non-muscle invasive disease will be censored at the last date of assessment or date of death if death is not attributed to bladder cancer.
Time to regional nodal progression - defined as the number of whole days between the date of randomisation and the date of detection of loco-regional recurrence in lymph nodes within the true pelvis or death from bladder cancer, whichever occurs first. Patients with no evidence of regional nodal disease will be censored at the last date of assessment or date of death if death is not attributed to bladder cancer.
Time to local progression - defined as the number of whole days between the date of randomisation and the date of the first local progression or death from bladder cancer, whichever occurs first. Local progression includes detection of local muscle invasive disease, local non-muscle invasive disease or regional nodal disease. Patients with no evidence of local disease will be censored at the last date of assessment or date of death if death is not attributed to bladder cancer.
Time to distant progression - defined as the number of whole days between the date of randomisation and the date of detection of distant progression or death from bladder cancer, whichever occurs first. Patients with no evidence of distant progression will be censored at the last date of assessment or date of death if death is not attributed to bladder cancer.
Cystectomy within one year - defined as the proportion of patients who undergo a cystectomy within one year of randomisation.
Quality of life - will be assessed using the questionnaires EORTC QLQ-C30 and QLQ-BLM30.
Overall survival time - defined as above.
Stage 3:
Time to local progression, time to distant progression, acute/late toxicity and quality of life are defined as above.
Percentage of target drug delivered - defined as the amount of durvalumab being administered as a proportion of the protocol defined dose.
Cystectomy rate - defined as the proportion of patients who undergo a cystectomy.
Disease-free survival time - defined as the number of whole days between the date of randomisation and the date of detection of any progression of bladder cancer or death from bladder cancer, whichever occurs first. Patients with no evidence of progression will be censored at the last date of assessment or date of death if death is not attributed to bladder cancer.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Stage 1 (Pilot):
Feasibility will be measured at the end of the Pilot Stage.
Stage 2 (Efficacy): All measured at end Stage 2 except:
Delivery of core target therapy - at the end of treatment
Cystectomy within one year - at one year
Quality of Life - at baseline, end of treatment (30 days post treatment discontinuation) and at 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48 and 60 months post randomisation
Stage 3 (Efficacy):
All at end Stage 3 except:
Percentage of target drug delivered - end of treatment
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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 | 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) | 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| 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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| The end of trial will be 6 months after the last patient has a minimum of 5 years follow-up. This will allow sufficient time for the completion of protocol procedures, data collection and data input. |
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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 | 10 |
| 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 | 10 |
| 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 | 0 |
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