RATIONALE: Drugs used in chemotherapy, such as ZD4054, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. ZD4054 may also stop the growth of prostate cancer by blocking blood flow to the tumor.

PURPOSE: This randomized phase II trial is studying ZD4054 to see how well it works compared to placebo in treating patients with prostate cancer and bone metastases.

Condition	Treatment or Intervention	Phase
adenocarcinoma of the prostate recurrent prostate cancer stage IV prostate cancer bone metastases	Drug: ZD4054  Procedure: anti-cytokine therapy  Procedure: antiangiogenesis therapy  Procedure: biological response modifier therapy  Procedure: chemotherapy  Procedure: growth factor antagonist therapy	Phase II

Further Study Details: 

OBJECTIVES: Primary

• Compare the effect of 2 different doses of ZD4054 vs placebo on time to progression in patients with hormone-refractory prostate cancer and bone metastases.
• Determine the optimal dose of ZD4054 for future phase III studies.

Secondary

• Compare the effect of these regimens on objective response rate, prostate specific antigen (PSA), and overall survival of these patients.
• Compare the tolerability and safety profile of these regimens in these patients.
• Determine the pharmacokinetics of ZD4054 in these patients.
• Compare the rate of development of new bone lesions in patients treated with these regimens.

Tertiary

• Determine the effect of ZD4054 on biomarkers of bone metastasis and endothelin 1 in these patients.
• Determine the effect of this drug on PSA response and time to PSA progression in these patients.
• Determine the effect of this drug on pain reduction in symptomatic patients and delaying the onset of pain in asymptomatic patients.
• Correlate pharmacokinetics with pharmacodynamics of this drug in these patients.
• Determine the feasibility of quality-of-life tools that are planned for use in future ZD4054 phase III studies.

OUTLINE: This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Patients are stratified according to participating center. Patients are randomized to 1 of 3 treatment arms.

• Arm I: Patients receive oral ZD4054 once daily.
• Arm II: Patients receive ZD4054 as in arm I but at a different dose.
• Arm III: Patients receive oral placebo once daily. In all arms, treatment continues for up to 2 years in the absence of disease progression or unacceptable toxicity. After 2 years, patients who are clinically benefiting from the study treatment may continue to receive study treatment until they are no longer deriving benefit.

Quality of life and pain are assessed at baseline, monthly during study treatment, at completion of study treatment, and then periodically thereafter.

After completion of study treatment, patients are followed for 4 weeks. Patients who discontinue study treatment due to disease progression are followed every 6 months for up to 2 years from the beginning of study treatment. Patients who discontinue study treatment prior to disease progression are followed every 4 weeks until disease progression and then every 6 months for up to 2 years from the beginning of study treatment.

PROJECTED ACCRUAL: A total of 260 patients (approximately 86 per treatment arm) will be accrued for this study within 8 months.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed adenocarcinoma of the prostate
• Metastatic disease
• Evidence of bone metastasis by bone scintigraphy*
• Less than 75% disease involvement of the spine, pelvis, or ribs in the anteroposterior or posteroanterior view NOTE: *Additional scan (e.g., CT scan, MRI, or x-ray) required to confirm metastatic disease (for patients whose bone scintigraphy shows ≤ 3 hot spots)
• No pain OR controlled pain (i.e., mildly symptomatic but does not require opiates) from bone metastases
• Hormone-refractory disease, defined as biochemical progression while castrate
• Rising prostate-specific antigen (PSA) measured at ≥ 2-week intervals within the past 6 months, as defined by 1 of the following criteria:
• 3 consecutively rising PSA levels
• 2 consecutively rising PSA levels followed by a third PSA level < the second PSA level and a fourth PSA level > the second PSA level
• The second PSA level ≥ 2 times the first PSA level AND the third PSA level ≥ 2 times the first PSA level
• Surgically castrated OR continuously medically castrated* with luteinizing hormone-releasing hormone (LHRH) analogue NOTE: *Medically castrated patients must have been on a stable dose of LHRH analogue for ≥ 8 weeks before study entry AND remain on LHRH analogue during study participation
• PSA ≥ 5 ng/mL
• Testosterone ≤ 50 ng/dL
• No neurologic signs or symptoms of acute or evolving spinal cord compression by MRI
• Stable, previously treated spinal cord compression allowed
• No CNS metastasis
• Ineligible for OR refused standard chemotherapy

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• WHO 0-1

Life expectancy

• At least 6 months

Hematopoietic

• Neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 75,000/mm^3
• Hemoglobin > 9 g/dL

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT and AST ≤ 1.5 times ULN
• No unstable or uncompensated hepatic disease

Renal

• Creatinine clearance > 60 mL/min
• No unstable or uncompensated renal disease

Cardiovascular

• No unstable or uncompensated cardiac disease
• No New York Heart Association class II, III, or IV congestive heart failure
• QTc interval ≤ 470 msec

Pulmonary

• No unstable or uncompensated respiratory disease

Other

• Fertile patients must use effective contraception
• No epilepsy or other seizure disorder (unless approved by AstraZeneca)
• No other severe or uncontrolled systemic disease or significant clinical disorder or laboratory finding that would preclude study participation
• No other serious condition that would preclude study participation

PRIOR CONCURRENT THERAPY: Biologic therapy

• Not specified

Chemotherapy

• No prior cytotoxic chemotherapy for recurrent prostate cancer, including any of the following:
• Estramustine
• Paclitaxel
• Docetaxel
• Mitoxantrone

Endocrine therapy

• See Disease Characteristics
• More than 4 weeks since prior corticosteroids (e.g., hydrocortisone) for recurrent prostate cancer
• Corticosteroids administered for other reasons allowed provided the patient is on a stable dose for ≥ 12 weeks before study entry
• More than 6 weeks since prior bicalutamide or nilutamide (4 weeks for flutamide)

Radiotherapy

• More than 12 weeks since prior strontium chloride Sr 89, rhenium-186 hydroxyethylidene diphosphonate, or samarium Sm 153 lexidronam pentasodium for bone metastases
• More than 4 weeks since prior radiotherapy to bone metastases

Surgery

• See Disease Characteristics

Other

• No prior endothelin-receptor antagonists
• More than 4 weeks since prior investigational drugs in another clinical anticancer therapy study
• More than 2 weeks since prior systemic retinoids
• More than 2 weeks since prior herbal medicines or remedies (e.g., PC-SPES or saw palmetto)
• More than 4 weeks since prior bisphosphonates*
• Concurrent bisphosphonates* allowed provided the patient is on a stable dose for ≥ 12 weeks before study entry AND remains on the same dose during study participation
• No initiation of bisphosphonates during study participation NOTE: *Must be administered ≥ 1 week before bone scan, if infused
• More than 2 weeks since prior and no concurrent highly potent inhibitors or inducers of CYP450 3A4, including any of the following:
• Indinavir
• Itraconazole
• Ketoconazole
• Ritonavir
• Carbamazepine
• Phenobarbital
• Phenytoin
• Rifampin
• Hypericum perforatum (St. John's wort)
• No concurrent oral, parenteral, or transdermal opiates, including any of the following:
• Anileridine
• Codeine
• Morphine
• Oxymorphone
• Dextromoramide
• Diamorphine
• Methadone
• Fentanyl
• Hydromorphone
• Levorphanol
• Meperidine
• Oxycodone
• Propoxyphene
• Dipipanone
• Pethidine
• Pentazocine
• Phenazocine
• Butorphanol
• Buprenorphine

California
      Jonsson Comprehensive Cancer Center, UCLA, Los Angeles,  California,  90095,  United States; Recruiting

Study chairs or principal investigators

Steven Wong, MD,  Study Chair,  Jonsson Comprehensive Cancer Center   

Study ID Numbers:  CDR0000422433; UCLA-0407043-01; ZENECA-D4320C00006; ZENECA-4054IL/0006; NCT00090363
Record last reviewed:  March 2005
Last Updated:  April 5, 2005
Record first received:  April 5, 2005
ClinicalTrials.gov Identifier:  NCT00107146
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08