S0421, Docetaxel and Prednisone With or Without Atrasentan in Treating Patients With Stage IV Prostate Cancer and Bone Metastases That Did Not Respond to Previous Hormone Therapy

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as docetaxel, prednisone, and atrasentan work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. It is not yet known whether docetaxel, prednisone, and atrasentan are more effective than docetaxel and prednisone in treating prostate cancer. PURPOSE: This randomized phase III trial is studying docetaxel, prednisone, and atrasentan to see how well they work compared to docetaxel and prednisone in treating patients with stage IV prostate cancer and bone metastases that did not respond to previous hormone therapy.

Detailed Description
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OBJECTIVES: Primary Compare the survival and progression-free survival of patients with hormone-refractory stage IV prostate cancer and bone metastases treated with docetaxel and prednisone combined with either atrasentan vs placebo. Secondary Compare pain progression of patients treated with these regimens. Compare the qualitative and quantitative toxicity of these regimens in these patients. Compare the quality of life, in terms of palliation of metastatic bone pain and improvement in functional status, of patients treated with these regimens. Compare prostate-specific antigen (PSA) response rates in patients treated with these regimens. Compare objective response in patients with measurable disease treated with these regimens. Determine whether a 30% reduction in PSA and the slope of PSA from baseline to 3 months is a surrogate marker for survival in patients treated with these regimens. Correlate PSA progression with clinical progression and death in patients treated with these regimens. OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to disease progression (measurable or non-measurable disease progression vs prostate-specific antigen progression only), use of bisphosphonates at study entry (yes vs no), worst pain, measured by the Brief Pain Inventory pain scale (< grade 4 vs ≥ grade 4), and extraskeletal metastases (yes vs no). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive docetaxel IV over 1 hour on day 1. Patients also receive oral atrasentan and oral prednisone once daily on days 1-21. Treatment repeats every 21 days for up to 12 courses. Patients with stable or responding disease after course 12 may register for continued oral atrasentan treatment for up to 52 weeks in the absence of disease progression* or unacceptable toxicity. Arm II: Patients receive docetaxel and prednisone as in arm I. Patients also receive oral placebo once daily on days 1-21. Treatment repeat every 21 days for up to 12 courses. Patients with stable or responding disease after course 12 may register for continued oral placebo treatment for up to 52 weeks in the absence of disease progression* or unacceptable toxicity. NOTE: *Patients with PSA progression alone will be allowed to continue treatment Quality of life is assessed at baseline, before courses 4, 7, and 10, and then after completion of study treatment. After completion of study treatment, patients are followed every 3 months for 1 year and then every 6 months for up to 3 years from study entry. PROJECTED ACCRUAL: A total of 930 patients will be accrued for this study within 4 years.

Official Title
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Phase III Study of Docetaxel and Atrasentan Versus Docetaxel and Placebo for Patients With Advanced Hormone Refractory Prostate Cancer

Conditions
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Metastatic Cancer, Prostate Cancer

Intervention / Treatment
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* Drug: atrasentan hydrochloride
* Drug: docetaxel
* Drug: prednisone
* Other: placebo


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the prostate Stage IV disease (any T, any N, M1b) Evidence of bone metastases by bone scan or MRI Measurable or nonmeasurable disease Soft tissue disease that has been irradiated within the past 2 months is not assessable as measurable disease Hormone-refractory disease despite androgen deprivation and antiandrogen withdrawal, as defined by 1 of the following criteria: Prostate-specific antigen (PSA) progression, defined as 3 consecutive rising PSA levels* taken ≥ 1 week apart PSA ≥ 5 ng/mL NOTE: *If the third confirmatory PSA level is < the second level, the patient is considered eligible provided a fourth PSA level is > the second level Progression of measurable disease Progression of nonmeasurable disease by bone scan Must have undergone surgical or medical (e.g., luteinizing hormone-releasing hormone [LHRH] agonist [e.g., leuprolide or goserelin] or LHRH antagonist therapy) castration Patients who have undergone medical castration must continue LHRH agonist or antagonist therapy during study treatment Must have completed 12 courses of blinding protocol treatment (atrasentan/placebo) AND stopped docetaxel for any reason (including completion of 12 courses) other than progressive disease No symptomatic pleural effusion No third space fluid accumulation (e.g., ascites) No prior or concurrent brain metastases Patients with clinical evidence of brain metastases must have a negative brain CT scan or MRI within the past 8 weeks PATIENT CHARACTERISTICS: Age 18 and over Performance status Zubrod 0-3* NOTE: For a performance status of 3, the cause must be due to pain secondary to bone metastases Life expectancy Not specified Hematopoietic Not specified Hepatic Not specified Renal Not specified Other Fertile patients must use effective contraception Able to take oral medication without crushing, dissolving, or chewing tablets No major infection No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or stage I or II cancer in complete remission No symptomatic sensory neuropathy ≥ grade 2 No history of hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80 No other significant, active medical illness that would preclude study treatment or survival PRIOR CONCURRENT THERAPY: Biologic therapy No more than 1 prior systemic vaccine or biologic therapy At least 4 weeks since prior vaccine or biologic therapy and recovered No concurrent biological response modifiers No concurrent prophylactic colony-stimulating factors Chemotherapy More than 2 years since prior adjuvant therapy with a single non-taxane-containing cytotoxic regimen No prior cytotoxic chemotherapy for metastatic prostate cancer No other concurrent chemotherapy Endocrine therapy See Disease Characteristics At least 6 weeks since prior bicalutamide or nilutamide AND has subsequent disease progression At least 4 weeks since prior flutamide or ketoconazole AND has subsequent disease progression Prior or concurrent megestrol for treatment of hot flashes allowed No other concurrent corticosteroid or hormonal therapy unless continuing luteinizing hormone-releasing hormone treatment and/or bisphosphonate therapy Radiotherapy See Disease Characteristics Prior samarium allowed At least 3 weeks since prior radiotherapy and recovered No prior radiotherapy to ≥ 30% of the bone marrow No prior strontium No concurrent radiotherapy Surgery See Disease Characteristics At least 3 weeks since prior surgery and recovered Other More than 4 weeks since prior investigational drugs Concurrent bisphosphonates allowed provided therapy is started prior to study entry, dose is maintained during the first 12 weeks of study treatment, and patient meets criteria for disease progression No initiation of bisphosphonates during the first 12 weeks of study treatment No concurrent herbal medications or food supplements (e.g., PC-SPES, saw palmetto, Hypericum perforatum [St. John's wort]) Concurrent daily vitamins and calcium supplements allowed At least 14 days since prior and no concurrent administration of any of the following: Antibiotics (e.g., clarithromycin, erythromycin, troleandomycin, rifampin, rifabutin, and rifapentine) Antifungals (e.g., itraconazole, ketoconazole, fluconazole [doses > 200 mg/day], and voriconazole) Antidepressants (e.g., nefazodone and fluvoxamine) Calcium channel blockers (e.g., verapamil, diltiazem) Miscellaneous (e.g., amiodarone [no use within 6 months prior to study entry], grapefruit juice, bitter orange, or modafinil) Anticonvulsants (e.g., phenytoin, carbamazepine, phenobarbital, and oxcarbazepine) Antibiotics (e.g., rifampin, rifabutin, and rifapentine)

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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I: placebo<br>Patients receive docetaxel and prednisone as in arm I. Patients also receive oral placebo once daily on days 1-21. Treatment repeat every 21 days for up to 12 courses. Patients with stable or responding disease after course 12 may register for continued oral placebo treatment for up to 52 weeks. | Drug: docetaxel<br>* Docetaxel given IV and prednisone given orally<br>* Other names: taxotere;Drug: prednisone<br>* Docetaxel given IV and prednisone given orally<br>* Other names: steroid;Other: placebo<br>* Given orally<br>|
| Experimental: Arm II: atrasentan hydrochloride<br>Patients receive docetaxel IV over 1 hour on day 1. Patients also receive oral atrasentan and oral prednisone once daily on days 1-21. Treatment repeats every 21 days for up to 12 courses. Patients with stable or responding disease after course 12 may register for continued oral atrasentan treatment for up to 52 weeks. | Drug: atrasentan hydrochloride<br>* Given orally<br>* Other names: atrasentan;Drug: docetaxel<br>* Docetaxel given IV and prednisone given orally<br>* Other names: taxotere;Drug: prednisone<br>* Docetaxel given IV and prednisone given orally<br>* Other names: steroid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare Survival Between a Control or Standard Therapy Arm of Docetaxel + Placebo + Prednisone With Docetaxel + Atrasentan + Prednisone in Patients With Hormone Refractory Prostate Cancer. | Measured from date of registration to date of death due to any cause. Patient last known to be alive are censored at date of last contact. | Up to 7 years after study opens | 
| Compare Progression-free Survival Between a Control or Standard Therapy Arm of Docetaxel + Placebo + Prednisone With Docetaxel + Atrasentan + Prednisone in Patients With Hormone Refractory Prostate Cancer. | Measured from date of registration to date of first observation of progressive disease, or death due to any cause. Patients without progression are censored at date of last contact. Disease progression is defined by confirmed bone disease progression, soft tissue or pain progression. | Up to 7 years after study opens | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare Pain Progression Between the Two Study Arms. | Pain progression is defined as patients reporting an increase of at least two Worst Pain points, maintained for at least two consecutive assessments, increase to Level 3 (strong opioid) on the Pain Medication Log Analgesic Code for patients receiving Level 2 (weak opioid) analgesics at randomization, or an increase to Level 2 or 3 analgesics for patients receiving Level 0 or 1 analgesics at randomization. | Up to 52 weeks | 
| Compare Qualitative and Quantitative Toxicity Between the Two Study Arms | Only adverse events that are possibly, probably or definitely related to study drug are reported. | Assessed every 3 weeks up to 52 weeks | 
| Compare Prostate Specific Antigen (PSA) Response Rates Between the Experimental Arm and the Standard Arm. | PSA Partial Response: Greater than or equal to 50% reduction in baseline PSA. There must be no evidence of soft tissue progression, or confirmed none disease progression, or pain progression. | Up to 7 years after study opens | 
| Compare Objective Responses Between the Two Treatment Groups in Patients With Measurable Disease as Defined by RECIST Criteria. | Complete Response (CR): Complete disappearance of all measurable and non-measurable disease. No new lesions. No disease related symptoms. Normalization of markers and other abnormal lab values. PSA ≤ .2 ng/ml. Partial Response (PR): Applies only to patients with at least one measurable lesion. Greater than or equal to 30% decrease under baseline of the sum of longest diameters of all target measurable lesions. No unequivocal progression of non-measurable disease. No new lesions. | Up to 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the prostate, stage IV prostate cancer, recurrent prostate cancer, bone metastases