Adjuvant Leuprolide With or Without Docetaxel in High Risk Prostate Cancer After Radical Prostatectomy

This is a prospective, multicenter, open-label, randomized phase III study in participants at high risk of recurrent prostate cancer after radical prostatectomy. The study will investigate

* Treatment with docetaxel (TAXOTERE®) every three weeks (q3w) plus leuprolide acetate (ELIGARD®) versus leuprolide acetate alone (ELIGARD®)
* Immediate treatment following prostatectomy versus deferred treatment at the time of relapse

Using a 2x2 factorial design participants will therefore be randomized to

* Immediate adjuvant treatment with docetaxel plus leuprolide acetate (chemotherapy and hormonal therapy)
* Immediate adjuvant treatment with leuprolide acetate alone (hormonal therapy)
* Deferred treatment with docetaxel plus leuprolide acetate (chemotherapy and hormonal therapy)
* Deferred treatment with leuprolide acetate alone (hormonal therapy)

Primary Objective:

* The primary objective of the study is to compare progression-free survival using a 2x2 factorial design

Secondary Objectives:

* To compare the 5-year overall, cancer-specific and metastasis-free survival after systemic treatment between the groups
* To compare the safety and tolerability between Docetaxel in combination with leuprolide acetate and leuprolide acetate alone.
* To evaluate quality of life as measured by the FACT-P questionnaire.

Originally, 1696 participants were planned in the study (with 424 participants randomized to each arm). However, only a total of 211 participants completed the randomization procedure as of 26 September 2007. Thus, sanofi-aventis, in accordance with the Steering Committee, decided to stop the participant recruitment as of 26 September 2007. Participants who had already signed their Informed Consent (IC) before September 26, 2007 were allowed to enter the randomization if they met eligibility criteria. The final revised number of planned participants to be randomly assigned to the 4 treatment arms was 250, and 228 participants were actually randomized.

The final sample size did not allow all the statistical analyses to be conducted on efficacy data. Therefore, the protocol was amended to reflect the change in the plans for statistical analysis. The study was underpowered to serve as the basis for drawing conclusions regarding efficacy and quality of life (QoL) endpoints.

The study consisted of the following:

* Randomization of eligible participants within 120 days of prostatectomy
* For participants assigned to immediate therapy, a treatment period up to 18 months within 8 days of randomization
* For participants assigned to deferred treatment, a treatment period up to 18 months after evidence of progression prior to December 2010. Participants who did not progress before December 2010 were withdrawn from the study.

Eligibility Criteria:
Inclusion Criteria:

Participants who met all of the following criteria were considered for enrollment into the study.

* Pathologically confirmed adenocarcinoma of the prostate based on central pathology review. All other variants are excluded
* Randomization should occur less than 120 days after prostatectomy AND lymphadenectomy.
* A predicted probability of 5-year freedom from progression ≤ 60%, as determined by the postoperative nomogram developed by M. Kattan.
* Bone-scan without evidence of metastasis (within 6 months of randomization)
* Chest x-ray without evidence of metastasis (within 6 months of randomization)
* Abdominal computed tomography (CT) Scan without evidence of metastasis (within 6 months of randomization)
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
* Hematology evaluation within 2 weeks prior to randomization:

  * Neutrophils ≥ 2,000/mm3
  * Hemoglobin ≥ 10 g/dL
  * Platelets ≥ 100,000/mm3
* Hepatic and renal function evaluation within 2 weeks prior to randomization:

  * Serum creatinine ≤1.5 × Upper normal limit (UNL) for the institution. If serum creatinine is \> 1.5 × UNL, calculate creatinine clearance (should be ≥ 60ml/minute).
  * Total serum bilirubin ≤ UNL for the institution. Participants with Gilbert's syndrome may be eligible if indirect serum bilirubin levels at the time of randomization and, at least 6 month prior to randomization, confirm this condition (i.e. elevated indirect serum bilirubin).
  * Serum glutamic oxaloacetic transaminase (SGOT) and/or serum glutamic pyruvic transaminase (SGPT) ≤ 1.5 × institutional UNL if alkaline phosphatase is ≤ UNL OR
  * alkaline phosphatase ≤ 5 × UNL if SGOT and SGPT are ≤ UNL
* Prostate Specific Antigen (PSA) evaluation within 9 months prior to prostatectomy. However, a 120-day timeframe is recommended
* Post operative PSA necessary for eligibility is defined as a level ≤ 0.2ng/mL using a standard assay at least 30 days after radical prostatectomy and within 7 days prior to randomization. Note that randomization should occur within 120 days after radical prostatectomy
* Serum testosterone ≥ 150ng/dL within 6 months prior to randomization.

Exclusion Criteria:

Participants presenting with any of the following will not be included in the study.

* Prior systemic treatment for prostate cancer with hormonal therapy, chemotherapy, or any other anticancer therapy.
* Prior radiation therapy.
* Participants who received, are receiving or scheduled to receive post-operative radiotherapy.
* Participants taking alternative therapies for cancer must stop taking these therapies prior to randomization. Alternative therapies are not allowed during the treatment or follow-up portions of the study. This includes (but is not limited to) alternative therapies such as :

  * PC-SPES (all types)
  * 5-alpha reductase inhibitors
* Bisphosphonates are to be stopped prior to randomization and are not allowed during the study.
* Chronic treatment with corticosteroids unless initiated \> 6 months prior to study entry and at low dose ( ≤ 20 mg methylprednisolone per day or equivalent).
* History of a malignancy other than prostate cancer. Exceptions to these criteria include:

  * participants with adequately treated non-melanoma skin cancers, and
  * participants with a history of another malignancy that was curatively treated (including participants with superficial bladder cancer) and who have not had evidence of disease for a minimum of 5 years.
* Peripheral neuropathy ≥ Grade 2.
* Electrocardiogram (ECG) with significant abnormalities (as determined by the investigator) within 90 days prior to randomization.
* Participants who are medically unstable, including but not limited to active infection, acute hepatitis, gastrointestinal bleeding, uncontrolled cardiac arrhythmias, interstitial lung disease, inflammatory bowel disease, uncontrolled angina, uncontrolled hypercalcemia, uncompensated congestive heart failure, uncontrolled diabetes, dementia, seizures, superior vena cava syndrome.
* Participants with history of hypersensitivity to polysorbate 80.
* Participants with a known history of viral hepatitis (B, C).

The above information was not intended to contain all considerations relevant to potential participation in a clinical trial.