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Trial record 1 of 1 for:    NCT03674424
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Avelumab as Neoadjuvant Therapy in Subjects With Urothelial Muscle Invasive Bladder Cancers (AURA Trial) (AURA)

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ClinicalTrials.gov Identifier: NCT03674424
Recruitment Status : Recruiting
First Posted : September 17, 2018
Last Update Posted : May 14, 2019
Sponsor:
Collaborator:
Merck KGaA, Darmstadt, Germany
Information provided by (Responsible Party):
Jules Bordet Institute

Brief Summary:

Open-label, interventional, multi-centre, randomized phase II study. Cancer studied is non-metastatic muscle invasive bladder cancer (MIBC).

Avelumab administered every 2 weeks is used as neoadjuvant therapy in subjects with urothelial muscle invasive bladder cancers in combination with standard chemotherapy or alone.


Condition or disease Intervention/treatment Phase
Non-metastatic Muscle Invasive Bladder Cancer Drug: Avelumab Procedure: cystectomy Combination Product: CG Combination Product: DD-MVAC Combination Product: PG Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 166 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Open-label, randomized study. 2 cohorts possible depending on cisplatin-eligibility. Afterwards randomization between 2 arms into the cohort.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Avelumab as Neoadjuvant Therapy in Subjects With Urothelial Muscle Invasive Bladder Cancers
Actual Study Start Date : June 1, 2018
Estimated Primary Completion Date : January 1, 2022
Estimated Study Completion Date : April 1, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer
Drug Information available for: Avelumab

Arm Intervention/treatment
Experimental: DD-MVAC + avelumab

Methotrexate, vinblastine, doxorubicin and cisplatin (DD-MVAC) given in combination with Avelumab.

DD-MVAC consists of Methotrexate 30 mg/m2 iv day 1, Vinblastine 3 mg/m2 iv day 2, Cisplatin 70 mg/m2 iv day 2 and Doxorubicin 30 mg/m2 iv day 2. Each cycle is given every 2 weeks for a maximum of 4 administrations Chemotherapy is associated with Avelumab 10 mg/kg, 1-hour intravenous (iv) infusion, given on day 2 every 2 weeks.

Cystectomy will be performed 3 to 6 weeks after last administration of chemotherapy

Drug: Avelumab
Chemotherapy with or without avelumab followed by surgery

Procedure: cystectomy
Cystectomy 3 to 6 weeks after last administration of chemotherapy

Combination Product: DD-MVAC
Chemotherapy 4 cycles of 2 weeks

Experimental: CG+ avelumab

Cisplatin, gemcitabine (CG) consists of Gemcitabine 1000 mg/m2 iv in day 1 and day 8 and Cisplatin 70 mg/m2 iv in day 1. Each cycle is given every 3 weeks for a maximum of 4 administrations.

Chemotherapy is associated with Avelumab 10 mg/kg, 1-hour intravenous (iv) infusion, given on day 1 every 2 weeks Cystectomy will be performed 3 to 6 weeks after last administration of chemotherapy

Drug: Avelumab
Chemotherapy with or without avelumab followed by surgery

Procedure: cystectomy
Cystectomy 3 to 6 weeks after last administration of chemotherapy

Combination Product: CG
Chemotherapy 4 cycles of 3 weeks

Experimental: PG+ avelumab

Paclitaxel, gemcitabine (PG) consists of Paclitaxel 80 mg/m2 iv in day 1 and day 15 and Gemcitabine 1000 mg/m2 iv in day 1 and day 15. Each cycle is repeated every 3 weeks for a maximum of 4 administrations.

Chemotherapy is associated with Avelumab 10 mg/kg, 1-hour intravenous (iv) infusion, given on day 1 every 2 weeks Cystectomy will be performed 3 to 6 weeks after last administration of chemotherapy

Drug: Avelumab
Chemotherapy with or without avelumab followed by surgery

Procedure: cystectomy
Cystectomy 3 to 6 weeks after last administration of chemotherapy

Combination Product: PG
Chemotherapy 2 cycles of 4 weeks

Experimental: Avelumab

Avelumab will be administered at a dose of 10 milligram per kilogram (mg/kg) 1-hour intravenous (iv) infusion once every 2 weeks. Dose reductions are not allowed.

Avelumab will be given alone for 4 administrations. Cystectomy will be performed 2 weeks after the last administration of avelumab

Drug: Avelumab
Chemotherapy with or without avelumab followed by surgery

Procedure: cystectomy
Cystectomy 3 to 6 weeks after last administration of chemotherapy




Primary Outcome Measures :
  1. To determine the pathologic complete response (ypT0/Tis ypN0) following neoadjuvant treatment in patients with non-metastatic MIBC. [ Time Frame: during surgery ]
    - Outcome measure: Pathological complete response is defined as the absence of invasive carcinoma (ypT0/Tis) disease and the absence of microscopic lymph node metastases (ypN0) on the final surgical specimen.


Secondary Outcome Measures :
  1. To determine the pathologic response rate (<ypT2N0) following neoadjuvant treatment in patients with non-metastatic MIBC. [ Time Frame: during surgery ]
    Outcome measure: Pathologic response is defined as the absence of muscle invasive carcinoma (<ypT2N0 disease) on the final surgical specimen.

  2. Assessment of the toxicity profile of regimen using the adverse events reported: NCI CTCAE v4.03 [ Time Frame: through study completion, an average of 3 months ]
    Outcome measure: adverse events reported during the study according to NCI CTCAE v4.03



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

General Inclusion Criteria:

  1. Age ≥ 18 years old
  2. Must have histologically confirmed muscle invasive urothelial carcinoma (transitional cell carcinoma) or urothelial carcinoma with mixed histology of the bladder, renal pelvis or ureters. Stage permitted: T2, T3 or T4a. T stage is based on the standard of care transurethral resection of the bladder tumour (TURBT) sample
  3. Patients may have nodal disease (Nx, N0, N1 or N2) at imagery but there must be no evidence of distant metastases (M0)
  4. Performance status 0 or 1 on the Eastern Cooperative Oncology Group (ECOG).
  5. Be a medically appropriate candidate for surgery as determined by an attending urologist
  6. Adequate bone marrow function as defined below:

    • Absolute neutrophil count ≥1500/µL or 1.5x109/L
    • Hemoglobin ≥ 9 g/dL
    • Platelets ≥100000/µL or 100x109/L 7)
  7. Adequate liver function as defined below:

    • Serum total bilirubin ≤ 1.5 x ULN. In case of known Gilbert's syndrome < 3xUNL is allowed
    • AST (SGOT)/ALT (SGPT) ≤ 2.5 x ULN
  8. Serum pregnancy test (for subjects of childbearing potential) negative within 7 days prior to study treatment administration.
  9. Women of childbearing potential must agree to use one highly effective method of contraception prior study entry, during the course of the study and up to 6 months after the last administration of study treatment. Men with childbearing potential partner must agree to use condom during the course of this study and up to 6 months after the last administration of the study treatment.
  10. Completion of all necessary screening procedures within 28 days prior to treatment.
  11. Availability of biological material for screening and/or translational research activities
  12. Signed Informed Consent form (ICF) obtained prior to any study related procedure.

    Cisplatin-eligible cohort specific criteria:

  13. Glomerular filtration rate (GFR) or Creatinine Clearance≥ 60 mL/min according to the Cockcroft-Gault formula (or local institutional standard method) and
  14. Peripheral neuropathy ≤ grade 1 and
  15. Hearing impaired ≤ grade 1 and
  16. Adequate cardiac function (Left Ventricular Ejection Fraction LVEF ≥ 55%) by MUGA (Multiple-Gated Acquisition) scan or echocardiography

    Cisplatin ineligible cohort specific criteria (if any of the following criteria):

  17. Glomerular filtration rate (GFR) or Creatinine Clearance ≥ 30mL/min according to the Cockcroft-Gault formula (or local institutional standard method) or
  18. Peripheral neuropathy ≥ grade 2 or
  19. Hearing impaired ≥ grade 2

    Inclusion criterion specific for France:

  20. Patients must be affiliated to a social security system

Exclusion Criteria:

Subjects meeting one of the following criteria are not eligible for this study:

  1. Metastatic disease (M1)
  2. Has had prior systemic chemotherapy, targeted small molecule therapy, or radiation therapy for urothelial carcinoma
  3. Prior treatment with drug specifically targeting T-cell co-stimulation or checkpoint pathways
  4. Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
  5. Has an active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
  6. Has had a prior organ transplantation including allogenic stem-cell transplantation.
  7. Has an active infection requiring systemic therapy
  8. Has a known history of Human Immunodeficiency Virus (HIV) or known acquired immunodeficiency syndrome.
  9. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA is detected)
  10. Has received vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines such as influenza vaccine.
  11. Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 28 days prior to study registration
  12. History of prior invasive malignancy within 2 years (exception of adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localised prostate cancer or ductal carcinoma in situ)
  13. Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3)
  14. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrolment), myocardial infarction (< 6 months prior to enrolment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication."
  15. Pregnant and/or lactating women.
  16. Subject with a significant medical, neuro-psychiatric, or surgical condition, currently uncontrolled by treatment, which, in the principal investigator's opinion, may interfere with completion of the study.
  17. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade >1); however, alopecia, sensory neuropathy Grade ≤2, or other Grade ≤2 not constituting a safety risk based on investigator's judgment are acceptable.
  18. Other severe acute chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behaviour; or laboratory abnormalities that may increase the risk associated with the study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

    Exclusion criterion specific for France:

  19. Vulnerable persons according to the article L.1121-6 of the CSP, adults who are the subject of a measure of legal protection or unable to express their consent according to article L.1121-8 of the CSP.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03674424


Locations
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Belgium
Centre Hospitalier Universitaire et Psychiatrique de Mons-Borinage Recruiting
Mons, Hainaut, Belgium, 7000
Contact: Vinciane Casert, MD    0032 65 39 22 83    vinciane.casert@hap.be   
Institut Jules Bordet Recruiting
Brussels, Belgium, 1000
Contact: Thierry Gil, MD    0032 2 541 31 88    thierry.gil@bordet.be   
CHU de Liège Sart Tilman Recruiting
Liège, Belgium, 4000
Contact: Brieuc Sautois, MD    0032 4 366 82 03    Brieuc.Sautois@ulg.ac.be   
CHU Namur - Sainte Elisabeth Recruiting
Namur, Belgium, 5000
Contact: Vincent Vanhaudenarde    0032 81 72 05 47    vincent.vanhaudenarde@uclouvain.be   
Sponsors and Collaborators
Jules Bordet Institute
Merck KGaA, Darmstadt, Germany

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Responsible Party: Jules Bordet Institute
ClinicalTrials.gov Identifier: NCT03674424     History of Changes
Other Study ID Numbers: IJB-AURA-ODN-004
First Posted: September 17, 2018    Key Record Dates
Last Update Posted: May 14, 2019
Last Verified: September 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs