A Study Evaluating Chemotherapy With Fractionated Cisplatin/Gemcitabine Versus Carboplatin/Gemcitabine in the Treatment of Advanced or Metastatic Urothelial Cancer With Impaired Renal Function. (VEFORA)

Randomized, Multicenter, Phase II/III Study, Evaluating Fractionated Cisplatin Chemotherapy/Gemcitabine Versus Carboplatin/Gemcitabine in the Treatment of Advanced or Metastatic Urothelial Cancer With Impaired Renal Function.

This is a phase II/III, multicenter, randomized study which includes 420 patients on six years + 3 years follow up. 92 patients will be included during the phase II ; additional 328 patients will be included.

Patients with an advanced or metastatic urothelial cancer with impaired renal function will be randomized in one of the two following chemotherapy arm:

• Fractionated Cisplatin + Gemcitabine.
• Carboplatin + Gemcitabine.

The main objective of the part II study will be to evaluate the efficacy and the safety of a chemotherapy with a doublet platinum salt compound/Gemcitabine with fractionated Cisplatin or Carboplatin in this population.

The main objective of the part III study will be to compare the efficacy in terms of overall survival of a chemotherapy with a doublet platinum salt/Gemcitabine with fractionated Cisplatin or Carboplatin in this population.

Study Overview

• Status: Completed
• Conditions: Metastatic Urothelial Cancer; Advanced Urothelial Cancer
• Intervention / Treatment: Drug: Carboplatin; Drug: Gemcitabine; Drug: Fractionated Cisplatin

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• France
  • Angers, France, 49933
    • Institut de Cancérologie de l'Ouest - Site Paul Papin
  • Besançon, France, 25030
    • CHRU BESANCON - Hôpital Jean Minjoz
  • Bordeaux, France, 33076
    • Institut Bergonié
  • Caen, France, 14076
    • Centre Francois Baclesse
  • Dijon, France, 21079
    • Centre Georges François Leclerc
  • Le Chesnay, France, 78157
    • CH Versailles - Hôpital André Mignot
  • Limoges, France, 87042
    • CHU Limoges - Hôpital Dupuytren
  • Lyon, France, 69373
    • Centre Léon Bérard
  • Marseille, France, 13273
    • Institut Paoli Calmettes
  • Mont de Marsan, France, 40024
    • CH Mont de Marsan
  • Montpellier, France, 34298
    • Institut Régional du Cancer Montpellier
  • Paris, France, 75010
    • Ap-Hp-Hopital Saint-Louis
  • Saint-Herblain, France, 44805
    • Institut de Cancérologie de l'Ouest - Site René Gauducheau
  • Saint-Priest en Jarez, France, 42271
    • Institut de Cancérologie Lucien Neuwirth
  • Strasbourg, France, 67091
    • CHU de Strasbourg
  • Toulouse, France, 31052
    • Institut Claudius Régaud
  • Tours, France, 37044
    • CHRU Tours
  • Villejuif, France, 94805
    • Institut Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. . Age < or = 18 years, patients aged 75 years or more will benefit from a geriatric assessment.
2. . Advanced or metastatic urothelial cancer confirmed histologically or cytologically.
3. . Patients liable to receive a first -line chemotherapy for advanced or metastatic urothelial carcinoma.
4. . Measurable disease according to RECIST criteria V1.1.
5. . Patients who received neoadjuvant or adjuvant chemotherapy based on platinum salt must have completed treatment at least 6 months before entering the study.
6. . Performance status < or = 2.
7. . Life expectancy > 3 months.
8. . Patients with creatinine clearance between 40 and 60 ml / min ( according to Cockcroft and Gault ).
9. . Patients having no contra-indication to overhydration.
10. . Satisfactory hematological tests: Neutrophils > 1.5 G / l Platelets > 150 G / l , hemoglobin ≥ 10 g / dl.
11. . Satisfactory liver function tests: total bilirubin < 1.5 x ULN (upper limit of normal), AST (aspartate aminotransferase) and ALT (alanine aminotransferase)<or = 2.5 x ULN (or 5 x ULN if liver metastases).
12. . In case of prior radiotherapy, a minimum of 14 days must relapse between the end of radiotherapy and study entry.
13. . For women of childbearing age , use an effective contraceptive method to study entry and for the duration of the study and 6 months after the last dose of study treatment ; For sexually active fertile men having a partner of childbearing age using effective contraception for the duration of the study and 6 months after the last dose of study treatment.
14. . Patient affiliated to a social security system in France.
15. . Patient signed informed consent before inclusion in the study and before any specific procedure for the study.

Exclusion Criteria:

1. . Any concomitant or previous malignancy within 5 years prior to the study ( with the exception of basal cell or squamous cell carcinoma in situ).
2. . Pregnant or lactating women.
3. . Patients with brain metastases or meningeal or symptoms suggestive of such secondary locations.
4. . Bisphosphonate or Denosumab treatment initiated within 28 days prior to randomization into the study or patient who have started such treatment during the study ( a bisphosphonate or denosumab treatment initiated within a period longer than 28 days before randomization may be continued without change during the study ).
5. . Other concomitant cancer (radiation therapy, radiopharmaceutical agent chemotherapy).
6. . Patients with uncontrolled infection.
7. . Patients with peripheral neuropathy grade> 1, whatever the origin or patients with hearing loss.
8. . Patient with unstable disease (eg: unstable diabetes, poorly controlled hypertension , congestive heart failure or myocardial infarction within 3 months prior to study entry).
9. . Known hypersensitivity to study drugs.
10. . Treatment with any other investigational drug within 30 days before inclusion.
11. . Any psychological condition , familial, sociological or geographical not to comply with medical monitoring and / or procedures in the study protocol.
12. . Patient protected by law.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Carboplatin/Gemcitabine	Drug: Carboplatin; Carboplatin AUC (area under curve) 4,5 at day 1 of each cycle until 6 cycles.; Drug: Gemcitabine; Gemcitabine 1000mg/m² at day 1 and day 8 of each cycle until 6 cycles.
Experimental: Fractionated Cisplatin/Gemcitabine	Drug: Gemcitabine; Gemcitabine 1000mg/m² at day 1 and day 8 of each cycle until 6 cycles.; Drug: Fractionated Cisplatin; Cisplatin 35mg/m² at day 1 and day 8 of each cycle until 6 cycles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase II: Efficacy - Rate of non progression at the end of treatment (C6D21).	Progression is defined according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria V1.1.	5 years.
Phase III: Overall survival (in months).	Overall survival is defined as the time from randomization until death or last follow up news (censured data).	9 years.
Phase II: Tolerance - Percentage of patients for whom at least one of the 3 defined tolerance criteria (see description) is observed.	Defined tolerance criteria : Postponement of chemotherapy > or = 2 weeks.; Alteration of renal function.; Need to decrease twice Gemcitabine dose on day 1 for : NCI CTC (National Cancer Institut Common Toxicity Criteria) grade III or IV non-hematologic toxicity, hematologic toxicity.	5 years.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase II and III: Objective response.	Objective response (ie complete or partial response) will be evaluated according to RECIST v1.1 criteria.	Phase II: 5 years ; Phase III: 9 years.
Phase II and III: Tolerance according to NCI toxicity scale (version 4.0).		Phase II: 5 years ; Phase III: 9 years.
Phase II and III: Geriatric evaluation using questionnaires.	The geriatric assessment will be evaluate using the following questionnaires: G8 (oncodage) , ADL (activity of daily living), CIRSG (cumulating illness rating scale geriatric) , MMS (mini-mental score), IADL (instrumental activities of daily living), GDS (geriatric depression scale), MNA (mini-nutritional assessment).	Phase II: 5 years ; Phase III: 9 years.
Phase II and III: Quality of life using the EORTC QLQ - C30 questionnaire (European Organization for research and treatment of Cancer - Quality of life questionnaire).		Phase II: 5 years ; Phase III: 9 years.
Phase II and III: Pharmacokinetics - Platin concentrations		At cycles 1 and 2 day 1 - 5 mn before the end of infusion, one hour after the end of infusion, 3 hours (arm A) or 4 hours (arm B) after the end of infusion.
Phase II and III: Pharmacogenetics, exploration of cytidine deaminase activity and study of its genetic polymorphisms.		Prior to the initial dose on cycle 1 day 1.
Phase II and III: Progression free survival.	Progression free survival will be evaluated according to RECIST v1.1 criteria.	Phase II: 5 years ; phase III: 9 years.
Phase II and III: Overall survival.	Overall survival is defined as the time from randomization until death from all causes combined.	Phase II: 5 years ; Phase III: 9 years.
Phase II and III: Time to treatment failure.	Time to treatment failure is defined as the time from randomization to treatment discontinuation, whatever its cause.	Phase II: 5 years ; Phase III: 9 years.

Collaborators and Investigators

• Sponsor: Institut Claudius Regaud
• Investigators: Study Chair: Loic MOUREY, MD, Institut Claudius Régaud

Study record dates

Study Major Dates

• Study Start (Actual): January 21, 2015
• Primary Completion (Actual): April 10, 2018
• Study Completion (Actual): July 15, 2019

Study Registration Dates

• First Submitted: September 5, 2014
• First Submitted That Met QC Criteria: September 11, 2014
• First Posted (Estimate): September 15, 2014

Study Record Updates

• Last Update Posted (Actual): August 9, 2019
• Last Update Submitted That Met QC Criteria: August 7, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Urothelial cancer, renal function impaired.
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gemcitabine; Carboplatin
• Other Study ID Numbers: 13 URO 02