Adjuvant Leuprolide With or Without Docetaxel in High Risk Prostate Cancer After Radical Prostatectomy
Condition: Prostatic Neoplasms
MeSH terms: Prostatic Neoplasms
Intervention: Docetaxel (TAXOTERE®) Chemotherapy; Leuprolide acetate ( ELIGARD®) Hormonal Therapy; Docetaxel (TAXOTERE®) Chemotherapy; Leuprolide acetate ( ELIGARD®) Hormonal Therapy; Leuprolide acetate ( ELIGARD®) Hormonal Therapy
Intervention description: 75 mg/m^2 docetaxel administered intravenously over 1 hour on Day 1 every three weeks (q3w) for 6 cycles. The first cycle was to be administered within 8 days after randomization.
Corticosteroid pre-medication was mandatory. The following schedule was recommended - 8 mg Dexamethasone orally for 6 doses given - the night before chemotherapy, the morning of chemotherapy, 1 hour before docetaxel infusion, the night of chemotherapy, the morning of the day after chemotherapy and the night of the day after chemotherapy.; 22.5 mg leuprolide acetate injection administered subcutaneously (SC) every 3 months for 18 months. The first injection was to be administered within 8 days after randomization.; 75 mg/m^2 docetaxel administered IV over 1 hour on Day 1 q3w for 6 cycles. The first cycle was to be administered within 30 days after progression was confirmed.
Corticosteroid pre-medication was mandatory. The following schedule was recommended - 8 mg Dexamethasone orally for 6 doses given - the night before chemotherapy, the morning of chemotherapy, 1 hour before docetaxel infusion, the night of chemotherapy, the morning of the day after chemotherapy and the night of the day after chemotherapy.; 22.5 mg leuprolide acetate injection administered subcutaneously (SC) every 3 months for 18 months. The first injection was to be administered within 30 days after progression is confirmed (on Day 1 of docetaxel administration).; 22.5 mg leuprolide acetate injection administered subcutaneously (SC) every 3 months for 18 months. The first injection was to be administered within 30 days after progression is confirmed.
Intervention MeSH terms: Docetaxel; Leuprolide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Enrollment: 228.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

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.