Neoadjuvant Upper Tract Invasive Cancer Trial (NAUTICAL)

Study Overview
=================
Brief Summary
-----------------
Upper tract urothelial cancer (UTUC) is cancer in the lining of the kidney or ureter (the tube that drains the kidney). This type of cancer is rare and as a result, there are only a few studies that have looked at it. Standard of care for UTUC would be surgery followed by chemotherapy (adjuvant chemotherapy). However, we know from studies that have looked at cancer of the lining of the bladder, which is a similar cancer in many ways, that treating people with chemotherapy before surgery (neoadjuvant chemotherapy) can lead to longer survival compared to the standard of care. There are no studies to show this in UTUC. Neoadjuvant chemotherapy is thought to help improve survival by treating any cancer that may have spread from the original tumour but that is not visible yet on scans. This study would be the first clinical trial in Canada to evaluate the use of chemotherapy before surgery in this disease setting. Since UTUC is rare, the purpose of this study is to determine if it is possible to enrol enough patients to a trial looking at the use of chemotherapy before surgery.

Official Title
-----------------
Neoadjuvant Chemotherapy in Upper Tract Urothelial Cancer: A Multicentre, Feasibility Pilot Trial

Conditions
-----------------
Bladder Cancer, Bladder Urothelial Carcinoma

Intervention / Treatment
-----------------
* Drug: Gemcitabine
* Drug: Cisplatin
* Drug: Carboplatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Newly diagnosed radiographically visible (CT or MRI) cT1-4 N0 M0 with positive selective urinary cytology, positive bladder urinary cytology, or endoscopic biopsy for high grade urothelial cell carcinoma Age ≥18 years of age Eastern Cooperative Oncology Group (ECOG) score 0-1 Medically appropriate candidate for radical nephroureterectomy or ureterectomy as per participating site attending urologic oncologist Medically appropriate candidate for cisplatin-based chemotherapy as per participating site attending medical oncologist Adequate organ system function defined as follows: absolute neutrophil count ≥ 1500/mm3, platelets ≥ 100,00/mm3, hemoglobin ≥ 90 g/L, ALT and AST < 2.5 x upper limit of normal, electrolytes (Na, K, Mg, Ca): within normal limits, GFR ≥ 60 mL/min Patients who are randomized to the adjuvant chemotherapy will be reassessed for suitability to receive adjuvant chemotherapy after definitive surgery (nephroureterectomy or ureterectomy) based on the following criteria: pT2-4 N0-3 M0 or pT any N1-3 M0 with predominant urothelial component ECOG score 0-2 Medically appropriate candidate for platin-based chemotherapy as per participating site attending medical oncologist Adequate organ system function defined as follows: absolute neutrophil count ≥ 1500/mm3, platelets ≥ 100,00/mm3, hemoglobin ≥ 90 g/L, ALT and AST < 2.5 x upper limit of normal, electrolytes (Na, K, Mg, Ca): within normal limits, GFR ≥ 30 mL/min Exclusion Criteria: Metastatic disease Radiographically visible nodal disease Concurrent muscle-invasive bladder cancer (non-muscle invasive bladder cancer is acceptable) Solitary kidney Other cancer diagnosis or systemic chemotherapy use within 2 years of study enrollment (prior bladder cancer and intravesical therapy allowed) Concomitant diseases that are a formal exclusion to cisplatin chemotherapy (deafness, ≥ grade II neuropathy, serious active infection) Concomitant use of any other investigational drugs Pregnancy or breast feeding (you must remain on contraception, not father a child or donate sperm while receiving gemcitabine/cisplatin and for 6 months following the last dose)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant Chemotherapy Arm<br>Gemcitabine/Cisplatin will be administered on a 3-week cycle for up to 4 cycles. This will be followed by surgical intervention (nephroureterectomy or ureterectomy). | Drug: Gemcitabine<br>* Gemcitabine 1000 mg/m^2, IV infusion on days 1 and 8 of each 3-week cycle<br>* Other names: Gemzar;Drug: Cisplatin<br>* Cisplatin 70 mg/m^2, IV infusion on day 1 of each 3-week cycle<br>* Other names: Platinol;|
| Active Comparator: Adjuvant Chemotherapy Arm (Standard of Care)<br>Patients will undergo surgical intervention (nephroureterectomy or ureterectomy) followed by adjuvant chemotherapy. Patients with a GFR greater or equal to 60 mL/min will receive Gemcitabine/Cisplatin while those with a GFR greater or equal to 30 mL/min but less than 60 mL/min will receive Gemcitabine/Carboplatin. Gemcitabine/Cisplatin will be administered on a 3-week cycle for up to 4 cycles. Gemcitabine/Carboplatin will be administered on a 3-week cycle for up to 4 cycles. | Drug: Gemcitabine<br>* Gemcitabine 1000 mg/m^2, IV infusion on days 1 and 8 of each 3-week cycle<br>* Other names: Gemzar;Drug: Cisplatin<br>* Cisplatin 70 mg/m^2, IV infusion on day 1 of each 3-week cycle<br>* Other names: Platinol;Drug: Carboplatin<br>* Carboplatin AUC 5-6 calculated using the Calvert formula on day 1 of each cycle<br>* Other names: Paraplatin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of enrolling cT1-4N0 M0 UTUC patients in a randomized trial of neoadjuvant chemotherapy versus standard of care by assessing pilot trial recruitment rates |  | 24 months | 
| Disease-free survival (DFS) | DFS is defined as the time from randomization to development of intravesical recurrence, contralateral upper tract recurrence or distant metastasis | 36 months | 
| Rate of complete pathologic response | Complete pathologic response is defined as pT0 N0 | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Site-specific enrolment rate |  | 24 months | 
| Number of patients approached per site per month |  | 24 months | 
| Number of patients randomized per site per month |  | 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Upper tract urothelial carcinoma, UTUC