Safety and Efficacy Study of MAGE-A3 + AS-15 in Patients With Muscle-invasive Bladder Cancer After Cystectomy

Study Overview
=================
Brief Summary
-----------------
The purpose of this clinical trial was to demonstrate the benefit of the immunotherapeutic product recMAGE-A3 + AS-15 given to patients with bladder cancer after removal of the bladder. A course of 13 injections was administered over 27 months.

Detailed Description
-----------------
This study assessed an investigational treatment for patients with Muscle Invasive Bladder Cancer in whom the urinary bladder had been surgically removed. The investigational treatment aimed to increase the body's immune response to a specific antigen expressed by the cancer. The tumour tissue was first tested whether it expressed the MAGE-A3 antigen. The MAGNOLIA study was open to male and female patients with pathologically confirmed muscle invasive transitional cell carcinoma of the urinary bladder with expression of the antigen MAGE-A3 with or without limited lymph node involvement who had no evidence of disease after surgery confirmed with imaging procedures (scans CT/MRI).

Official Title
-----------------
A Randomized, Double Blind, Placebo Controlled Phase II Trial to Evaluate the Safety and Efficacy of recMAGE-A3 + AS15 ASCI in Patients With MAGE-A3 Positive Muscle Invasive Bladder Cancer After Cystectomy

Conditions
-----------------
Urinary Bladder Neoplasms

Intervention / Treatment
-----------------
* Biological: recMAGE-A3 + AS15 ASCI
* Biological: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Aged greater than or equal to 18 years at the time ICF is signed, either sex. Histologically confirmed (after cystectomy or if needed transurethral resection) urothelial carcinoma of the bladder which is MAGE-A3 positive. Written informed consent for tissue sampling, the mandatory analyses and for the complete study has been obtained prior to the performance of any other protocol-specific procedure. TNM classification at pathological examination of surgically removed specimen: Stage T2,3 N0 or N1 or N2 and M0 disease or Stage T4 N0 M0 disease. 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 no more than 13 weeks prior to randomization. Other examinations should be performed as clinically indicated. 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. 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. World Health Organization (WHO) performance status 0 - 1 at the time of randomization. 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. The patient should be affiliated to health insurance or benefit of such an insurance Exclusion Criteria: 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. The patient has received any anti cancer systemic treatment, including immunotherapy (local intravesical BCG is allowed), 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 The patient has received radiotherapy of the abdominal or pelvic region, within 6 months prior to randomization. Women who are pregnant or breast feeding. The patient has a known infection with human immunodeficiency virus (HIV) or chronic hepatitis B or C. The patient has a history of allergic disease or reactions likely to be exacerbated by any component of the study investigational product. The patient has any confirmed or suspected immunosuppressive or immunodeficient condition or potential immune-mediated diseases as. Patients with vitiligo are not excluded to participate in the trial. Patient has received a major organ allograft. 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. 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. The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures. 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. The patient uses alternative treatments eg. plant extracts. Adults under legal supervision

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: recMage-A3 + AS15 ASCI<br>MAGE-A3 positive patients treated with recMAGE-A3 + AS15 ASCI | Biological: recMAGE-A3 + AS15 ASCI<br>* 5 doses were administered (intramuscular) at 3-week intervals followed by 8 doses administered at 3-month intervals for a total maximum duration of study treatment administration of 27 months<br>|
| Placebo Comparator: Placebo<br>MAGE-A3 positive patients treated with placebo | Biological: Placebo<br>* 5 doses were administered (intramuscular) at 3-week intervals followed by 8 doses administered at 3-month intervals for a total maximum duration of study treatment administration of 27 months<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival | To evaluate of the clinical efficacy in terms of Disease Free Survival of treatment versus placebo in the overall population of patients with bladder cancer with MAGE-A3 expression after cystectomy. Disease Free Survival is the time from randomization to either the date of first recurrence of the disease or the date of death (whatever the cause), whichever occurred first. Types of recurrence considered as an event included loco-regional and distant metastases. In addition, any death occurring without prior documentation of tumor recurrence was considered as an event (and was not censored in the statistical analysis) as this approach is less prone to introduce bias. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | To evaluate overall survival in the overall study population. Overall Survival was defined as the interval from randomization to the date of death, irrespective of the cause of death; patients still alive were censored at the date of the last assessment. | 5 years | 
| Disease-free Specific Survival | To evaluate Disease-free specific survival in the overall population.Disease-free specific survival was defined as the interval from randomization to the date of first recurrence of disease or date of death due to bladder carcinoma, whichever occurred first. Patients without recurrence or death were censored at the date of last assessment. Patients without recurrence who died from another cause were censored at the date of death. | 5 years | 
| Distant Metastasis-free Survival | To evaluate Distant metastasis-free survival in the overall study population. Distant metastasis-free survival was defined as the interval from randomization to the date of first distant metastasis or date of death, whichever occurred first. Patients alive and without distant metastasis were censored at the date of last assessment. | 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Urinary Bladder neoplasms, Lymphoproliferative Disorders, Immune System Diseases, Cystectomy, Adjuvants, Immunologic, Immunologic Factors