Avelumab as neoadjuvant therapy in subjects with urothelial muscle invasive bladder cancers

Phase 1

Conditions: rothelial Carcinoma
MedDRA version: 21.1Level: LLTClassification code 10022877Term: Invasive bladder cancerSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2017-002758-35-BE

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

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)Subjects 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 enrolment.
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
Inclusion criterion specific for France:
Subjects must be affiliated to a social security system

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

Exclusion Criteria

1)Metastatic disease (M1)
2)Has had prior systemic chemotherapy, targeted small molecule therapy, or radiation therapy for urothelial carcinoma (previous BCG injections permitted)
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. Subjects 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 (antibiotics)
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) (test to be performed except if there are results available from less than 1 year).
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 enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (= New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.”
15)Pregnant or lactating women.
16)Subject with a significant medical, neuropsychiatric, 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 behavior; 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 subject inappropriate for entry into this study.
Exclusion criterion spe

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) following neoadjuvant treatment in patients with non-metastatic MIBC.<br>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.;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 neoadjuvant treatment in patients with non-metastatic MIBC.<br>Outcome measure: Pathologic response is defined as the absence of muscle invasive carcinoma (<ypT2N0 disease) on the final surgical specimen.<br>- To assess the toxicity profile<br>Outcome measure: using the adverse events reported during the study according to NCI CTCAE v4.03;Timepoint(s) of evaluation of this end point: end of the study

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