Clinical trial NCT01952223: A Phase III of Cabazitaxel and Pelvic Radiotherapy in Localized Prostate Cancer and High-risk Features of Relapse
Official title: A Randomized Phase III, Factorial Design, of Cabazitaxel and Pelvic Radiotherapy in Patients With Localized Prostate Cancer and High-risk Features of Relapse
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Adenocarcinoma of Prostate
Progression of Prostate Cancer
Keywords: adenocarcinoma
prostate
relapse
Radiotherapy
Androgen Deprivation Therapy
Cabazitaxel
Lead sponsor: UNICANCER
Sponsor class: OTHER
Collaborators: name: Sanofi
First posted: 2013-09-27
Enrollment: 761
Sex: MALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: The objective of this study is to assess the effect of neoadjuvant cabazitaxel and pelvic radiotherapy in combination with androgen deprivation therapy (ADT)-radiotherapy on clinical progression-free survival in patients with high-risk localized prostate cancer (with a stringent selection of patients with at least 2 high-risk features), in a 2 by 2 factorial trial.

Detailed description: Eligible patients can be randomized via the TENALEA web site process that insure centralization of the randomization.

Randomization will be performed according a 1:1:1:1 ratio. The randomization will be stratified (by minimization) according to the number of risk factors (2 vs.3), disease extent (pN- vs. pN+ vs. pNx) and the site.

The minimization will be defined with a similar weight for all 3 stratification factors and a probability of assigning the treatment that minimize the imbalance equal to 80%.

The main analysis of progression-free survival (PFS) will be event driven (\> 247 events). It will likely be performed when the median follow-up is approximately 6 years, i.e. 4 years after the inclusion of the last patient (assuming an accrual of 4 years).

A long-term analysis (allowing for robust PFS and overall survival (OS) data) will also be performed when the follow-up is approximately 10 years. Its exact timing will be discussed with the steering committee and the IDMC.

An interim analysis of the primary endpoint is planned. This interim analysis will be performed at a 0.001 level (Peto) after 50% of the events i.e. 125 have occurred.

For each comparison (CT comparison and pelvic RT comparison) the two PFS curves will be compared using the adjusted logrank test (bilateral test): adjusted logrank on pelvic RT for the CT comparison and on CT for the pelvic RT comparison. A multivariate analysis using the Cox model will also be used.

An Independent Data Monitoring Committee (IDMC) composed of international experts (at least 2 physicians and 1 statistician) will be selected.

For safety purpose, the IDMC will meet after the inclusion of 20 patients (and then again after accrual of 50 patients) in the cabazitaxel and pelvic radiotherapy arm, to assess tolerance, (i.e. after the inclusion of approximately 80 and then 200 patients in the trial). Depending on the results of this feasibility phase and of any new relevant clinical results in such a population, the remaining patients (n=848) will be enrolled.

During this second phase, the IDMC will then meet every two years approximately during accrual to carefully assess accrual rate and toxicity and examine the efficacy interim analysis results in the light of the results of similar trials.

Eligibility criteria: Inclusion Criteria:

1. Any T histologically confirmed adenocarcinoma of the prostate
2. No clinically or radiologically suspected metastases, including no enlarged pelvic lymph nodes (\> 1 cm in small diameter)
3. Gleason score ≥ 6
4. Meets at least 2 of the following criteria for high-risk:

   * Gleason score ≥ 8
   * T3 or T4 disease (T3 defined by MRI is acceptable)
   * Prostate-specific antigen equal or greater than 20 ng/mL
5. No prior treatment for prostate cancer except lymph node dissection (patients with pN- and pN+ disease can be accrued) or ADT (started up to 6 weeks before randomization).
6. 18 years ≤ Age ≤ 75 years
7. Eastern Cooperative Oncology Group (ECOG) 0-1 performance status
8. Expected life expectancy of more than 10 years
9. Absolute neutrophil count ≥ 1.5 x 10⁹/L
10. Platelets ≥ 100 x 10⁹/L
11. Hb ≥ 9.0 g/dL
12. Hepatic function: serum bilirubin ≤ 1 upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
13. Renal function (creatinine clearance using the Chronic Kidney Disease Epidemiology group (CKD-EPI) formula ≥ 60 mL/min).
14. Potentially reproductive patients must agree to use an effective contraceptive method while on treatment and for 6 months after the final dose of investigational product.
15. Patients must be affiliated to a Social Security System or should fulfill the country legislation for clinical trials.
16. Patients who have received the information sheet and signed the informed consent form.
17. Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures

Exclusion Criteria:

1. Patients with other known concurrent severe and/or uncontrolled medical disease which could compromise participation in the study, such as:

   1. infection,
   2. cardiac disease such as uncontrolled hypertension, congestive cardiac failure, ventricular arrhythmias, active ischemic heart disease, myocardial infarction within one year, left ventricular ejection fraction (LVEF) \> grade 2,
   3. uncontrolled diabetes mellitus,
   4. current active hepatic or biliary disease (with exception of subjects with Gilbert's syndrome, asymptomatic gallstones, stable chronic liver disease per investigator assessment),
   5. renal disease,
   6. active GI tract ulceration, malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with active, uncontrolled ulcerative colitis are also excluded,
   7. known severely impaired lung function (spirometry and diffusing capacity of the lungs for carbon monoxide (DLCO) 70% or less of normal and O2 saturation of 88% or less at rest on room air).
2. Other prior malignancy within the last 5 years, except basal cell skin cancer
3. Physical or psychological condition that would preclude study compliance
4. Hypersensitivity to cabazitaxel (hypersensitivity reaction ≥grade 3), to other taxanes, or to any excipients of the formulation including polysorbate 80
5. Patients with significantly altered mental status prohibiting the understanding of the study or with psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
6. Patients who received any other investigational drugs within the 30 days prior to the start of cabazitaxel.
7. Previous pelvic irradiation that make prostatic irradiation impossible
8. Severe GI disorders precluding pelvic irradiation
9. Patients already included in another therapeutic trial involving an experimental drug
10. Individual deprived of liberty or placed under the authority of a tutor.
11. Concomitant prohibited treatment. Concurrent or planned treatment with strong inhibitors or strong inducers of cytochrome P450 3A4/5 (see Appendix 6). A one week wash-out period is necessary for patients who are already on these treatments

Primary outcomes:
measure: progression free survival
timeFrame: 10 years
Secondary outcomes:
measure: prostate-specific antigen response at 3 months
timeFrame: 10 years
measure: biochemical progression-free survival
timeFrame: 10 years
measure: metastases-free survival
timeFrame: 10 years
measure: local relapse-free survival
timeFrame: 10 years
measure: overall survival
timeFrame: 10 years
measure: prostate cancer-specific survival
timeFrame: 10 years
measure: acute toxicity
timeFrame: 10 years
measure: impact of treatment on serum testosterone
timeFrame: 10 years
measure: long-term toxicity
timeFrame: 10 years
measure: predictive biomarkers of treatment efficacy
timeFrame: 10 years
measure: quality of life
timeFrame: 10 years
Other outcomes:
Locations:
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: ICO-René Gauducheau - St Herblain
name: Emmanuelle BOMPAS, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut Jean Godinot - Reims
name: Jean-Christophe EYMARD, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut Bergonié Bordeaux
name: Guilhem ROUBAUD, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut Curie Paris
name: Philippe BEUZEBOC, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut de Cancérologie Lucien Neuwirth -ST Priest en Jarez
name: Aline GUILLOT, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Catherine de Sienne - Nantes
name: Claude EL KOURI, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: CHD VENDEE - La Roche sur Yon
name: Frank PRIOU, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: CENTRE LEON BERARD - lyon
name: Aude FLECHON, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinique Pasteur Toulouse
name: Igor LATORZEFF, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Gustave Roussy, Cancer Campus Grand Paris-Paris
name: Karim FIZAZI, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinique Ste Marguerite - Hyères
name: Jean BERDAH, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital St Louis - Paris
name: Stéphane CULINE, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: ICO - Paul Papin - Angers
name: Sophie ABADIE-LACOURTOISIE, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre hospitalier de Chambéry - Chambéry
name: Philippe FOURNERET, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre hospitalier de Mulhouse - mulhouse
name: Alain GRANDGIRARD, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinique Armoricaine de Radiologie - St Brieuc
name: Dominique BESSON, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut Claudius REGAUD - Toulouse
name: Loïc MOUREY, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre hospitalier Lyon Sud - Pierre Bénite
name: Alain RUFFION, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: CHRU Jean Minoz - Besançon
name: Tristan MAURINA, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Limoges - Limoges
name: Pierre CLAVERE, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut de Cancérologie de Lorraine
name: Véronique BECKENDORF, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Vall d'Hebron - Barcelone
name: Joan Carles, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Fondazione IRCCS Istituto Nazionale dei tumori - Milan
name: Riccardo Valdagni, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Azuréen de Cancérologie - Mougins
name: Philippe RONCHIN, Docteur
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital de la conception - Marseille
name: Eric LECHEVALLIER, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut Paoli Calmettes - Marseille
name: Gwenaëlle GRAVIS, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: CHR Orléans La Source - Orléans
name: Elise CHAMPEAUX-ORANGE, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Saint-Gregoire Private Hospital Center
name: Xavier ARTIGNAN, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinique Générale d'Annecy
name: Anne DONEUX, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Haut L'Evèque - Pessac
name: Thibaud HAASER, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: STRASBOURG ONCOLOGIE LIBERALE - CLINIQUE SAINTE ANNE - Strasbourg
name: Youssef TAZI, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: HOPITAL EUROPEEN GEORGES POMPIDOU - Paris
name: Stéphane OUDARD, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: CENTRE EUGENE MARQUIS - Rennes
name: Brigitte LAGUERRE, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: CENTRE JEAN PERRIN - Clermont Ferrand
name: Hakim MAHAMMEDI, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: CHRU de Nîmes Caremeau - Nîmes
name: Nadine HOUEDE, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: CH Paris Saint Joseph - Paris
name: Gaël DEPLANQUE, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Nord Marseille
name: Marjorie BACIUCHKA-PALMARO, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Henri Mondor - Créteil
name: yazid BELKACEMI, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: L'Institut Mutualiste Montsouris-Paris
name: Mostefa BENNAMOUN, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinique Pasteur - Brest
name: ali HASBINI, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital privé Clairval - Marseille
name: Emmanuel GROSS, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU de TOURS Hôpital Bretonneau
name: Bérengère NARCISO RAHARIMANANA, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital d'instruction des armées Bégin - St mandé
name: Carole HELISSEY, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital del Mar
name: Marta GUIX, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario Virgen del Rocio -Sevilla
name: Begoña PEREZ-VALDERRAMA, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Parc Tauli Sabadell Hospital Universitari - Sabadell
name: Enrique GALLARDO, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: H. Virgen de la Victoria - Malaga
name: Maria SAEZ, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Althaia, Xarxa Universitaria i assistencial de Manresa
name: Montserrat DOMENECH, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: H. Lucus Augusti - Lugo
name: Sergio VAZQUEZ ESTEVEZ, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: H. Teresa Herrera - Coruna
name: Luis Miguel Anton APARICIO, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: H. Reina Sofia
name: Maria José MENDEZ VIDAL, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: M.D. Anderson Cancer Center
name: Pilar LOPEZ CRIADO, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Clinic of Barcelona
name: Begoña MELLADO GONZALEZ, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Salamanca
name: Francisco GOMEZ VEIGA, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: ICO Badalona - H.U. Germans Trias
name: Salvador VILLA i FREIXA, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario 12 de Octubre
name: Daniel CASTELLANO, Doctor
role: PRINCIPAL_INVESTIGATOR
References: