Trial Evaluating the Safety of 2 Schedules of Cabazitaxel in Elderly Men With mCRPC Previously Treated With a Docetaxel
- Conditions
- Prostate Cancer Metastatic
- Interventions
- Registration Number
- NCT02961257
- Lead Sponsor
- Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie
- Brief Summary
The purpose of this study is to evaluate the incidence of grade ≥ 3 neutropenia and/or neutropenic complications (febrile neutropenia, neutropenic infection) with two schedules of cabazitaxel (bi-weekly versus tri-weekly) plus prednisone in elderly men (≥ 65 years) with mCRPC previously treated with a docetaxel-containing regimen.
- Detailed Description
Randomized, open-label, phase 3 trial in mCRPC patients aged ≥ 65 years.
Number of subjects:
Total:170 to 200 (85 to 100 per arm)
Treatment:
* Arm A : cabazitaxel 25 mg/m² on Day 1 of a 3-week cycle plus daily prednisone or
* Arm B: cabazitaxel 16 mg/m² on Day 1 and Day 15 of a 4-week cycle plus daily prednisone.
* Treatment will be continued for a maximum of 10 cycles unless there is documented disease progression or unacceptable toxicity.
* Standard cabazitaxel premedication will be used
* Prophylactic G-CSF (GRANOCYTE) will be injected from Day 3 to Day 7 after every administration cycle of cabazitaxel· All new hormonal treatment, including ODM-201, prior to study entry is allowed.
* Patients who received Radium-223 are eligible for this study
* Treatment with LHRH should not be discontinued.
Exploratory assessments:
CT-Scan (abdominal/pelvic/chest) or whole body MRI and Bone scan: at screening, every 3 months and EOT.
FACT-P questionnaire:at C1D1,each subsequent visit and EOT
Exploratory substudy Blood samples will be collected in France (4 or 6 sites) and the Netherlands (2 sites). Biomarker analysis will be conducted at the Urology and The Tumor Immunology Laboratory at Radboud UMC in NL.
Biomarker schedule Arm A (25mg/m2): Baseline - Week 6 - Week 12 - at progression Arm B (16mg/m2): Baseline - Week 6 - Week 12 - at progression Optional sample points are at C1D8.
Number of subjects: 50
Statistical analysis:
A sample size of 77 to 90 evaluable patients per arm will achieve 80% power to detect a 20% difference in G3 neutropenia incidence between the 2 arms. The incidence in group cabazitaxel 25 mg/m2 q3w is assumed to be 32% and 12% on bi-weekly cabazitaxel arm. The test used is a two-sided Fisher's exact test at 0.05 significance level. Assuming 10% non-evaluable patients, 85 to 100 patients should be included in each arm for a total of 170 to 200.
Patients will be stratified according to G8 score (\< 14 vs. ≥ 14), and age (\< 70 vs. ≥ 70) before randomization.
Exploratory sub-study The trial is powered on a clinical endpoint, namely to detect a 20% difference in G3 nThe trial is powered on a clinical endpoint, namely to detect a 20% difference in G3 neutropenia incidence between arms (32% in arm A vs 12% arm B; power 80% with two-sided alpha of 5%, correcting for 10% non-evaluable patients (=17 patients).
From the 153 to 180 evaluable patients, we have 76 to 90 patients in each arm, of which we expect 40-60 evaluable patients for translational studies (calculations performed on 25 per arm).
In arm A, we expect 8 patients (32% of patients) with G3 neutropenia, and 17 patients that do not. In arm B, we expect 3 patients (12% of patients) with G3 neutropenia, and 22 patients that do not. For the MDSC analyses, we therefore will be comparing 11 patients with G3 neutropenia to 39 patients.
For all continuous variables, including all immune subpopulations present in blood, mean (sd) will be presented if the distribution seems to be symmetric and in case of a skewed distribution the median and IQR. For categorical data, number and percentage will be presented. For comparison of continuous data linear regression analyses or correlation (Spearman or Pearson) will used. For comparison of continuous data with categorical data logistic regression analysis will be used. For comparison of two sets of categorical data the chi-square test of Fisher's exact test will be utilized. For the radiological PFS analyses the estimates of the hazard ratio and corresponding 95% confidence interval will be tested using a Cox Proportional hazard model. For the overall survival, a stratified log-rank test will be used to compare between groups.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 196
-
Patient aged ≥ 65 years with mCRPC previously treated with docetaxel
-
Medical or surgical castration with castrate level of testosterone (< 50 ng/dl) based on the EAU definition of castrate level of testosterone
-
Progressive disease according to PCWG2
-
Histologically proven prostate carcinoma
-
Health status allowing use of chemotherapy: G8 > 14; or G8 score ≤ 14 with geriatric assessment concluding to reversible impairment allowing use of chemotherapy
-
ECOG-PS 0, 1 or 2(ECOG-PS 2 should be related to prostate cancer)
-
Adequate hematologic, liver and renal functions:
- Neutrophil count ≥1.5 109/L
- Haemoglobin ≥10 g/ dL
- Platelet count ≥100.109/L
- Total bilirubin ≤ 1 the upper limit of normal (ULN)
- Transaminases ≤ 1.5 ULN
- Serum creatinine ≤ 2.0 ULN
-
Ongoing LHRH therapy at study entry
-
Signed informed consent
- History of severe hypersensitivity reaction (≥grade 3) to docetaxel
- History of severe hypersensitivity reaction (≥grade 3) to polysorbate 80 containing drugs
- Uncontrolled severe illness or medical condition (including uncontrolled diabetes mellitus)
- Concurrent or planned treatment with strong inhibitors or strong inducers of cytochrome P450 3A4/5 (a one week wash-out period is necessary for patients who are already on these treatments) (see Appendix E)
- PS >2 not related to prostate cancer disease
- G8 ≤ 14 with geriatric assessment contra-indicating standard cabazitaxel regimen
- Concomitant vaccination with yellow fever vaccine
- Patient who cannot be regularly followed or cannot answer to quality of life questionnaires because of psychological, social, familial or geographic reasons
- Participation in another clinical trial with any investigational drug within 30 days prior to study enrolment.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm A cabazitaxel Cabazitaxel 25 mg/m² intravenously over 1 hour on Day 1of a 3-week cycle, plus prednisone (or prednisolone) 10 mg orally given daily for a maximum of 10 cycles (ie 30 weeks of treatment). Prophylactic Granulocyte colony-stimulating factor G-CSF (Granocyte) will be injected from Day 3 to Day 7 after every administration of cabazitaxel. Arm A Granulocyte colony-stimulating factor (G-CSF) Cabazitaxel 25 mg/m² intravenously over 1 hour on Day 1of a 3-week cycle, plus prednisone (or prednisolone) 10 mg orally given daily for a maximum of 10 cycles (ie 30 weeks of treatment). Prophylactic Granulocyte colony-stimulating factor G-CSF (Granocyte) will be injected from Day 3 to Day 7 after every administration of cabazitaxel. Arm B Granulocyte colony-stimulating factor (G-CSF) Cabazitaxel 16 mg/m2 on Day 1 and Day 15 of a 4-week cycle plus prednisone (or prednisolone) 10 mg per day up to 10 cycles (ie 40 weeks of treatment). Prophylactic Granulocyte colony-stimulating factor G-CSF (Granocyte) will be injected from Day 3 to Day 7 after every administration of cabazitaxel. Arm A Prednisone Cabazitaxel 25 mg/m² intravenously over 1 hour on Day 1of a 3-week cycle, plus prednisone (or prednisolone) 10 mg orally given daily for a maximum of 10 cycles (ie 30 weeks of treatment). Prophylactic Granulocyte colony-stimulating factor G-CSF (Granocyte) will be injected from Day 3 to Day 7 after every administration of cabazitaxel. Arm B cabazitaxel Cabazitaxel 16 mg/m2 on Day 1 and Day 15 of a 4-week cycle plus prednisone (or prednisolone) 10 mg per day up to 10 cycles (ie 40 weeks of treatment). Prophylactic Granulocyte colony-stimulating factor G-CSF (Granocyte) will be injected from Day 3 to Day 7 after every administration of cabazitaxel. Arm B Prednisone Cabazitaxel 16 mg/m2 on Day 1 and Day 15 of a 4-week cycle plus prednisone (or prednisolone) 10 mg per day up to 10 cycles (ie 40 weeks of treatment). Prophylactic Granulocyte colony-stimulating factor G-CSF (Granocyte) will be injected from Day 3 to Day 7 after every administration of cabazitaxel.
- Primary Outcome Measures
Name Time Method Number of grade ≥ 3 neutropenia and/or neutropenic complications Up to 11 months To evaluate the incidence of grade ≥ 3 neutropenia (measured at Day 7 and Day 14) and/or neutropenic complications (febrile neutropenia, neutropenic infection) with two schedules of cabazitaxel (bi-weekly versus tri-weekly) plus prednisone in elderly men (≥ 65 years) with mCRPC previously treated with a docetaxel-containing regimen.
with two schedules of -+cabazitaxel (bi-weekly versus tri-weekly) plus prednisone in elderly men with mCRPC previously treated with a docetaxel-containing regimen
- Secondary Outcome Measures
Name Time Method Dose delay Up to 11 months Radiological progression-free survival (rPFS) Up to 11 months CT-Scan (abdominal/pelvic/chest) or whole body MRI and Bone scan
Time to PSA progression Up to 11 months Assessed at C1D1, at every each subsequent visit and EOT
Adverse events Up to 11 months Time to first symptomatic Skeletal-Related Event (SRE) and incidence of SREs Up to 11 months Assessed at C1D1, at every each subsequent visit and EOT
Prostate-specific antigen (PSA) response rate Up to 11 months Assessed at C1D1, at every each subsequent visit and EOT
Objective response rate (ORR) in measurable lesions (RECIST criteria 1.1 - only on metastasis Up to 11 months CT-Scan (abdominal/pelvic/chest) or whole body MRI
Quality of Life (FACT-P) Up to 11 months Assessed at C1D1, at every each subsequent visit and EOT
Factors influencing survival Up to 11 months Factors influencing survival (duration of response to first ADT, serum testosterone, cumulative dose of cabazitaxel, neutrophils/lymphocytes ratio, Gleason score, G8, grade ≥3 neutropenia)
Dose reductions through study completion, an average of 40 weeks Up to 11 months
Time to opioid treatment (if relevant) Up to 11 months Time to onset of grade ≥3 neutropenia Up to 11 months Hematology every week until EOT
Grade ≥3 neutropenia duration ( from date of onset of grade ≥ 3 until grade ≤ 2) Up to 11 months Hematology every week until EOT
Overall Survival (OS) up to 11 months Time to onset of grade ≥3 neutropenia by cycle Up to 11 months Analysis of grade ≥3 neutropenia and/or neutropenia by cycle
Trial Locations
- Locations (31)
CHU Henri-Mondor
🇫🇷Créteil, France
Hôpital Universitaire Tenon
🇫🇷Paris, France
Institut de Cancérologie du Gard - CHU
🇫🇷Nîmes, France
Clinique Pasteur-CFRO
🇫🇷Brest, France
Polyclinique Saint-Côme
🇫🇷Compiègne, France
Hôpital Saint André, CHU de Bordeaux
🇫🇷Bordeaux, France
Hôpital Jean Minjoz
🇫🇷Besançon, France
Hôpital Européen Georges Pompidou
🇫🇷Paris, France
Hôpital FOCH
🇫🇷Suresnes, France
Urologische Praxis am Hasselbachplatz
🇩🇪Magdeburg, Germany
Centre Maurice Tubiana
🇫🇷Caen, France
GHIRM
🇫🇷Montfermeil, France
HIA Bégin 69 avenue de Paris
🇫🇷Saint-Mandé, France
Centre Hospitalier de Sens
🇫🇷Sens, France
Hôpital Cochin
🇫🇷Paris, France
Universitäts-klinik für Urologie und Kinderurologie
🇩🇪Magdeburg, Germany
Universitätsklinikum Münster, Klinik für Urologie und Kinderurologie,
🇩🇪Münster, Germany
Universitätsklinikum Hamburg-Eppendorf
🇩🇪Hamburg, Germany
Hôpital Belle-Isle
🇫🇷Metz, France
Urologisch-onkologische Schwerpunktpraxis
🇩🇪Bernburg, Germany
Centre Oscar Lambret Lille
🇫🇷Lille, France
CHU de Rouen
🇫🇷Rouen, France
Centre de cancérologie Les Dentellières
🇫🇷Valenciennes, France
Urologie und Kinderurologie Marienkrankenhaus Bergisch
🇩🇪Gladbach, Germany
Uniklinik Köln, Urologie, Uro-Onkologie, spezielle urologische und Roboter-assistierte Chirurgie
🇩🇪Köln, Germany
Clinique Victor Hugo
🇫🇷Le Mans, France
CHU de Poitiers
🇫🇷Poitiers, France
Clinique Armoricaine de Radiologie
🇫🇷Saint-brieuc, France
Institut Mutualiste Montsouris
🇫🇷Paris, France
Hôpitaux universitaires de Strasbourg
🇫🇷Strasbourg, France
Studienpraxis Urologie
🇩🇪Nürtingen, Germany