Avelumab as neoadjuvant therapy in subjects with urothelial muscle invasive bladder cancers
- Conditions
- rothelial CarcinomaMedDRA version: 20.0Level: LLTClassification code 10022877Term: Invasive bladder cancerSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2017-002758-35-FR
- Lead Sponsor
- Insitut Jules Bordet
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 183
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 =100,000/µL or 100x10 9/L
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 CockcroftGault formula (or local
institutional standard method) or
18) Peripheral neuropathy = grade 2 or
19) Hearing impaired = grade 2
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 83
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 100
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 immuno-stimulatory 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.
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: Primary objective: To assess the efficacy of Avelumab (anti-PD-L1) associated to different cytotoxic agents or in monotherapy in patients with non-metastatic MIBC as measured by the pathologic complete response rate (ypT0/Tis ypN0) following neoadjuvant treatment;Secondary Objective: To assess the safety and tolerability of the regimens used;Primary end point(s): To determine the pathologic complete response (ypT0/Tis ypN0)<br>following neoadjuvant treatment in patients with non-metastatic MIBC.<br>Outcome measure: Pathological complete response is defined as the<br>absence of invasive carcinoma (ypT0/Tis) disease and the absence of<br>microscopic lymph node metastases (ypN0) on the final surgical<br>specimen.;Timepoint(s) of evaluation of this end point: end of the study
- Secondary Outcome Measures
Name Time Method Secondary end point(s): To determine the pathologic response rate (<ypT2N0) following<br>neoadjuvant treatment in patients with non-metastatic MIBC.<br>Outcome measure: Pathologic response is defined as the absence of<br>muscle invasive carcinoma (<ypT2N0 disease) on the final surgical<br>specimen.<br>- To assess the toxicity profile<br>Outcome measure: using the adverse events reported during the study<br>according to NCI CTCAE v4.03;Timepoint(s) of evaluation of this end point: end of the study