Docetaxel, Androgen Ablation, and External-Beam Radiation Therapy in Patients With High-Risk Localized Prostate Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Androgens can cause the growth of prostate cancer cells. Antihormone therapy, such as leuprolide, may lessen the amount of androgens made by the body. Radiation therapy uses high energy x-rays to kill tumor cells. Giving docetaxel together with androgen ablation therapy and external-beam radiation therapy may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of docetaxel when given together with androgen ablation therapy and external-beam radiation therapy and to see how well they work in treating patients with high-risk localized prostate cancer.

Detailed Description
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OBJECTIVES: Primary Determine the dose-limiting toxicity and maximum tolerated dose of docetaxel when administered in combination with androgen ablation therapy and adaptive external-beam radiotherapy in patients with high-risk localized adenocarcinoma of the prostate. Secondary Determine the 2-year biochemical progression-free survival of patients treated with this regimen. OUTLINE: This is a multicenter, open-label, dose-escalation study of docetaxel. Androgen ablation therapy: Patients receive leuprolide acetate or other luteinizing hormone-releasing hormone agonist beginning 2-3 months prior to the start of chemoradiotherapy and continuing for up to 2 years. Chemoradiotherapy: Patients receive docetaxel IV over 1 hour on day 1 and high-dose external-beam radiotherapy on days 1-5. Treatment repeats every 7 days for 8 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of docetaxel until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. After completion of study treatment, patients are followed every 3 months.

Official Title
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A Phase I/II Study of Concurrent Weekly Docetaxel (Taxotere®), Androgen Ablation, and Adaptive External Beam Radiotherapy for Localized High-Risk Adenocarcinoma of the Prostate

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: docetaxel
* Drug: leuprolide acetate
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed adenocarcinoma of the prostate with any of following clinical features: A) T3 or T4 B) T1-2 + Gleason Score 8-10 C) T1-2 + Gleason Score 7 + Prostate Specific Antigen (PSA) >10 ng/mL D) T1-2 + Any Gleason Score + PSA >20 ng/mL No evidence of metastatic disease on chest x-ray, bone scan or CT scan of abdomen/pelvis. Age > 18 The Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 Peripheral neuropathy: must be < grade 1 Hematologic parameters A) Absolute neutrophil count > 1,500/mm3 B) Hemoglobin > 8.0 g/dL C) Platelet count > 100,000/mm3. Hepatic parameters / Renal function A) Total Bilirubin must be ≤ 1.2 mg/dL B) Transaminases (AST and ALT) must be < 1.5 x upper limit of normal (ULN) C) Alkaline phosphatase must be < 2.5 x ULN D) Creatinine < 1.5 x ULN ( < 2.1 mg/dL) No prior pelvic or prostate radiation or chemotherapy for prostate cancer. Androgen ablation therapy with one of the luteinizing hormone-releasing hormone (LH-RH) agonists prior to enrollment is acceptable as long as protocol treatment with radiotherapy and chemotherapy is started within 3 months of the initiation of androgen ablation. Patient must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter. Exclusion Criteria: Documented metastases on staging studies Life expectancy <10 years secondary to co-morbid illness Myocardial infarction or significant change in anginal pattern within one year prior to study entry or current congestive heart failure (New York Heart Association Class 2 or higher) Patients with a history of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80 History of invasive malignancy within the last five years prior to study entry except for carcinoma in situ or nonmelanoma skin cancer. Psychiatric conditions which would prevent compliance with treatment or adequate informed consent. Patients receiving another investigational agent during chemo- and radiotherapy Uncontrolled intercurrent illness or other conditions that limit compliance with protocol treatment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Single Arm Intervention<br>Single Arm Intervention where after enrollment (or prior to enrollment but before starting radiotherapy) patients will initially receive leuprolide acetate (Lupron®) intramuscular (IM). Patients will begin adaptive external-beam radiation therapy 2-3 months following the initiation of hormonal therapy. Each patient receives a dose of docetaxel at 10 mg/m2 intravenously over 1 hour weekly for eight weeks, for a total of eight weeks. | Drug: docetaxel<br>* Docetaxel will be administered per the designated cohort starting at 10 mg/m2 intravenously over 1 hour weekly for eight weeks, for a total of eight treatments.<br>* Other names: Taxotere;Drug: leuprolide acetate<br>* Leuprolide acetate will be administered at 22.5 mg IM and will be initiated 2 to 3 months prior to radiotherapy and chemotherapy with docetaxel.<br>* Other names: Zoladex;Radiation: radiation therapy<br>* The total dose will be 7800 cGy in 200 centigray (cGy) per fraction for a total of 39 treatments.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Experiencing Dose-Limiting Toxicities | Determine the number of patients experiencing dose-limiting toxicities (DLT) at each dose level. DLT was defined as grade 3-4 non-haematological or grade 4 haematological toxicity, using the Common Terminology Criteria for Adverse Events, version 3.0. | Average follow up of 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biochemical Progression-free Survival (PFS) | Measure of the activity of a treatment on a disease. In this study it is measured from the date of enrollment to the date on which the prostate cancer progresses or the date the patient dies. Survival curves were estimated using the Kaplan-Meier technique. Biochemical (PSA) failure is defined, in accordance to the American Society for Therapeutic Radiology and Oncology consensus definition, as three consecutive rise in PSA. The date of biochemical failure is considered to be the midpoint between the last non-rising PSA and the first rising PSA. | Average follow up of 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the prostate, stage I prostate cancer, stage II prostate cancer, stage III prostate cancer, stage IV prostate cancer