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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Multicenter, Open-Label, Randomized, Phase III Trial Comparing Immediate Adjuvant Hormonal Therapy (ELIGARD®- Leuprolide Acetate) in Combination With TAXOTERE® (Docetaxel) Administered Every Three Weeks Versus Hormonal Therapy Alone Versus Deferred Therapy Followed by the Same Therapeutic Options in Patients With Prostate Cancer at High Risk of Relapse After Radical Prostatectomy

Conditions
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Prostatic Neoplasms

Intervention / Treatment
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* Drug: Docetaxel (TAXOTERE®) Chemotherapy
* Drug: Leuprolide acetate ( ELIGARD®) Hormonal Therapy
* Drug: Docetaxel (TAXOTERE®) Chemotherapy
* Drug: Leuprolide acetate ( ELIGARD®) Hormonal Therapy
* Drug: Leuprolide acetate ( ELIGARD®) Hormonal Therapy


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Docetaxel / Leuprolide Acetate - Immediate Treatment (I-CHT)<br>Participants administered docetaxel every three weeks (q3w) for 6 cycles in combination with leuprolide acetate every 3 months for 18 months immediately following prostatectomy. | Drug: Docetaxel (TAXOTERE®) Chemotherapy<br>* 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.<br>Drug: Leuprolide acetate ( ELIGARD®) Hormonal Therapy<br>* 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.<br>|
| Active Comparator: Leuprolide Acetate - Immediate Treatment (I-HT)<br>Participants administered leuprolide acetate every 3 months for 18 months immediately following prostatectomy. | Drug: Leuprolide acetate ( ELIGARD®) Hormonal Therapy<br>* 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.<br>|
| Experimental: Docetaxel / Leuprolide Acetate - Deferred Treatment (D-CHT)<br>Participants in whom treatment was deferred from randomization until first progression - i.e. PSA progression and/or radiologically or histologically documented progression. Participants were treated with docetaxel every three weeks (q3w) for 6 cycles in combination with leuprolide acetate every 3 months for 18 months. | Drug: Docetaxel (TAXOTERE®) Chemotherapy<br>* 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.<br>Drug: Leuprolide acetate ( ELIGARD®) Hormonal Therapy<br>* 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).<br>|
| Active Comparator: Leuprolide Acetate - Deferred Treatment (D-HT)<br>Participants in whom treatment was deferred from randomization until first progression - i.e. PSA progression and/or radiologically or histologically documented progression. Participants were treated with with leuprolide acetate every 3 months for 18 months. | Drug: Leuprolide acetate ( ELIGARD®) Hormonal Therapy<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) Assessment - Number of Participants With Disease Progression | PFS is the interval from the date of surgery to date of progression. The date of progression was the earlier of first PSA increase to ≥ 0.4 ng/mL confirmed within two weeks date of the nadir, if PSA nadir did not reach < 0.4 ng/mL (for deferred arm) first radiological/ histological evidence of tumor progression death. Median PFS was to be estimated using Kaplan-Meier curves. However, enrollment was not met, and meaningful conclusions for efficacy or QoL could not be drawn. Median PFS could not be estimated. Reported is the number of participants with disease progression. | from the date of surgery up to 3 years after randomization of the last participant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Overall Survival (OS) | Overall survival (OS) was the time interval from the date of surgery to the date of death due to any cause. Median OS was to be estimated using Kaplan-Meier Curves. However, enrollment was not met, and meaningful conclusions for efficacy or QoL could not be drawn. Moreover, median OS could not be estimated. Reported is the number of participants who died from any cause. | from the date of surgery up to 3 years after randomization of the last participant | 
| Median Cancer-specific Survival (CSS) | The CSS was the time from the date of surgery to the date of death due to prostate cancer. Median CSS was to be estimated using Kaplan-Meier curves. However, enrollment was not met, and meaningful conclusions for efficacy or QoL could not be drawn. Therefore, based on a protocol amendment, median CSS was not estimated. | from the date of surgery up to 3 years after randomization of the last participant | 
| Median Metastasis-free Survival (MFS) | MFS was the interval from the date of surgery to the date of the first clinical evidence of metastasis after treatment initiation. Metastasis was evaluated by a physical exam or radiologically on bone scan or CT scan. Local (palpable) progression, documented histologically or by imaging techniques was considered evidence of progression. Median MFS was to be estimated using Kaplan-Meier curves. However, enrollment was not met, and meaningful conclusions for efficacy or QoL could not be drawn. Therefore, based on a protocol amendment, median MFS was not estimated. | from the date of surgery up to 3 years after randomization of the last participant | 
| To Evaluate Quality of Life (QoL) as Measured Using a Functional Assessment of Cancer Therapy-Prostate (FACT-P) Questionnaire | The FACT-P is a 39-item participant questionnaire which assesses physical well-being (7 items), social/family well-being (7 items), emotional well-being (6 items), functional well-being (7 items), and additional prostate cancer specific concerns (12 items). All items are scored from 0 (not at all) to 4 (very much). The total FACT-P score ranges from 0-156, with higher scores representing a better QoL with fewer symptoms. A score of 156 represents the best outcome. Note: Enrollment was not met, and meaningful conclusions for efficacy or QoL could not be drawn due to the low sample size. | from 30 days before randomization (baseline) and 18 months after treatment initiation (for change from baseline) | 
| Assessment of Safety and Tolerability - Number of Participants With Adverse Events (AE) | Number of participants with treatment-emergent adverse events (TEAE). A TEAE was as any adverse event that occurred or worsened during the on-treatment period, which was the period from the day of first infusion of study treatment until 30 days after the last infusion of study treatment. | from treatment initiation up to 19 months after treatment initiation |