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

• Compare survival between a control or standard therapy arm of docetaxel + placebo + prednisone with docetaxel + atrasentan + prednisone in patients with hormone refractory prostate cancer. [ Time Frame: Up to 7 years after study opens ] [ Designated as safety issue: No ]
  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.
  
  
• 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. [ Time Frame: Up to 7 years after study opens ] [ Designated as safety issue: No ]
  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.
  
  

• Compare pain progression between the two study arms. [ Time Frame: Up to 52 weeks ] [ Designated as safety issue: No ]
  Measured from date of registration to date of first observation of symptomatic pain progression, date of first confirmed bone disease progression, or initiation of palliative radiation therapy. Patients who die or have soft tissue progression without pain progression are censored at those events. 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. Pain progression will continue to be evaluated through Step 2. Required Palliative Radiotherapy.
  
  
• Compare qualitative and quantitative toxicity between the two study arms [ Time Frame: Assessed every 3 weeks up to 52 weeks ] [ Designated as safety issue: Yes ]
  Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal
  
  
• Compare prostate specific antigen (PSA) response rates between the experimental arm and the standard arm. [ Time Frame: Up to 7 years after study opens ] [ Designated as safety issue: No ]
  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.
  
  
• Compare objective responses between the two treatment groups in patients with measurable disease as defined by RECIST criteria. [ Time Frame: Up to 52 weeks ] [ Designated as safety issue: No ]
  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.
  
  
• Compare elements of Quality of Life between treatment arms: pain palliation response, as measured by the Brief Pain Inventory (BPI) [ Time Frame: up to 18 months study period ] [ Designated as safety issue: No ]
  Pain palliation is the proportion of patients showing a two-point reduction in the Worst Pain score (WPS) maintained for two consecutive assessments with no increase in analgesic use. Increase in analgesic use is defined as an increase in Analgesic code Level to 2 (weak opioid) or 3 (strong opioid). Patients will be classified as pain palliated or not palliated. Patients with a WPS of "0" will be defined as "stable" if their WPS remains "0" for Weeks 7 and 10 with no increase in analgesic use, but they will not be categorized as responders. Pain palliation response is measured by BPI short form that has the following: yes/no question about pain today; 4 pain rating questions (worst pain, least pain, average pain, and current pain); pain medications and pain relief; 7 items addressing effect of pain on functioning. For patients continue to receive treatment beyond 12 treatment cycles, the Worst Pain item is measured by Pain Medication Log and Pain Assessment
  
  
• Compare elements of Quality of Life between treatment arms: change in functional status as measured by the Trial Outcome Index score from the FACT-P [ Time Frame: up to 18 months study period ] [ Designated as safety issue: No ]
  Functional status will be measured with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) Trial Outcome Index. The FACT-P also addresses four general domains of QOL (physical, functional, emotional, and social well-being subscales) as well as symptom concerns associated with prostate cancer and its treatment.
  
  

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.