Avelumab as Neoadjuvant Therapy in Subjects With Urothelial Muscle Invasive Bladder Cancers (AURA Trial)

• Status: Recruiting
• Trial end date: 2022-12-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Jules Bordet Institute
• Collaborators: Merck KGaA, Darmstadt, Germany; Merck Sharp & Dohme Corp.
• Treatments: Antibodies, Monoclonal; Avelumab

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.