Official Title: “A Randomized Double-Blinded Placebo Controlled Phase III Trial Comparing Docetaxel and Prednisone With and Without Bevacizumab (IND #7921, NSC #704865) In Men With Hormone Refratory 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. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. It is not yet known whether docetaxel, prednisone, and bevacizumab are more effective than docetaxel and prednisone in treating prostate cancer.

PURPOSE: This randomized phase III trial is studying docetaxel, prednisone, and bevacizumab to see how well they work compared to docetaxel and prednisone in treating patients with prostate cancer that did not respond to hormone therapy.

Study Type: Interventional

Study Design: Treatment, Randomized, Double-Blind, Placebo Control

Study Primary Completion Date: December 2007

OBJECTIVES:

Primary - Compare overall survival of patients with hormone-refractory metastatic adenocarcinoma of the prostate treated with docetaxel and prednisone with vs without bevacizumab.

Secondary - Compare progression-free survival of patients treated with these regimens. - Compare the proportion of patients treated with these regimens who experience a 50% post-treatment prostate-specific antigen decline from baseline. - Compare the proportion of patients treated with these regimens who experience ≥ grade 3 toxic effects.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to predicted 24-month survival probability (< 10% vs 10-29.9% vs ≥ 30%), age (< 65 years vs ≥ 65 years), and prior history of arterial events (i.e., cardiac ischemia/infarction, CNS cerebrovascular ischemia, peripheral arterial ischemia, or CNS hemorrhage) (yes vs no). Patients are randomized to 1 of 2 treatment arms. - Arm I: Patients receive docetaxel IV over 1 hour and placebo IV over 30-90 minutes on day 1. Patients also receive oral prednisone once daily on days 1-21. - Arm II: Patients receive docetaxel and prednisone as in arm I. Patients also receive bevacizumab IV over 30-90 minutes on day 1.

In both arms, courses repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for up to 5 years.

PROJECTED ACCRUAL: Approximately 1,020 patients (510 per treatment arm) will be accrued for this study within 3 years.

Intervention(s) in this Clinical Trial

• Drug: bevacizumab
  • Given IV
• Drug: docetaxel
  • Docetaxel given IV; prednisone given orally
• Drug: placebo
  • Given IV
• Drug: prednisone
  • Docetaxel given IV; prednisone given orally

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: Arm I
  • Patients receive docetaxel IV over 1 hour and placebo IV over 30-90 minutes on day 1. Patients also receive oral prednisone once daily on days 1-21.
• Experimental: Arm II
  • Patients receive docetaxel and prednisone as in arm I. Patients also receive bevacizumab IV over 30-90 minutes on day 1.

Primary Measures

• Overall survival
  • Safety Issue?: No

Secondary Measures

• Proportion of patients who experience a 50% post-treatment prostate-specific antigen (PSA) decline from baseline
  • Safety Issue?: No
• Progression-free survival (PFS)
  • Safety Issue?: No
• Biochemical (PSA) PFS
  • Safety Issue?: No
• Toxicity
  • Safety Issue?: Yes

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the prostate
• Clinically metastatic disease by bone scan, CT scan, or MRI
• Meets 1 of the following criteria:
• Measurable disease with any level of prostate-specific antigen (PSA)
• At least 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques (i.e., physical exam or chest x-ray) OR ≥ 10 mm by spiral CT scan or MRI
• Nonmeasurable disease AND PSA ≥ 5 ng/mL
• The following are considered nonmeasurable disease:
• Bone lesions
• Pleural or pericardial effusions or ascites
• CNS lesions or leptomeningeal disease
• Irradiated lesions unless disease progression is documented after radiotherapy
• Patients with PSA ≥ 5 ng/mL only and no other radiographic evidence of metastatic prostate cancer are not eligible
• Progressive systemic disease (since the most recent change in therapy) despite castrate levels of testosterone due to orchiectomy or luteinizing hormone-releasing hormone (LHRH) agonist therapy
• Castrate levels of testosterone must be maintained
• Primary testicular androgen suppression (e.g.,LHRH agonists) should be continued during study treatment for patients who have not had a bilateral orchiectomy
• Progressive disease is defined as any of the following:
• Measurable disease progression
• Increase of > 20% in the sum of the longest diameters of target lesions from the time of maximal regression OR the appearance of ≥ 1 new lesion
• Bone scan progression
• Appearance of ≥ 1 new lesion on bone scan attributable to prostate cancer AND PSA ≥ 5 ng/mL
• PSA progression
• PSA ≥ 5 ng/mL that has risen serially from baseline on at least 2 occasions (taken ≥1 week apart) after the discontinuation of antiandrogen therapy
• If the confirmatory PSA value is < the screening PSA value, an additional test for rising PSA is required to document progression
• Testosterone ≤ 50 ng/dL for patients who have not had a bilateral orchiectomy
• Have an established Gleason sum
• Patients enrolled on CALGB-90202 are eligible provide they have documented disease progression and have received ≥ 4 weeks of open-label zoledronic acid treatment
• No known brain metastases (MRI or CT scan is not required)

PATIENT CHARACTERISTICS:

• Age
• 18 and over
• Performance status
• ECOG 0-2
• Life expectancy
• Not specified
• Hematopoietic
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• No other significant bleeding episode within the past 6 months
• Hepatic
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST ≤ 1.5 times ULN
• Renal
• Creatinine ≤ 1.5 times ULN
• Urine protein to creatinine ratio < 1.0
• Cardiovascular
• History of hypertension allowed provided blood pressure (BP) is controlled (i.e., BP <
• 160/90 mm Hg) by anti-hypertensive therapy
• No New York Heart Association class II-IV congestive heart failure
• No arterial thrombotic events within the past 6 months, including any of the following:
• Transient ischemic attack
• Cerebrovascular accident
• Unstable angina
• Angina requiring surgical or medical intervention
• Myocardial infarction
• Clinically significant peripheral artery disease (i.e., claudication on less than 1 block)
• Any other arterial thrombotic event
• Pulmonary
• No hemoptysis within the past 6 months
• Gastrointestinal
• No upper or lower gastrointestinal (GI) bleeding within the past 6 months
• No history of GI perforation within the past 12 months
• Other
• Fertile patients must use effective contraception during and for at least 3 months after completion of study treatment
• No serious or non-healing wound, ulcer, or bone fracture
• No peripheral neuropathy ≥ grade 2
• No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies

PRIOR CONCURRENT THERAPY:

• Biologic therapy
• No prior thalidomide or bevacizumab
• No other prior antiangiogenesis agents
• No concurrent prophylactic filgrastim (G-CSF), pegfilgrastim, or sargramostim (GM-CSF)
• Chemotherapy
• No prior estramustine or suramin
• No other prior cytotoxic chemotherapy
• No other concurrent chemotherapy
• Endocrine therapy
• See Disease Characteristics
• At least 4 weeks since prior flutamide, megestrol, bicalutamide, or nilutamide
• At least 4 weeks since any other prior hormonal therapy (e.g., ketoconazole, aminoglutethimide)
• 5α-reductase inhibitors (e.g., finasteride, dutasteride) may be discontinued any time prior to study entry
• No concurrent hormonal therapy except for the following:
• Steroids for adrenal insufficiency
• Hormones for non-disease-related conditions (e.g., insulin for diabetes)
• Intermittent dexamethasone as an antiemetic
• Radiotherapy
• See Disease Characteristics
• At least 4 weeks since prior radiotherapy, including palliative, and recovered
• At least 8 weeks since prior strontium chloride Sr 89 or samarium Sm 153 lexidronam pentasodium
• No concurrent palliative radiotherapy
• Surgery
• See Disease Characteristics
• At least 4 weeks since prior major surgery and recovered
• Other
• Concurrent bisphosphonates allowed provided patient is on a stable dose and initiated treatment ≥ 4 weeks prior to study entry
• No initiation of bisphosphonates during study treatment
• Concurrent full-dose anticoagulation allowed provided patient is on a stable dose of warfarin AND has an in-range INR OR patient is on a stable dose of low-molecular weight heparin
• Concurrent antiplatelet agents allowed, including daily prophylactic aspirin or anticoagulation for atrial fibrillation
• No concurrent herbal medications or food supplements (e.g., PC-SPES, saw palmetto, or Hypericum perforatum [St. John's wort])
• Concurrent daily vitamins and calcium supplements allowed

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: Cancer and Leukemia Group B

Overall Clinical Trial Officials and Contacts

William K. Kelly, DO Study Chair Yale University  

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00110214

Study ID Number: CDR0000427290

ClinicalTrials.gov Identifier: NCT00110214

Health Authority: United States: Food and Drug Administration

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

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