E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients who get a cystectomy due to muscle invasive bladder cancer which is MAGE-A3 positive |
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E.1.1.1 | Medical condition in easily understood language |
Patients with a surgically removed urinary bladder due to muscle invasive bladder cancer from which the bladder tumor is MAGE-A3 positive |
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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 | 19.0 |
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 |
The primary objective of this Phase II study is to evaluate the clinical efficacy in terms of Disease Free Survival of recMAGE-A3 + AS 15 ASCI versus placebo in the overall population. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate Disease-free (DFS) in the subpopulations with and without use of neo-adjuvant chemotherapy and in the subpopulations with and without use of adjuvant chemotherapy
• To evaluate
- overall survival
- Disease-free specific survival (DFSS)
- Distant metastasis-free survival (DMFS)
- the safety of recMAGE-A3 + AS15 ASCI |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Aged greater than or equal to 18 years at the time ICF is signed, either sex.
2. Histologically confirmed (after cystectomy or if needed transurethral resection) urothelial carcinoma of the bladder which is MAGE-A3 positive.
3. Written informedconsent for tissue sampling, the mandatory analyses and for the complete study has been obtained prior to the performance of any other protocol-specific procedure.
4. TNM classification at pathological examination of surgically removed radical cystectomy specimen: Stage T2,3 N0 or N1 or N2 and M0 disease or Stage T4 N0 M0 disease. (TNM classification see Appendix 3)
5. The patient is free of residual disease and free of metastasis, as
confirmed by a negative baseline Computer Tomogram (CT scan) or Magnetic Resonance Imaging (MRI) of the pelvis, abdomen and chest after cystectomy and no more than 13 weeks prior to randomization.
6. Patient is fully recovered from surgery within 13 weeks following
cystectomy. For patients who receive adjuvant chemotherapy, the
patient is fully recovered within 3-6 weeks following chemotherapy.
7. The patient must have adequate bone-marrow reserve, defined as an absolute neutrophil count ≥ 1.0 x 109/L, and a platelet count ≥ 75 x 109/L, adequate renal function, defined as a serum creatinine ≤ 1.5 times the Upper Limit of Normal (ULN), and adequate hepatic function, defined as a Total bilirubin ≤ 1.5 times the ULN, and a Alanine transaminase(ALAT) and Aspartate Transaminase (ASAT) ≤ 2.5 times the ULN as assessed by standard laboratory criteria.
8. World Health Organization (WHO) performance status 0 – 1 at the time of randomization.
9. If the patient is female, she must be of non-childbearing potential, i.e. have a current tubal ligation, hysterectomy, ovariectomy or be post menopausal, or if she is of childbearing potential, she must practice adequate contraception for 30 days prior to administration of study treatment, have a negative pregnancy test and continue such precautions during all study treatment period and for 2 months after completion of the injection series.
10. The patient should be affiliated to health insurance or benefit of such an insurance |
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E.4 | Principal exclusion criteria |
1. The patient has previous or concomitant malignancies at other sites except effectively treated non-melanoma skin cancer, cervical carcinoma in situ, incidental localised prostatic carcinoma or effectively treated malignancy that has been in remission for over 5 years.
2. The patient has received any anticancer systemic treatment, including
immunotherapy (local intravesical BCG is allowed) or chemotherapy,
except:
* For the treatment of previous malignancies as allowed by the protocol (i.e., non-melanoma skin cancer, cervical carcinoma in situ, incidental localised prostatic carcinoma or effectively treated malignancy that has been in remission for over 5 years).
* For the treatment with neo-adjuvant chemotherapy for their muscle invasive bladder cancer
* For the treatment with adjuvant cisplatinum-based chemotherapy for
their muscle invasive bladder cancer .3. The patient has received radiotherapy of the abdominal or pelvic region, within 6 months prior to randomisation.
4. Women who are pregnant or breast feeding.
5. The patient has a known infection with human immunodeficiency virus (HIV) or chronic hepatitis B or C.
6. The patient has a history of allergic disease or reactions likely to be exacerbated by any component of the study investigational product.
7. The patient has any confirmed or suspected immunosuppressive or immunodeficient condition or potential immune-mediated diseases as specified in table 8 of the protocol. Patients with vitiligo are not excluded to participate in the trial.
8. Patient has received a major organ allograft.
9. The patient requires concomitant treatment with systemic corticosteroids, or any other immunosuppressive agents. Note: the use of prednisone, or equivalent, < 0,125 mg/kg/day (absolute maximum 10 mg/day), or inhaled corticosteroids or topical steroids is permitted.
10. The patient has received any investigational or non-registered medicinal product other than the study medication within the 30 days preceding the first dose of study medication, or plans to receive such a drug during the study.
11. The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures.
12. The patient has other concurrent severe medical problems, unrelated to the malignancy, that would significantly limit full compliance with the study or expose the patient to unacceptable risk. For example, but not limited to: uncontrolled congestive heart failure or uncontrolled hypertension, unstable heart disease (coronary heart disease or myocardial infarction), uncontrolled arrhythmia or patients taking
anticoagulant treatment or having a coagulation disorder.
13. The patient uses alternative treatments eg. plant extracts.
14. Adults under legal supervision. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Disease-free Survival (DFS):
• Defined as the time from randomization to either the date of first recurrence of the disease or the date of death (whatever the cause), whichever occurs first.
• Types of recurrence to be considered as an event include loco-regional and distant metastases.
• In addition, any death occurring without prior documentation of tumor recurrence will be considered as an event (and will not be censored in the statistical analysis) as this approach is less prone to introduce bias.
• If no event has occurred by the time of the analysis, then the time to event will be censored at the date of the last assessment of the patient in question.
• Any new primary cancer at another site, including transitional carcinoma of the upper urinary tract, will not be considered as recurrence and should be reported as a SAE. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Timepoint after randomization at which either the date of first recurrence of the disease or the date of death (whatever the cause), whichever occurs first up to a maximum of 5 years from the first administration of study treatment |
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E.5.2 | Secondary end point(s) |
- Overall Survival.
· Defined as the interval from randomization to the date of death, irrespective of the cause of
death; patients still alive will be censored at the date of the last assessment.
- Disease-free specific survival (DFSS).
· Defined as the interval from randomization to the date of first recurrence of disease or date
of death due to bladder carcinoma, whichever occurs first. Patients without recurrence or death are censored at the date of last assessment. Patients without recurrence who die from another cause are censored at the date of death.
- Distant metastasis-free survival (DMFS).
· Defined as the interval from randomization to the date of first distant metastasis or date of death, whichever occurs first. Patients alive and without distant metastasis are censored at the date of last assessment.
- Adverse events.
· Occurrence of adverse events, including potential immune-mediated diseases
- Serious adverse events.
· Occurrence of serious adverse events
- To evaluate the efficacy of the recMAGE-A3 + AS15 ASCI compared to placebo in terms of DFS separately in the population presenting the predictive gene signature, and in the population of patients who do not present this signature
- To evaluate the efficacy of the recMAGE-A3 + AS15 ASCI compared to placebo in terms of overall survival in the overall study population, in the population of patients presenting the predictive gene signature and in the population of patients who do not present this signature;
-To evaluate the safety in the overall study population;
- To evaluate Gene expression profiles of the primary tumor by microarray. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoint after randomization at which either the date of first recurrence of the disease or metastase, occurrence of (S)AEs or the date of death (whatever the cause), whichever occurs first up to a maximum of 5 years from the first administration of study 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 | 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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 85 |
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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Last visit of the last subject |
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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 | 7 |
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 | 7 |
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 |