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

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.

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