Urinary Bladder Neoplasms
Conditions
Keywords
Urinary Bladder neoplasms, Lymphoproliferative Disorders, Immune System Diseases, Cystectomy, Adjuvants, Immunologic, Immunologic Factors
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).
Interventions
BIOLOGICALrecMAGE-A3 + AS15 ASCI
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
BIOLOGICALPlacebo
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
Sponsors
GlaxoSmithKline
European Association of Urology Research Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 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. 4. 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. 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 no more than 13 weeks prior to randomization. Other examinations should be performed as clinically indicated. 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
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 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 3. The patient has received radiotherapy of the abdominal or pelvic region, within 6 months prior to randomization. 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. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Free Survival | 5 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 5 years | 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. |
| Disease-free Specific Survival | 5 years | 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. |
| Distant Metastasis-free Survival | 5 years | 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. |
Countries
Czechia, France, Germany, Italy, Netherlands, Poland, Romania, Russia, Spain, Ukraine
Participant flow
Recruitment details
83 patients were randomised, 52 for recMAGE-A3 +AS15 and 31 for placebo treatment. 6 patients did not start treatment due to ineligibility (4 for recMAGE-A3 +AS15 and 2 for placebo treatment).
Participants by arm
| Arm | Count |
|---|---|
| recMage-A3 + AS15 ASCI MAGE A3 positive patients treated with recMAGE-A3 + AS15 ASCI
recMAGE-A3 + AS15 ASCI: 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 | 48 |
| Placebo Placebo: 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 | 29 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Disease progression/recurrence | 17 | 10 |
| Overall Study | Facial palsy | 1 | 0 |
| Overall Study | IC withdrawal due to study cancellation | 1 | 0 |
| Overall Study | Patient decision | 3 | 0 |
| Overall Study | Patient moved to another city | 1 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Study Discontinuation, amendment 4 | 5 | 11 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | recMage-A3 + AS15 ASCI |
|---|---|---|---|
| Age, Continuous | 65.5 years STANDARD_DEVIATION 9.6 | 65.6 years STANDARD_DEVIATION 8.8 | 65.7 years STANDARD_DEVIATION 8.4 |
| Dominant Histological Type adenocarcinoma | 0 Participants | 1 Participants | 1 Participants |
| Dominant Histological Type Not available | 0 Participants | 1 Participants | 1 Participants |
| Dominant Histological Type squamous cell carcinoma | 0 Participants | 3 Participants | 3 Participants |
| Dominant Histological Type transitional (urothelial) cell carcinoma | 29 Participants | 72 Participants | 43 Participants |
| M-category of bladder cancer at diagnosis M0 | 29 Participants | 77 Participants | 48 Participants |
| M-category of bladder cancer at diagnosis M1 | 0 Participants | 0 Participants | 0 Participants |
| Mean Height | 169 cm STANDARD_DEVIATION 9.8 | 171 cm STANDARD_DEVIATION 8.4 | 172 cm STANDARD_DEVIATION 7.2 |
| Mean weight | 75.1 kg STANDARD_DEVIATION 12.8 | 74.1 kg STANDARD_DEVIATION 13.4 | 73.5 kg STANDARD_DEVIATION 13.3 |
| N-category classification of bladder cancer at diagnosis N0 | 22 Participants | 58 Participants | 36 Participants |
| N-category classification of bladder cancer at diagnosis N1 | 4 Participants | 11 Participants | 7 Participants |
| N-category classification of bladder cancer at diagnosis N2 | 3 Participants | 8 Participants | 5 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Czechia | 1 participants | 7 participants | 6 participants |
| Region of Enrollment France | 3 participants | 12 participants | 9 participants |
| Region of Enrollment Germany | 3 participants | 10 participants | 7 participants |
| Region of Enrollment Italy | 2 participants | 2 participants | 0 participants |
| Region of Enrollment Netherlands | 7 participants | 11 participants | 4 participants |
| Region of Enrollment Poland | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Russia | 2 participants | 5 participants | 3 participants |
| Region of Enrollment Spain | 11 participants | 29 participants | 18 participants |
| Sex: Female, Male Female | 8 Participants | 16 Participants | 8 Participants |
| Sex: Female, Male Male | 21 Participants | 61 Participants | 40 Participants |
| T-category of bladder cancer at diagnosis T2 | 13 Participants | 35 Participants | 22 Participants |
| T-category of bladder cancer at diagnosis T3 | 13 Participants | 34 Participants | 21 Participants |
| T-category of bladder cancer at diagnosis T4 | 3 Participants | 8 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 48 | 5 / 29 |
| other Total, other adverse events | 30 / 48 | 10 / 29 |
| serious Total, serious adverse events | 13 / 48 | 5 / 29 |
Outcome results
Primary
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.
Time frame: 5 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| recMage-A3 + AS15 ASCI | Disease Free Survival | 27.5 months |
| Placebo | Disease Free Survival | 19.8 months |
Secondary
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.
Time frame: 5 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| recMage-A3 + AS15 ASCI | Disease-free Specific Survival | 27.5 months |
| Placebo | Disease-free Specific Survival | 19.8 months |
Secondary
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.
Time frame: 5 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| recMage-A3 + AS15 ASCI | Distant Metastasis-free Survival | 31.5 months |
| Placebo | Distant Metastasis-free Survival | 21.4 months |
Secondary
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.
Time frame: 5 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| recMage-A3 + AS15 ASCI | Overall Survival | 35.5 months |
| Placebo | Overall Survival | 24.1 months |