Docetaxel and Prednisone With or Without Cediranib in Treating Patients With Metastatic Prostate Cancer That Did Not Respond to Hormone Therapy

Study Overview
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Brief Summary
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This randomized phase II trial is studying how well giving docetaxel and prednisone together with or without cediranib works in treating patients with metastatic prostate cancer that did not respond to hormone therapy. Drugs used in chemotherapy, such as docetaxel and prednisone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Cediranib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving docetaxel together with prednisone, with or without cediranib, may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine the 6-month progression-free survival rate of patients with hormone refractory metastatic adenocarcinoma of the prostate treated with docetaxel and prednisone with vs without cediranib. SECONDARY OBJECTIVES: I. To evaluate the safety profile of cediranib, docetaxel, and prednisone in patients with metastatic hormone-refractory prostate cancer. II. To determine the duration of prostate-specific antigen (PSA) response and PSA control in patients with metastatic hormone-refractory prostate cancer treated with cediranib, docetaxel, and prednisone. III. To determine the partial and complete response rate in patients with measurable disease treated with cediranib, docetaxel, and prednisone. IV. To determine time to progression in patients with metastatic hormone-refractory prostate cancer treated with cediranib, docetaxel, and prednisone. V. To determine overall survival in patients with metastatic hormone-refractory prostate cancer. VI. To perform correlative marker studies measuring serum levels of VEGF, PDGF, sICAM, bFGF, interleukin (IL)-6, and IL-8. VII. To perform a pilot study of [F18]FMAU positron emission test (PET) imaging on patients receiving cediranib, docetaxel, and prednisone. OUTLINE: This is a multicenter study. Patients are stratified by participating institution. Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive oral cediranib once daily on days 1-21, docetaxel IV over 1 hour on day 1, and oral prednisone twice daily on days 1-21. ARM II: Patients receive docetaxel and prednisone as in arm I. In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Archival paraffin-embedded tissue blocks or slides from time of diagnosis (or subsequent, but prior to therapy) are evaluated for expression of molecular targets relevant to this study. Blood specimens from baseline, after courses 1 and 2, and after completion of study treatment are analyzed for protein markers. Samples are analyzed by ELISA and IHC for angiogenesis-associated plasma proteins, plasma levels of VEGF, tumor expression of PDGFR, and interleukin (IL)-6 and IL-8 plasma levels. Patients also undergo positron emission test (PET) scans utilizing fluorodeoxyglucose (FDG) at baseline and after course 1. After completion of study treatment, patients are followed every 3 months for 52 weeks.

Official Title
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A Randomized, Phase II Trial of AZD2171, Docetaxel, and Prednisone Compared to Docetaxel and Prednisone in Patients With Metastatic, Hormone Refractory Prostate Cancer

Conditions
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Adenocarcinoma of the Prostate, Stage IV Prostate Cancer

Intervention / Treatment
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* Drug: cediranib maleate
* Drug: docetaxel
* Drug: prednisone
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical/radiologic metastases with objective evidence of disease progression by imaging or by rising prostate-specific antigen (PSA) despite androgen deprivation therapy Rising PSA must be determined based on a rising trend with 2 successive elevations at a minimum interval of 1 week Meets 1 of the following criteria: Measurable disease, with any level of PSA, at least 1 unidimensionally measurable lesion (longest diameter to be recorded) >= 20 mm by conventional techniques or >= 10 mm by spiral CT scan, nonmeasurable disease, PSA >= 5 ng/mL OR new areas of bony metastases on bone scan Castrate levels of testosterone < 50 ng/dL must be maintained and documented Luteinizing hormone-releasing hormone (LHRH) agonist therapy must be continued, if required to maintain castrate levels of testosterone Total bilirubin normal Patients with radiological evidence of stable brain metastases are eligible provided they are asymptomatic and do not require corticosteroids or have been treated with corticosteroids and show clinical and radiological evidence of stabilization at least 10 days after discontinuation of steroids ECOG performance status (PS) =< 2 or Karnofsky PS 60-100% Life expectancy > 12 weeks Leukocytes >= 3,000/mcL Absolute neutrophil count >= 1,500/mcL Platelet count >= 100,000/mcL Histologically confirmed adenocarcinoma of the prostate AST and ALT =< 2.5 times upper limit of normal Creatinine normal OR creatinine clearance >= 60 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Proteinuria =< 1+ and urine protein:creatinine ratio =< 1.0 OR 24-hour urine protein < 1,000 mg Peripheral neuropathy >= grade 2 Uncontrolled intercurrent illness including, but not limited to, any of the following: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness/social situations that would limit compliance with study requirements Congestive heart failure, second or third degree heart block, or recent myocardial infarction within the past 6 months QTc prolongation > 500 msec OR other ECG abnormality noted within 14 days of treatment New York Heart Association class III or IV cardiac disease; Class II disease controlled with treatment and monitoring allowed History of poorly controlled hypertension (e.g., resting blood pressure > 150/90 mm Hg with or without hypertensive therapy) History of a curatively treated malignancy with a survival prognosis of less than 5 years or concurrent malignancy except for adequately treated basal cell or squamous cell skin cancer or carcinoma in situ History of significant gastrointestinal impairment, as judged by the investigator, that would significantly affect the absorption of cediranib History of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80 Significant hemorrhage (30 mL bleeding/episode in previous 3 months) or hemoptysis (5 mL fresh blood in previous 4 weeks) Prior enrollment or randomization of treatment in the present study Patients must be off flutamide antiandrogen therapy for ≥ 4 weeks (6 weeks for bicalutamide or nilutamide) No prior chemotherapy for metastatic prostate cancer No major surgery within the past 14 days or a surgical incision that is not fully healed No HIV-positive patients on combination antiretroviral therapy No conditions requiring concurrent use of drugs or biologics with proarrhythmic potential No other investigational agents within 30 days prior to study enrollment No untreated unstable brain or meningeal metastases Known hypersensitivity to cediranib or any of its excipients

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral cediranib maleate once daily on days 1-21, docetaxel IV over 1 hour on day 1, and oral prednisone twice daily on days 1-21. | Drug: cediranib maleate<br>* Given orally<br>* Other names: Recentin;Drug: docetaxel<br>* Given IV<br>* Other names: TXT;Drug: prednisone<br>* Given orally<br>* Other names: Deltra;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Active Comparator: Arm II<br>Patients receive docetaxel and prednisone as in arm I. | Drug: docetaxel<br>* Given IV<br>* Other names: TXT;Drug: prednisone<br>* Given orally<br>* Other names: Deltra;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-month Progression-free Survival (PFS) Proportion | The proportion of patients on each treatment arm who survive ≥ 6.00 months progression-free | Followed for 52 weeks at 3 month intervals after coming off treatment, time period equal to the length of treatment + up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prostate-specific Antigen (PSA) Response in Accordance With the Prostate Specific Antigen Working Group | PSA < 4.0 ng/ml. is a CR. A 50% decline or better in PSA is a PR. Less than a 50% decline in PSA and less than a 25% increase in PSA is SD. A 25% or greater increase in PSA level by at least 5 ng/mL is PD by PSA only. The point estimate and 95% Wilson CI estimates of the proportion for the Prostate-specific antigen (PSA) response will be computed . | Up to 52 weeks | 
| Overall Response Rate Evaluated by the RECIST Criteria | The overall response is determined by combining the patient's status on target lesions, PSA, non-target lesions, and new disease as defined in the following table. Target Lesions CR CR PR SD PD Any Any Any PSA Response CR PR PR Non-PD Any Any PD Any Non-Target Lesions CR Non-CR/Non-PD Non-PD Non-PD Any PD Any Any New Lesions No No No No Yes or No Yes or No Yes or No Yes Overall Response CR PR PR SD PD PD PD PD | Up to 52 weeks | 
| Time to Progression | Analyzed with standard K-M methodology. Both point and 95% CI estimates of the median and other statistics (e.g., the 3-month rate, 6-month rate, etc.) will be computed from the censored distribution of TTP. These point and CI estimates will be reported for all patients combined, and separately for each treatment arm. | The time from registration date until documented clinical disease progression, or until date of death, whichever occurs first, assessed up to 52 weeks | 
| Overall Survival | Analyzed with standard K-M methodology. A 12 month survival rate will be calculated since median survival was not reached by the end of the study period. | The time from registration date until death from any cause, assessed up to 52 weeks |