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

RATIONALE: 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.

PURPOSE: 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.

Study Type: Interventional

Study Design: Treatment, Randomized

Study Primary Completion Date: June 2008

OBJECTIVES:

Primary - 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 - To evaluate the safety profile of cediranib, docetaxel, and prednisone in patients with metastatic hormone-refractory prostate cancer. - 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. - To determine the partial and complete response rate in patients with measurable disease treated with cediranib, docetaxel, and prednisone. - To determine time to progression in patients with metastatic hormone-refractory prostate cancer treated with cediranib, docetaxel, and prednisone. - To determine overall survival in patients with metastatic hormone-refractory prostate cancer. - To perform correlative marker studies measuring serum levels of VEGF, PDGF, sICAM, bFGF, interleukin (IL)-6, and IL-8. - 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 for 52 weeks.

Intervention(s) in this Clinical Trial

• Drug: cediranib
  • given orally
• Drug: docetaxel
  • given IV
• Drug: prednisone
  • given orally

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 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.
• Active Comparator: Arm II
  • Patients receive docetaxel and prednisone as in arm I.

Primary Measures

• Progression-free survival rate at 6 months
  • Safety Issue?: No

Secondary Measures

• Prostate-specific antigen (PSA) response duration
  • Safety Issue?: No
• PSA control duration
  • Safety Issue?: No
• Time to progression
  • Safety Issue?: No
• Overall survival
  • Safety Issue?: No
• Levels of the various serum correlative markers and positron emission test (PET) imaging correlates
  • Safety Issue?: No

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the prostate
• 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 < 100 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
• No untreated unstable brain or meningeal metastases
• 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

PATIENT CHARACTERISTICS:

Inclusion criteria:

• 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
• Total bilirubin normal
• 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

Exclusion criteria:

• 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
• Known hypersensitivity to cediranib or any of its excipients
• 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

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• 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

Gender Eligibility for this Clinical Trial: Male

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Barbara Ann Karmanos Cancer Institute

Overall Clinical Trial Officials and Contacts

Elisabeth I. Heath, MD Study Chair Barbara Ann Karmanos Cancer Institute  

Information obtained from ClinicalTrials.gov on August 28, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00527124

Study ID Number: CDR0000564449

ClinicalTrials.gov Identifier: NCT00527124

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database