PEACE2: A Phase III of Cabazitaxel and Pelvic Radiotherapy in Localized Prostate Cancer and High-risk Features of Relapse

Sponsor

UNICANCER (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01952223

Collaborator

Sanofi (Industry)

761

Enrollment

Location

Arms

331

Anticipated Duration (Months)

2.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of Prostate Progression of Prostate Cancer	Drug: Cabazitaxel Radiation: Pelvic radiotherapy Radiation: prostate radiotherapy	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

761 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Dec 1, 2013

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Jul 1, 2041

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ADT + pelvic RT ADT for a total duration of 3 years i.e. luteinizing hormone-releasing hormone (LHRH) agonist or LHRH antagonist +/-Peripheral anti-androgen Pelvic RT (by IMRT or IGRT protocol): Phase 1: pelvic radiotherapy (prostate, seminal vesicles, ilio-obturator, presacral lymph nodes) (46 or 50 Gy according to the center) Phase 2: prostate-only boost (EBRT) up to 74-78 Gy	Radiation: Pelvic radiotherapy Prostate+pelvic RT (2 Gy fractions, 5 times per week): Phase 1: pelvic radiotherapy (prostate, seminal vesicles, ilio-obturator, presacral lymph nodes) (46 or 50 Gy according to the center) Phase 2: prostate-only boost (EBRT) up to 74-78 Gy
Experimental: ADT + Cabazitaxel + prostate RT ADT Cabazitaxel: 4 CT cycles Prostate-only RT (IMRT or IGRT): Phase 1: prostate + seminal vesicle radiotherapy (46 or 50 Gy according to the center) Phase 2: prostate-only boost (EBRT) up to 74-78 Gy	Drug: Cabazitaxel Cabazitaxel administered at 25 mg/m² as a 1 hour intravenous infusion every 3 weeks (1 cycle = 21 days) for 4 cycles Other Names: jevtana Radiation: prostate radiotherapy Prostate-only RT (2 Gy fractions, 5 times per week): Phase 1: prostate + seminal vesicle radiotherapy (46 or 50 Gy according to the center) Phase 2: prostate-only boost (EBRT) up to 74-78 Gy
Experimental: ADT + cabazitaxel + pelvic RT ADT Cabazitaxel: 4 CT cycles Pelvic RT (IMRT or IGRT): Phase 1: pelvic radiotherapy (prostate, seminal vesicles, ilio-obturator, presacral lymph nodes) (46 or 50 Gy according to the center) Phase 2: prostate-only boost (EBRT) up to 74-78 Gy	Drug: Cabazitaxel Cabazitaxel administered at 25 mg/m² as a 1 hour intravenous infusion every 3 weeks (1 cycle = 21 days) for 4 cycles Other Names: jevtana Radiation: Pelvic radiotherapy Prostate+pelvic RT (2 Gy fractions, 5 times per week): Phase 1: pelvic radiotherapy (prostate, seminal vesicles, ilio-obturator, presacral lymph nodes) (46 or 50 Gy according to the center) Phase 2: prostate-only boost (EBRT) up to 74-78 Gy
Active Comparator: ADT + prostate radiotherapy ADT for a total duration of 3 years: LHRH agonist or LHRH antagonist +/- anti-androgen Prostate-only RT (IMRt or IGRT): Phase 1: prostate + seminal vesicle radiotherapy (46 or 50 Gy according to the center) Phase 2: prostate-only boost (EBRT) up to 74-78 Gy	Radiation: prostate radiotherapy Prostate-only RT (2 Gy fractions, 5 times per week): Phase 1: prostate + seminal vesicle radiotherapy (46 or 50 Gy according to the center) Phase 2: prostate-only boost (EBRT) up to 74-78 Gy

Outcome Measures

Primary Outcome Measures

progression free survival [10 years]

Secondary Outcome Measures

prostate-specific antigen response at 3 months [10 years]
biochemical progression-free survival [10 years]
metastases-free survival [10 years]
local relapse-free survival [10 years]
overall survival [10 years]
prostate cancer-specific survival [10 years]
acute toxicity [10 years]
impact of treatment on serum testosterone [10 years]
long-term toxicity [10 years]
predictive biomarkers of treatment efficacy [10 years]
quality of life [10 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Inclusion Criteria:

Any T histologically confirmed adenocarcinoma of the prostate
No clinically or radiologically suspected metastases, including no enlarged pelvic lymph nodes (> 1 cm in small diameter)
Gleason score ≥ 6
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

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).
18 years ≤ Age ≤ 75 years
Eastern Cooperative Oncology Group (ECOG) 0-1 performance status
Expected life expectancy of more than 10 years
Absolute neutrophil count ≥ 1.5 x 10⁹/L
Platelets ≥ 100 x 10⁹/L
Hb ≥ 9.0 g/dL
Hepatic function: serum bilirubin ≤ 1 upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
Renal function (creatinine clearance using the Chronic Kidney Disease Epidemiology group (CKD-EPI) formula ≥ 60 mL/min).
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.
Patients must be affiliated to a Social Security System or should fulfill the country legislation for clinical trials.
Patients who have received the information sheet and signed the informed consent form.
Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures

Exclusion Criteria:

Patients with other known concurrent severe and/or uncontrolled medical disease which could compromise participation in the study, such as:
infection,
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,
uncontrolled diabetes mellitus,
current active hepatic or biliary disease (with exception of subjects with Gilbert's syndrome, asymptomatic gallstones, stable chronic liver disease per investigator assessment),
renal disease,
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,
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).
Other prior malignancy within the last 5 years, except basal cell skin cancer
Physical or psychological condition that would preclude study compliance
Hypersensitivity to cabazitaxel (hypersensitivity reaction ≥grade 3), to other taxanes, or to any excipients of the formulation including polysorbate 80
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.
Patients who received any other investigational drugs within the 30 days prior to the start of cabazitaxel.
Previous pelvic irradiation that make prostatic irradiation impossible
Severe GI disorders precluding pelvic irradiation
Patients already included in another therapeutic trial involving an experimental drug
Individual deprived of liberty or placed under the authority of a tutor.
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Institut Gustave Roussy	Villejuif		France	F-94805

Sponsors and Collaborators

UNICANCER
Sanofi

Investigators

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