First-line Gemcitabine/Cisplatin +/- Avelumab in Locally Advanced or Metastatic Bladder Carcinoma

This study will assess efficacy (based on response rate) and safety (based on grade ≥ 3 severe adverse effects) of the combination Gemcitabine Cisplatin (GC) + anti-PD-L1 (avelumab) in first-line treatment for locally advanced or metastatic urothelial bladder cancer patients, after 6 cycles of treatment (or at 18 weeks if less than 6 cycles have been given, or earlier if a second line treatment is needed, before this new anticancer treatment has been started).

Recent results in cancer research highlight the importance of immune checkpoints in the control of immune response and provide access to molecules interfering with the inhibited immune response during the development of cancer. Drugs targeted against CTLA-4, PD-1 or PD-L1 have shown efficacy in various tumor types. In locally advanced or metastatic urothelial bladder cancer (MBC), the standard first-line treatment is the association of Gemcitabine and Cisplatin (GC). Objective responses and prolonged objective responses have been reported with monoclonal antibodies against PD-1 or PD-L1 in MBC patients after failure of chemotherapy. Avelumab is an investigational fully human anti-PD-L1 IgG1 monoclonal antibody. Avelumab treatment did not show unexpected cross-toxicity with chemotherapy when studied in phase I / II in patients with different tumor types. So the combination at full doses of GC and avelumab seems appropriate.

The experimental treatment is a combination of GC and avelumab given for 6 cycles. The duration of each cycle is 3 weeks (Gemcitabine: dose of 1000 mg/m2 as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle; Cisplatin: dose of 70 mg/m2 as a slow intravenous infusion over 2 to 4 hours on Day 1 of each 21-day cycle; Avelumab: 10 mg/kg body weight administered Iv once every 3 weeks).

Patients who have received all scheduled treatments and whose disease has not progressed at the end of treatment will enter into disease follow-up. During this follow-up period, patients will have disease and safety assessments performed every 3 months. Patients will remain in follow-up for up to 1 year from last dose of treatment and will have survival follow-up.

Eligibility Criteria:
Inclusion Criteria:

1. Signed and dated informed consent;
2. Male or female, age ≥18 years at time of informed consent signature;
3. Histological confirmed locally advanced (any T N2-3) or metastatic urothelial bladder carcinoma, eligible to first-line treatment (previous neo adjuvant or adjuvant treatment must have been given and stopped more than one year before);
4. Evidence of progressive disease in the previous 6 months, documented by chest and/or abdominal CT-scan or MRI;
5. Measurable disease according to RECIST 1.1;
6. Karnofsky index ≥ 70%;
7. Availability of a representative formalin-fixed, paraffin-embedded (FFPE) tumour specimen (infiltrative urothelial bladder carcinoma or metastasis) collected within 12 months before Cycle 1 Day 1;
8. At least 3 weeks since the end of prior local intravesical treatment (BCG-therapy or ametycine) with resolution of all treatment-related toxicity to grade ≤1 (NCI CTCAE 4.0);
9. Palliative local treatment is allowed if performed ≥ 2 weeks prior study entry for radiotherapy, cimentoplasty or minor surgery, and ≥4 weeks for major surgery;
10. Adequate organ function as defined by the following criteria:

    1. Absolute White Blood Cells count (WBC) ≥ 2000 cells/mm3
    2. Absolute Neutrophils count (ANC) ≥ 1500 cells/mm3
    3. Platelets ≥100 000 cells/mm3
    4. Hemoglobin ≥ 9.0 g/dL
    5. Total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and AST and ALT levels ≤ 2.5 × ULN or AST and ALT levels ≤ 5 x ULN (for subjects with documented metastatic disease to the liver).
    6. Calculated creatinine clearance ≥ 60 mL/min
11. Women of childbearing potential must have a negative serum βHCG or urine pregnancy test within 7 days prior to initiation of treatment; both sexually active females and males (and their female partners) patients must agree to use two methods of effective contraception one of them being a barrier method, or to abstain from sexual activity during the study, for at least 3 months after the last administration of study treatment;
12. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures;
13. Patient affiliated to a social security system or beneficiary of the same.

Exclusion Criteria:

1. Other prior first-line therapy;
2. Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment; focal radiation therapy less than 14 days prior to the first day of the first cycle;
3. Other invasive malignancy within 3 years (except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix or breast); Patient with low risk prostate cancer (defined as Stage T1/T2a, Gleason score ≤ 7 and PSA ≤ 10ng/mL) who are treatment-naïve and undergoing active surveillance are eligible;
4. 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;
5. Symptomatic central nervous system (CNS) metastases or untreated CNS metastases requiring concurrent treatment;
6. 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;
7. Uncontrolled adrenal insufficiency;
8. Active chronic liver disease;
9. Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, 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 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;
10. Active infection requiring systemic antibiotic;
11. Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines;
12. 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);
13. Major surgery less than 28 days prior to the first day of the first cycle. Minor surgery less than 14 days prior to the first day of the first cycle;
14. 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;
15. History of primary immunodeficiency;
16. History of organ transplant including allogeneic stem-cell transplantation;
17. 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);
18. Women who are pregnant or lactating;
19. Known history of testing positive for HIV or known acquired immunodeficiency syndrome;
20. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection.