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Feasibility of Neo-adjuvant Versus Adjuvant Chemotherapy in Upper Tract Urothelial Carcinoma (URANUS)

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ClinicalTrials.gov Identifier: NCT02969083
Recruitment Status : Recruiting
First Posted : November 21, 2016
Last Update Posted : July 22, 2019
Sponsor:
Collaborator:
Centre for Human Drug Research, Netherlands
Information provided by (Responsible Party):
The European Uro-Oncology Group

Brief Summary:
The aim of this study is to explore feasibility of Upper Tract Urothelial Carcinoma (UTUC) treatments based in real world data in various European countries. The study will allow to gain insight in the true proportion of patients that fit to receive complete cisplatin-based neo-adjuvant or adjuvant chemotherapy, and the proportion and clinical outcome of patients with poor prognostic factors (PS and renal function) who receive only standard treatment (Radical nephroureterectomy (RNU)). This comparison will be made using a uniform diagnostic and treatment protocol.

Condition or disease Intervention/treatment Phase
Upper Tract Urothelial Carcinoma Procedure: RNU Drug: Gemcitabine/Cisplatin Drug: M-VAC Protocol Phase 2

Detailed Description:

There are no definitive treatment recommendations for patients diagnosed with UTUC. Radical nephroureterectomy (RNU) has been considered the gold standard treatment for UTUC. However due to the high recurrence rates reported, patients are often offered perioperative chemotherapy provided that they have a good renal function and performance status. With regard to the choice of chemotherapy treatment, there are also no clear recommendations since there are no data from randomized studies. If perioperative chemotherapy is considered in daily practice, gemcitabine/cisplatin regimen is often chosen and occasionally dd-MVAC.

The aim of this study is to explore feasibility of UTUC treatments based in real world data in various European countries. Patients who fulfil good prognostic factors (inclusion criteria for treatment randomization) will be allocated to neo-adjuvant (Arm B) or adjuvant (Arm C) chemotherapy (receiving 3 cycles of gemcitabine/cisplatin or dose dense Methotrexate, Vinblastine, Adriamycin, and Cisplatin (MVAC). Patients who don't fulfil criteria for treatment randomization will undergo Radical nephroureterectomy (RNU) only (Arm A). Patients will be followed up for 5 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Neo-adjuvant Versus Adjuvant Chemotherapy in Upper Tract Urothelial Carcinoma: A Feasibility Phase II Randomized Clinical Trial ("URANUS")"
Actual Study Start Date : May 28, 2018
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : October 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Radical nephro-ureterectomy (RNU)
Patients who dont fulfil inclusion criteria for chemotherapy treatment randomization (poor renal function: Glomerular Filtration Rate (GFR) <55 ml/min)
Procedure: RNU
Radical surgical removal by open or laparoscopic access
Other Name: Radical nephro-ureterectomy

Gemcitabine/Cisplatin plus RNU
Patients who fulfil inclusion criteria for cisplatinum-based chemotherapy (renal function: GRF > or = 55 ml/min) receiving 3 cycles of Gemcitabine (1000 mg/m2) + Cisplatin (70 mg/m2) every 3 weeks before surgery
Procedure: RNU
Radical surgical removal by open or laparoscopic access
Other Name: Radical nephro-ureterectomy

Drug: Gemcitabine/Cisplatin
Gemcitabine (1000 mg/m²) day 1 and 8 and Cisplatin (70 mg/m²) day 1
Other Name: Gemcitabine plus Cisplatin

RNU plus Gemcitabine/Cisplatin
Patients who fulfil inclusion criteria for cisplatinum-based chemotherapy (renal function: GRF > or = 55 ml/min) receiving 3 cycles of Gemcitabine (1000 mg/m2) + Cisplatin (70 mg/m2) every 3 weeks after surgery
Procedure: RNU
Radical surgical removal by open or laparoscopic access
Other Name: Radical nephro-ureterectomy

Drug: Gemcitabine/Cisplatin
Gemcitabine (1000 mg/m²) day 1 and 8 and Cisplatin (70 mg/m²) day 1
Other Name: Gemcitabine plus Cisplatin

M-VAC protocol plus RNU
Patients who fulfil inclusion criteria for cisplatinum-based chemotherapy (renal function: GRF > or = 55 ml/min) receiving 3 cycles of MVAC every 2 weeks (Methotrexate (30 mg /m²) , Vinblastine (3 mg /m²) , Adriamycin (30 mg /m²) , and Cisplatin (70 mg /m²) before surgery
Procedure: RNU
Radical surgical removal by open or laparoscopic access
Other Name: Radical nephro-ureterectomy

Drug: M-VAC Protocol
Methotrexate (30 mg /m²) and Vinblastine 3 (mg /m²) day 1; Adriamycin 30 mg /m² and Cisplatin 70 mg /m² in day2
Other Name: DD MVAC

RNU plus M-VAC protocol
Patients who fulfil inclusion criteria for cisplatinum-based chemotherapy (renal function: GRF > or = 55 ml/min) receiving 3 cycles of MVAC every 2 weeks (Methotrexate (30 mg /m²) , Vinblastine (3 mg /m²) , Adriamycin (30 mg /m²) , and Cisplatin (70 mg /m²) after surgery
Procedure: RNU
Radical surgical removal by open or laparoscopic access
Other Name: Radical nephro-ureterectomy

Drug: M-VAC Protocol
Methotrexate (30 mg /m²) and Vinblastine 3 (mg /m²) day 1; Adriamycin 30 mg /m² and Cisplatin 70 mg /m² in day2
Other Name: DD MVAC




Primary Outcome Measures :
  1. Proportion of UTUC patients randomized to neo- or adjuvant chemotherapy that is actually able to start and finalize three courses of planned chemotherapy [ Time Frame: 6 months ]
    Percentage of patients randomised to adjuvant or neo-adjuvant treatment


Secondary Outcome Measures :
  1. Disease Free Survival (DFS) [ Time Frame: 1-2 years ]
    time from randomisation to local recurrence or distant metastasis

  2. Overall Survival (OS) [ Time Frame: 1-2 years ]
    time from randomisation to death for any cause different from urothelial carcinoma

  3. Cancer-Specific Survival (CSS) [ Time Frame: 1-2 years ]
    time from randomisation to death from urothelial carcinoma



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent
  • Age > 18 years
  • Histological and radiological defined UTUC: Histologically-confirmed diagnosis of predominantly urothelial carcinoma of the upper urinary tract Patients with UTUC cT2-pT4 cN0-N1 M0 (TNM classification)
  • Women with negative serum pregnancy test within 14 days of first dose of study treatment and agreement to use effective contraception
  • Patients without bladder cancer or with concomitant non muscle invasive bladder cancer
  • Adequate organ system function defined as follows: Hematologic: Absolute neutrophil count (ANC) 1.5 X 109/L; Haemoglobin 5.6 mmol/L (9.02g/dL); Platelets 100 X 109/L; Prothrombin time (PT) or international normalized ratio (INR)b 1.2 X ULN; Activated partial thromboplastin time (aPTT)1.2 X Upper limit of normal (ULN). Hepatic: Total bilirubin 1.5 X ULN; Alanine amino transferase (ALT) and Aspartate aminotransferase (AST) 2.5 X ULN. Renal: GRF <or> 55 ml/min: Electrolytes: potassium, magnesium and calcium: within normal limits.
  • CT scan of the chest, abdomen and pelvis and Bone scan without evidence of distant metastasis

Exclusion Criteria:

  • Histology of pure adenocarcinoma, pure squamous cell carcinoma, sarcomatoid or predominant small cell carcinoma.
  • History of cardiovascular conditions within the past 6 months.
  • Incidentally found asymptomatic pulmonary embolism (PE) or recent deep vein thrombosis (DVT) is not an exclusion criteria but requires anticoagulation treatment.
  • Any major contraindication to a surgical procedure.
  • Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures.
  • Active infection contraindicating chemotherapy
  • Concomitant diseases that are a formal exclusion to platinum-based chemotherapy (deafness, grade II neuropathy).
  • Other active neoplasms. Patients with in situ cervical carcinoma, non-melanoma skin cancer or prostate cancer T1 Gleason <7, Prostate specific antigen (PSA) <10. Patients with past medical history of cancer can be included if diagnosed at least 5 years ago.
  • Concomitant muscle invasive bladder cancer
  • Patients who have been or still are on methotrexate treatment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02969083


Contacts
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Contact: Cristina Alvarez, MSc, PhD +31(0)715264109 m.c.alvarez@lumc.nl

Locations
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Netherlands
Radboud University Medical Centre Recruiting
Nijmegen, Gelderland, Netherlands
Contact: Dr. Van der Heijden         
Leiden University Medical Centre Recruiting
Leiden, South Holland, Netherlands
Contact: Dr. Osanto         
Alrijne Ziekenhuis Recruiting
Leiderdorp, South-Holland, Netherlands
Contact: Dr. Goossens-Laan         
Norway
Haukeland University Hospital Recruiting
Bergen, Norway
Contact: Dr. Beisland         
Spain
Fundacion Puigvert Not yet recruiting
Barcelona, Spain
Contact: Dr. Palou         
Hospital San Pau Not yet recruiting
Barcelona, Spain
Contact: Dr. Maroto         
Sponsors and Collaborators
The European Uro-Oncology Group
Centre for Human Drug Research, Netherlands
Investigators
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Principal Investigator: Susanne Osanto, MD, PhD Leiden University Medical Centre

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Responsible Party: The European Uro-Oncology Group
ClinicalTrials.gov Identifier: NCT02969083     History of Changes
Other Study ID Numbers: EudraCT 2016-004017-27
First Posted: November 21, 2016    Key Record Dates
Last Update Posted: July 22, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: The results obtained in this study will be disseminated and published

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by The European Uro-Oncology Group:
UTUC
Upper Tract Urothelial Carcinoma
Neoadjuvant chemotherapy
Adjuvant chemotherapy
Radical nephroureterectomy

Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Cisplatin
Gemcitabine
Methotrexate
Doxorubicin
Vinblastine
Cyclophosphamide
Dactinomycin
Vincristine
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Dermatologic Agents
Folic Acid Antagonists
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors