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

Phase 2

Terminated

Conditions: Urinary Bladder Neoplasms

Interventions: Biological: recMAGE-A3 + AS15 ASCI
Biological: Placebo

Registration Number: NCT01435356

Lead Sponsor: European Association of Urology Research Foundation

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).

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 83

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
recMage-A3 + AS15 ASCI	recMAGE-A3 + AS15 ASCI	MAGE-A3 positive patients treated with recMAGE-A3 + AS15 ASCI
Placebo	Placebo	MAGE-A3 positive patients treated with placebo

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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.

Trial Locations

Locations (50): NKI
🇳🇱
Amsterdam, Netherlands
Saint Petersburg State Institution of Health Care "City Multi-Field Hospital #2"
🇷🇺
St. Petersburg, Russian Federation
St Antoniusziekenhuis
🇳🇱
Nieuwegein, Netherlands
RadboudUMC
🇳🇱
Nijmegen, Netherlands
Federal State Institution "Moscow Research Oncology Institute named after P.A. Gertsen" of the Ministry of Healthcare and Social Development of the Russian Federation
🇷🇺
Moscow, Russian Federation
Institution of the Russian Academy of Medical Science Russian Oncology Research Center named after N.N. Blokhin of RAMS
🇷🇺
Moscow, Russian Federation
Università Vita e Saluta
🇮🇹
Milano, Italy
Università di Roma, La Sapienza
🇮🇹
Rome, Italy
Ospedaliera di Perugia
🇮🇹
Perugia, Italy
Faculty teaching Hospital in Plzen
🇨🇿
Plzen, Czechia
Thomayerova nemocnice
🇨🇿
Prague, Czechia
Hospital Motol
🇨🇿
Prague, Czechia
Hôpital Edouard Herriot
🇫🇷
Lyon, France
Institut Curie
🇫🇷
Paris, France
Institut Bergonié
🇫🇷
Bordeaux, France
Krajska zdravotni, a.s. - Masarykova nemocnice v Usti nad Labem, o.z.
🇨🇿
Usti nad Labem, Czechia
Universitätsklinikum Aachen
🇩🇪
Aachen, Germany
Hôpital Rangueil
🇫🇷
Toulouse, France
Heinrich-Heine University
🇩🇪
Düsseldorf, Germany
Universitätsklinikum C.-G. Carus Dresden
🇩🇪
Dresden, Germany
Universitätsklinikum Giessen
🇩🇪
Giessen, Germany
Waldkrankenhaus St. Marien gGmbH
🇩🇪
Erlangen, Germany
Universitätsklinikum Marburg
🇩🇪
Marburg, Germany
Universitätklinikum Rostock
🇩🇪
Rostock, Germany
Universitätsklinikum Tübingen
🇩🇪
Tübingen, Germany
Klinikum rechts der Isar der TU München
🇩🇪
München, Germany
Universitätsklinikum Jena
🇩🇪
Jena, Germany
Universitätsmedizin
🇩🇪
Mannheim, Germany
Universitaria Policlinico Consorziale di Bari
🇮🇹
Bari, Italy
Universitaria Pisana
🇮🇹
Pisa, Italy
Clinical County Emergency Hospital Craiova
🇷🇴
Craiova, Romania
Fundeni Clinical Institute
🇷🇴
Bucharest, Romania
Kliniczny Dzial Urologii Swietokrzyskiego Centrum Onkologii
🇵🇱
Kielce, Poland
Federal State Budget Institution "Scientific Research Institute of Urology" of the Ministry of Healthcare and Social Development of the Russian Federation
🇷🇺
Moscow, Russian Federation
Municipal Budget Institution of Health Care "Clinical Diagnostic Center "Zdorovie" of Rostov-on-Don city"
🇷🇺
Rostov-on-Don, Russian Federation
Medical University of Warsaw
🇵🇱
Warsaw, Poland
Oddzial Urologii Miedzyleski Szpital Specjalistyczny w Warszawie
🇵🇱
Warsaw, Poland
Hospital Universitario A Coruña
🇪🇸
A Coruña, Spain
Hospital Universitario Principe de Asturias
🇪🇸
Alcalá de Henares, Spain
Hospital Universitario Fundación Alcorcón
🇪🇸
Alcorcón, Spain
Fundación Puigvert
🇪🇸
Barcelona, Spain
Hospital Clinic Barcelona
🇪🇸
Barcelona, Spain
Hospital del Mar
🇪🇸
Barcelona, Spain
Hospital Universitario Puerta del Mar
🇪🇸
Cádiz, Spain
Hospital 12 de Octubre, Fundación de Investigación Biomédica
🇪🇸
Madrid, Spain
Hospital Universitario La Paz
🇪🇸
Madrid, Spain
Hospital Infanta Sofia
🇪🇸
San Sebastián de los Reyes, Spain
Kyiv City Clinical Oncology Hospital
🇺🇦
Kiev, Ukraine
Hospital Universitario Central de Asturias
🇪🇸
Oviedo, Spain
Hôpital Huriez
🇫🇷
Lille, France