Neoadjuvant and Adjuvant Durvalumab in Combination With Neoadjuvant Chemotherapy in Patients With Operable Urothelial Cancer.

The main objective is to demonstrate that the addition of neoadjuvant and adjuvant immunotherapy with durvalumab, to standard neoadjuvant chemotherapy (with cisplatin/gemcitabine) and surgery in urothelial carcinoma could improve event-free survival.

Despite optimal surgical management the prognosis for localized muscle invasive urothelial cancer (MIUC) is unfavorable with 5-year overall survival of around 45%.

According to international guidelines the use of cisplatin-based neoadjuvant chemotherapy is considered standard of care in all patients with localized MIUC with planned curative local treatment.

However, the benefit of neoadjuvant chemotherapy is limited and there is a clear medical need for improvement for this patient population.

Durvalumab has been tested in a phase I/II open-label study including patients with metastatic urothelial cancer (mUC).

The results demonstrated an overall response rate (RR) of 31% in 42 response-evaluable patients. The side effect profile was favorable with most common grade 1/2 AE representing fatigue (13%), diarrhea (10%) and decreased appetite (8%). Three patients (4.9%) had treatment related grade 3 AE's, no grade 4/5 events were noted.

The combination of cisplatin/gemcitabine chemotherapy with modern immune-checkpoint inhibition has been demonstrated to be feasible with demonstration of favorable immunomodulatory effects.

In view of these data it appears a logical step to apply these novel agents in the curative setting of neoadjuvant treatment.

The expected benefit of combining chemotherapy with durvalumab and to continue durvaluamb postoperatively might be twofold:

* to increase the response rate in the pre-operative setting and subsequently to increase the rate of pathologic complete remission (pT0) and to reduce risk of local recurrence
* to evoke durable systemic anti-cancer responses and subsequently to increase disease free- and overall survival and furthermore to induce antitumor immune response.

Eligibility Criteria:
Inclusion Criteria:

* Written informed consent according to ICH/GCP regulations before registration and prior to any trial specific procedures
* Histologically proven urothelial cell carcinoma of the bladder, urethra or upper urinary tract (T2, T3, or T4a and ≤ N1 (defined as a solitary lymph node ≤ 2 cm in the greatest dimension), M0) and be considered suitable for curative multimodality treatment including surgery by a multidisciplinary tumor board. Cytological diagnosis is only allowed for upper tract urothelial carcinoma. In these cases tumor has to be documented by urography
* All histological subtypes eligible if urothelial carcinoma predominant (exception: small cell component)
* Age ≥ 18 years
* WHO performance status 0-1
* Bone marrow function: hemoglobin ≥ 90 g/L, neutrophil count ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L
* Hepatic function: bilirubin ≤ 1.5 x ULN (except for patients with Gilbert's disease ≤ 3.0 x ULN), AST ≤ 2.5 x ULN and ALT ≤ 2.5 x ULN, alkaline phosphatase ≤ 2.5 x ULN
* Renal function: estimated glomerular filtration rate (eGFR) \> 50 mL/min/1.73m², according to CKD-EPI formula
* Cardiac function: Left ventricular Ejection Fraction (LVEF) ≥ 50% as determined by echocardiography (ECHO)
* Women with child-bearing potential are using effective contraception (for details of definition see 9.9), are not pregnant or lactating and agree not to become pregnant during trial treatment and during 90 days thereafter. A negative pregnancy test before inclusion into the trial is required for all women with child-bearing potential
* Men agree not to father a child during trial treatment and during 90 days thereafter
* Body weight \> 30kg.

Exclusion Criteria:

* Any pathological evidence of small-cell carcinoma component
* Presence of any distant metastasis
* History of hematologic or primary solid tumor malignancy, unless in remission for at least 3 years before registration, with the exception of adequately treated cervical carcinoma in situ, localized non-melanoma skin cancer or low risk localized prostate cancer (T1-T2a, Gleason \<7, PSA \<10ng/ml)
* Any previous treatment with a PD-1 or PD-L1 inhibitor, including durvalumab
* Concurrent treatment with prednisone (or equivalent); except for the prophylactic medication before chemotherapy, treatment of acute hypersensitivity reactions or chronic treatment (initiated \> 6 months prior to registration) at low dose (≤ 10 mg/day of prednisone or an equivalent corticosteroid)
* Concurrent treatment with other experimental drugs or other anticancer therapy, treatment in a clinical trial within 28 days prior to registration
* Current or prior use of immunosuppressive medication within 28 days prior to registration, with the exception of intranasal and inhaled corticosteroids or systemic corticosteroids
* Major surgical procedure within 28 days prior to registration
* Preexisting peripheral neuropathy (\> grade 1)
* Uncontrolled diabetes mellitus
* Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion:

  * Patients with vitiligo or alopecia
  * Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
  * Any chronic skin condition that does not require systemic therapy
  * Patients without active disease in the last 5 years may be included but only after consultation with the coordinating investigator
  * Patients with celiac disease controlled by diet alone
* Known history of human immunodeficiency virus (HIV) or active chronic Hepatitis C or Hepatitis B Virus infection or any uncontrolled active systemic infection requiring intravenous (iv) antimicrobial treatment
* History of allogeneic organ transplant
* Receipt of live attenuated vaccine within 30 days prior to registration. Note: Patients, if enrolled, should not receive live vaccine during trial treatment and up to 30 days after the last dose
* Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
* Any concurrent drug contraindicated for blocking the effect of durvalumab; this includes systemic corticosteroids, methotrexate, azathioprine, and tumor necrosis factor (TNF)-α blockers. Any concurrent drug contraindicated for use with the other trial drugs according to the locally approved product information
* Known hypersensitivity to cisplatin, gemcitabine or durvalumab or to any excipient
* Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab.