A Phase III, Randomized, Open-Label, Multi-Center, Global Study to Determine the Efficacy and Safety of Durvalumab in Combination with Gemcitabine+Cisplatin for Neoadjuvant Treatment Followed by Durvalumab Alone for Adjuvant Treatment in Patients with Muscle-Invasive Bladder Cancer

The standard management for patients with muscle-invasive bladder cancer (MIBC)
involves radical cystectomy and pelvic lymph node dissection.
Despite improvements of pCR and survival rates with neoadjuvant chemotherapy,
many patients will still develop recurrence and will ultimately die of
metastatic bladder cancer.
The rationale for the present study is that PD-L1 inhibition through exposure
to durvalumab, in combination with chemotherapeutics such as G+C, may increase
both the long-term response rate and the frequency of response by preventing
the MIBC tumor cells from evading immune-mediated anti-tumor response.
Administering durvalumab may provide a benefit to patients by averting
intrinsic resistance. Adjuvant durvalumab monotherapy may further improve time
to disease relapse in patients.

This study has been transitioned to CTIS with ID 2023-510015-19-00 check the CTIS register for the current data.

The treatment options currently available for MIBC- patients remain limited,
current standard therapy is likely to result in modest improvements in
long-term survival, and additional and alternative therapies are required for
patients with MIBC. Therefore, there remains an unmet medical need for this
patient population. In this study, gemcitabine and cisplatin will be combined
with the PD-L1 inhibitor durvalumab to broaden the therapeutic effect of
durvalumab monotherapy for the treatment of patients with MIBC.

Approximately 1050 patients globally will be randomized to receive durvalumab +
G+C combination therapy (Arm1) or G+C combination therapy (Arm2) of neoadjuvant
chemotherapy prior to radical cystectomy. Following radical cystectomy and
during adjuvant therapy, patients in Arm 1 will receive durvalumab monotherapy
, and patients in Arm 2 will receive no adjuvant treatment.

Neo-adjuvant treatment
Patients randomized to the 2treatment arms, Arm 1 or Arm 2, will be treated
according to their renal function. Recruitment for patients with borderline
renal function will be limited to up to 20% of the targeted global population.

Patients with adequate renal function (creatinine clearance [CrCl]>=60 mL/min):
- Arm 1: Day 1: durvalumab 1500 mg intravenous (IV), cisplatin 70 mg/m2,
gemcitabine 1000 mg/m2; Day8: gemcitabine 1000mg/m2; every 21 days for 4
cycles.
- Arm 2: Day 1: cisplatin 70 mg/m2, gemcitabine 1000mg/m2; Day8:gemcitabine
1000mg/m2; every 21 days for 4 cycles.

Patients with borderline renal function (CrCl >=40 mL/min to <60 mL/min):
- Arm 1: Day 1: durvalumab 1500 mg IV, cisplatin 35mg/m2, gemcitabine 1000
mg/m2; Day 8: gemcitabine 1000 mg/m2, cisplatin 35 mg/m2; every 21 daysfor 4
cycles.
- Arm 2: Day 1: cisplatin 35 mg/m2, gemcitabine 1000mg/m2; Day8:gemcitabine
1000mg/m2, cisplatin 35 mg/m2; every 21 days for 4 cycles.

Adjuvant therapy (regardless of renal status)
- Arm 1: Day 1: durvalumab 1500 mg IV; every 28 days for 8 cycles.
- Arm 2: No adjuvant treatment.

Study subject will visit the hospital appr. 20 times for screening and
treatment visits. On several visits the subject will have the following
assessments done:
- Physical exam
- urine and blood tests
- ECG
- CT or MRI scan
- medical history, race and ethnicity, concomitant medication
- AE/SAE
- biopsy
- questionnaires (EORTC QLQ-C30, PGIS, and EQ-5D-5)
- ECOG performance status
- pregnancy test

Durvalumab and some of the study procedures may cause side effects. Most common
side effects with durvalumab are:
Diarrhea, rash/dry itchy skin, liver problems, feeling tired, nausea, vomiting,
abdominal pain, accumulation of fluid causing swelling, upper respiratory tract
infections, decreased appetite, shortness of breath, cough, pain in muscles and
joints and, fever.