Neoadjuvant and Adjuvant Durvalumab in Combination With Neoadjuvant Chemotherapy in Patients With Operable Urothelial Cancer. A Multicenter, Single-arm Phase II Trial
Overview
- Phase
- Phase 2
- Intervention
- Neoadjuvant and adjuvant durvalumab
- Conditions
- Urothelial Cancer
- Sponsor
- Swiss Group for Clinical Cancer Research
- Enrollment
- 61
- Locations
- 17
- Primary Endpoint
- event-free survival (EFS)
- Status
- Completed
- Last Updated
- 12 months ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
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
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
Arms & Interventions
Durvalumab in combination with standard therapy
Combination of standard therapy consisting (4 cycles cisplatin/ gemcitabin followed by surgery) with 4 cycles of neoadjuvant durvalumab and 10 cycles of adjuvant durvalumab
Intervention: Neoadjuvant and adjuvant durvalumab
Outcomes
Primary Outcomes
event-free survival (EFS)
Time Frame: 2 years after treatment start
The primary endpoint of the trial is Event-free survival (EFS) at 2 years after neoadjuvant trial treatment start. Event-free survival is defined as the time from treatment start until one of the following events, whichever comes first: * Progression during neoadjuvant treatment leading to inoperability * Recurrence of locoregional disease after surgery * Appearance of metastases at any localization * Death Patients not experiencing an event will be censored at the date of the last available assessment before initiation of a subsequent treatment, if any.
Secondary Outcomes
- Event-free survival (EFS)(at the occurrence of the event or latest 5 years after surgery)
- Recurrence-free survival (RFS) after R0 resection(at recurrence or latest 5 years after surgery)
- Overall survival (OS)(at death or latest 5 years after surgery)
- Quality of resection(after surgery or the latest 20 weeks after registration)
- Pathological complete response rate (ypT0)(after surgery or the latest 20 weeks after registration)
- Pathological response rate (PaR) defined by pathological downstaging to ≤ypT1N0M0(after surgery or the latest 20 weeks after registration)
- Pattern of recurrence(after recurrence or latest 5 years after surgery)
- Treatment feasibility(after treatment end or the latest 73 weeks after registration)
- Adverse events(within treatment start and 90 days after last trial treatment and resolution of all related AEs thereafter (at the latest 5 years after surgery))