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An Open Phase II, Two-centre, 1-Arm Safety Study of Once-daily Orally Administered 10 mg ZD4054 in Prior Chemotherapy Treated Patients With Metastatic Hormone-resistant Prostate Cancer

Phase 2
18 Years
90 Years
Open (Enrolling by invite only)
Prostate Cancer, Metastasis

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Trial Information

An Open Phase II, Two-centre, 1-Arm Safety Study of Once-daily Orally Administered 10 mg ZD4054 in Prior Chemotherapy Treated Patients With Metastatic Hormone-resistant Prostate Cancer

Study centres and number of patients planned This pilot study will be conducted in
approximately 24 patients recruited from two hospital-based Danish centres: department of
Urology K, Aarhus University Hospital, Skejby and department of Urologic Surgery D,
Rigshospitalet. The recruitment of patients will be competitive among centres. 1-2 months
before expected LSI it should be discussed if the target accrual should be expanded.

Study period Phase of development Estimated date of first patient enrolled August 1th 2009
II Estimated date of last patient completed July 31th 2012 Total study duration is
approximately 36 months, which includes 12 months' recruitment, 36-month follow-up for
safety and final survival analysis.


The primary objective of this study is:

To assess the safety and tolerability profile of ZD4054 after treatment with chemotherapy

- Adverse events

- Vital signs

- Laboratory data

- ECGs

- Physical Exam

- Death from any cause

The secondary objectives of the study are:

1. To investigate the effect of ZD4054 on rate of rise of PSA

2. To investigate the effect of ZD4054 on prostate cancer related pain

3. To investigate the effect of ZD4054 on the plasma concentration of circulating tumour
cells (CTC).

In addition, Time to Progression and Overall Survival (time to death) will be compared with
historical data in a post chemotherapy population.

Study design This is a prospective, Open, One-arm, Phase II clinical safety pilot-study. The
trial is designed to gain initial safety and efficacy-related data on once-daily orally
administered ZD4054 10 mg in prior chemotherapy treated patients with metastatic
hormone-resistant prostate cancer.

Patients could receive other therapies including prednisolone, estramustine, ketoconazole
and second-line or third-line antiandrogens at investigator's discretion without being
considered treatment failures or having to stop study therapy; however every attempt will be
made to avoid changes in medication for at least 12 weeks to minimise potential for
confounding on study endpoints over this time period. Chemotherapy and radiation therapy may
also be administered in addition to study therapy at investigator's discretion after
objective progression if the patient is considered likely to derive benefit. Patients will
be followed to death.

Target patient population A total number of 24 male patients aged 18 years or older with
metastatic hormone-resistant prostate cancer who have progressive disease (defined by rising
serum prostate-specific antigen levels despite medical or surgical castration) and
previously received cytotoxic chemotherapy (docetaxel) for the treatment of HRPC.

Investigational product, dosage and mode of administration

Patients will not be randomised and all patients will receive:

• ZD4054 10 mg given orally, once daily in tablet form. Duration of treatment Patients will
receive daily ZD4054 as long as they meet no withdrawal criteria. Following completion of
24 months of ZD4054, patients, who in the investigator's opinion are experiencing benefit
from study treatment, may continue on ZD4054, for as long as they meet no withdrawal

Statistical methods The study is a pilot study designed to collect safety/tolerability data
and assess markers of efficacy. A total of 24 patients will be recruited into this pilot
study and this is based primarily on the number of patients that can be recruited in a
reasonable time period at the centres and should be sufficient to make an initial assessment
of safety/tolerability and the efficacy markers.

For the assessment of tolerability and safety, incidence and severity of adverse events
(AEs) (based on National Cancer Institute Common Terminology Criteria for Adverse Events,
version 3 (NCI CTCAE) grading), laboratory values, vital signs, ECGs and physical exam will
be summarised.

Secondary endpoints will be presented and analysed to investigate trends in the data. The
interpretation of the analyses will consider the number of assessments being undertaken.

Pain will be assessed using the Brief Pain Inventory Demography and baseline data will be
summarised. Any analyses will be performed using SPSS and other validated software as

Inclusion Criteria:

1. Provision of informed consent

2. Male, aged 18 years or older

3. Histological or cytological confirmation of adenocarcinoma of the prostate

4. Documented evidence of bone metastasis on bone scans.

5. Surgically castrated or continuously medically castrated with serum testosterone less
than 2.4 nmol/L (70 ng/dL).

6. Previously (not inside 8 weeks) treated with at least two times 75 mg/m2 docetaxel.

7. Biochemical progression of prostate cancer after chemotherapy, documented while the
patient is castrate:

o Biochemical progression is defined as at least 2 stepwise increases (≥1ng/mL) in
PSA over a period of ≥1 month (values do not need to be consecutive but 2 values that
have increased since the previous highest value are required) with at least 14 days
between each measurement irrespective of assay or laboratory.

8. Life expectancy of 3 months or more.

Exclusion Criteria:

1. Use of potent CYP450 inducers (such as phenytoin, rifampicin, carbamazepine,
phenobarbitone and St John's Wort) within 2 weeks of starting study treatment.
Dexamethasone will be allowed if the investigator feels it is necessary but is
encouraged to use a different form of steroid treatment wherever possible

2. Have received investigational drug in another clinical study of anticancer therapy,
within 4 weeks of starting study treatment

3. Hypersensitivity to endothelin antagonists

4. Neurological symptoms or signs consistent with acute or evolving spinal cord
compression. If a patient has neurologic symptoms, an MRI must be performed that
demonstrates no impending or actual spinal cord compression. Stable, previously
treated patients are allowed

5. History of past or current epilepsy, epilepsy syndrome, or other seizure disorder

6. Stage II, III or IV cardiac failure (classified according to New York Heart
Association (NYHA) classification) or myocardial infarction within 6 months prior to
study entry

7. QT interval corrected for heart rate e.g., by Bazett's correction >470 msec

8. In the opinion of the investigator, any evidence of severe or uncontrolled systemic
disease (e.g., currently unstable or uncompensated respiratory, cardiac, hepatic or
renal disease) or evidence of any other significant clinical disorder or laboratory
finding that makes it undesirable for the patient to participate in the study

9. Hemoglobin (Hb) <5 mmol/L. Concomitant use of erythropoietin or blood transfusions
is allowed

10. Serum bilirubin >1.5 times the upper limit of normal (ULN). This will not apply to
patients with Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is
predominantly unconjugated in the absence of evidence of haemolysis or hepatic
pathology), who will be allowed in consultation with their physician

11. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 times the ULN
or 5 times the ULN in the presence of liver metastasis

12. Creatinine clearance of <50 mL/minute, determined using the Cockcroft-Gault equation
or by 24-hour creatinine clearance

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To assess the safety and tolerability profile of ZD4054 after treatment with chemotherapy

Outcome Time Frame:

2 years

Safety Issue:


Principal Investigator

Michael Borre, MD Phd DMSc

Investigator Role:

Study Chair

Investigator Affiliation:

Dpt Urology Aarhus University Hospital - DAPROCA


United States: Food and Drug Administration

Study ID:




Start Date:

October 2009

Completion Date:

November 2012

Related Keywords:

  • Prostate Cancer
  • Metastasis
  • Prostate cancer
  • Castration resistant
  • Chemotherapy resistant
  • Endothelial receptor A inhibitor
  • ZD4054
  • Neoplasm Metastasis
  • Prostatic Neoplasms