A Phase IIa. Open-label, Multicenter, Dose-escalation Study to Assess the Tolerability and Pharmacokinetics of ZD4054 (Zibotentan) Given Orally Once Daily in Subjects With Metastatic Prostate Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT00055471
First received: March 3, 2003
Last updated: October 23, 2012
Last verified: October 2012
Results First Received: March 29, 2011  
Study Type: Interventional
Study Design: Primary Purpose: Treatment
Conditions: Prostatic Neoplasms
Metastases, Neoplasm
Interventions: Drug: ZD4054 10 mg
Drug: ZD4054 15 mg
Drug: ZD4054 22.5 mg

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
22 male patients with metastatic prostate cancer and rising Prostate Specific Antigen (PSA) levels were recruited from 11th June 2003 (last subject completed on 31st October 2005). This study was conducted in 2 centres in the United States.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
6 of the 22 screened patients were not entered into the study as they did not fulfill the study eligibility criteria.

Reporting Groups
  Description
ZD4054 10 mg ZD4054 10 mg dose: 1 x 10 mg oral tablet once daily
ZD4054 15 mg ZD4054 15 mg dose: 1 x 10 mg + 2 x 2.5 mg oral tablets once daily
ZD4054 22.5 mg ZD4054 22.5 mg dose: 2 x 10 mg + 1 x 2.5 mg oral tablets once daily

Participant Flow for 2 periods

Period 1:   Period 1: Dose Escalation Period
    ZD4054 10 mg     ZD4054 15 mg     ZD4054 22.5 mg  
STARTED     3     10 [1]   3 [1]
COMPLETED     3     8     0  
NOT COMPLETED     0     2     3  
Adverse Event                 0                 1                 2  
Erroneously reported discont. criteria                 0                 0                 1  
Disease progression                 0                 1                 0  
[1] Dose level given only after lower dose was successfully administered.

Period 2:   Period 2: Extension Period
    ZD4054 10 mg     ZD4054 15 mg     ZD4054 22.5 mg  
STARTED     3 [1]   6 [2]   0  
COMPLETED     3     6     0  
NOT COMPLETED     0     0     0  
[1] Period 2 - attend Pts who,in the opinion of the Investigator,show benefit from treatment with ZD4054
[2] 2 pts discontinued after completion of Period1,therefore 9 pts proceeded to participate in Period2



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
ZD4054 10 mg ZD4054 10 mg dose: 1 x 10 mg oral tablet once daily
ZD4054 15 mg ZD4054 15 mg dose: 1 x 10 mg + 2 x 2.5 mg oral tablets once daily
ZD4054 22.5 mg ZD4054 22.5 mg dose: 2 x 10 mg + 1 x 2.5 mg oral tablets once daily
Total Total of all reporting groups

Baseline Measures
    ZD4054 10 mg     ZD4054 15 mg     ZD4054 22.5 mg     Total  
Number of Participants  
[units: participants]
  3     10     3     16  
Age  
[units: Years]
Mean ± Standard Deviation
       
Overall     72.3  ± 3.21     64.6  ± 9.72     66.3  ± 8.08     66.4  ± 8.72  
Gender  
[units: Participants]
       
Female     0     0     0     0  
Male     3     10     3     16  
Race/Ethnicity, Customized  
[units: Participants]
       
Caucasian     3     9     3     15  
Black     0     1     0     1  
Oriental     0     0     0     0  
Other     0     0     0     0  
Height  
[units: Centimeters (cm)]
Mean ± Standard Deviation
  177.33  ± 4.51     177.10  ± 8.02     176.33  ± 5.03     177  ± 6.69  
Weight  
[units: Kilograms (kg)]
Mean ± Standard Deviation
  87.33  ± 19.035     107.8  ± 21.060     103.00  ± 35.595     103.06  ± 23.405  



  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Dose Limiting Toxicities (DLTs)   [ Time Frame: Baseline to Day 29. ]

Measure Type Primary
Measure Title Dose Limiting Toxicities (DLTs)
Measure Description

DLT is defined as experiencing Common Toxicity Criteria (CTC) grade 3 or 4 headache with onset within 24 h of receiving ZD4054, CTC grade 2 rhinitis leading to the withdrawal of the subject, or other CTC grade 3 or 4 toxicity that was considered to be related to ZD4054 treatment.

The numbers of patients with a DLT are reported.

Time Frame Baseline to Day 29.  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
ZD4054 10 mg ZD4054 10 mg dose: 1 x 10 mg oral tablet once daily
ZD4054 15 mg ZD4054 15 mg dose: 1 x 10 mg + 2 x 2.5 mg oral tablets once daily
ZD4054 22.5 mg ZD4054 22.5 mg dose: 2 x 10 mg + 1 x 2.5 mg oral tablets once daily

Measured Values
    ZD4054 10 mg     ZD4054 15 mg     ZD4054 22.5 mg  
Number of Participants Analyzed  
[units: participants]
  3     10     3  
Dose Limiting Toxicities (DLTs)  
[units: Participants]
  0     0     2  

No statistical analysis provided for Dose Limiting Toxicities (DLTs)



2.  Secondary:   Total Prostate Specific Antigen (PSA) Concentration   [ Time Frame: Baseline to Day 15. ]

Measure Type Secondary
Measure Title Total Prostate Specific Antigen (PSA) Concentration
Measure Description Total Prostate Specific Antigen (PSA) concentration at Day 15 (14 doses of study treatment per patient – no dose was administered on Day 2).
Time Frame Baseline to Day 15.  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All dosed patients.

Reporting Groups
  Description
ZD4054 10 mg ZD4054 10 mg dose: 1 x 10 mg oral tablet once daily
ZD4054 15 mg ZD4054 15 mg dose: 1 x 10 mg + 2 x 2.5 mg oral tablets once daily
ZD4054 22.5 mg ZD4054 22.5 mg dose: 2 x 10 mg + 1 x 2.5 mg oral tablets once daily

Measured Values
    ZD4054 10 mg     ZD4054 15 mg     ZD4054 22.5 mg  
Number of Participants Analyzed  
[units: participants]
  3     10     2  
Total Prostate Specific Antigen (PSA) Concentration  
[units: ng/ml]
Geometric Mean ( Full Range )
  98.454  
  ( 78.00 to 142.60 )  
  62.366  
  ( 6.00 to 448.90 )  
  56.550  
  ( 36.80 to 86.90 )  

No statistical analysis provided for Total Prostate Specific Antigen (PSA) Concentration



3.  Secondary:   Change in Total Prostate Specific Antigen (PSA)   [ Time Frame: Baseline to Day 15. ]

Measure Type Secondary
Measure Title Change in Total Prostate Specific Antigen (PSA)
Measure Description

Percentage change in total Prostate Specific Antigen (PSA) (ng/mL) from baseline to Day 15 (14 doses of study treatment per patient – no dose was administered on Day 2).

Percentage change = [(measure at Day 15 – measure at baseline)/measure at baseline]*100

Time Frame Baseline to Day 15.  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The analysis population includes only patients dosed with ZD4054

Reporting Groups
  Description
ZD4054 10 mg ZD4054 10 mg dose: 1 x 10 mg oral tablet once daily
ZD4054 15 mg ZD4054 15 mg dose: 1 x 10 mg + 2 x 2.5 mg oral tablets once daily
ZD4054 22.5 mg ZD4054 22.5 mg dose: 2 x 10 mg + 1 x 2.5 mg oral tablets once daily

Measured Values
    ZD4054 10 mg     ZD4054 15 mg     ZD4054 22.5 mg  
Number of Participants Analyzed  
[units: participants]
  3     10     2  
Change in Total Prostate Specific Antigen (PSA)  
[units: Percentage Change]
Mean ± Standard Deviation
  2.235  ± 15.445     10.986  ± 21.345     18.404  ± 30.132  

No statistical analysis provided for Change in Total Prostate Specific Antigen (PSA)



4.  Secondary:   Change in Serum Concentration of Bone Alkaline Phosphatase (ALP)   [ Time Frame: Baseline to Day 15. ]

Measure Type Secondary
Measure Title Change in Serum Concentration of Bone Alkaline Phosphatase (ALP)
Measure Description Percentage change in serum concentration of Bone Alkaline Phosphatase (ALP) (ng/mL) from baseline to Day 15 (14 doses of study treatment per patient – no dose was administered on Day 2). Percentage change = [(measure at Day 15 – measure at baseline)/measure at baseline]*100
Time Frame Baseline to Day 15.  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The analysis population includes only patients dosed with ZD4054

Reporting Groups
  Description
ZD4054 10 mg ZD4054 10 mg dose: 1 x 10 mg oral tablet once daily
ZD4054 15 mg ZD4054 15 mg dose: 1 x 10 mg + 2 x 2.5 mg oral tablets once daily
ZD4054 22.5 mg ZD4054 22.5 mg dose: 2 x 10 mg + 1 x 2.5 mg oral tablets once daily

Measured Values
    ZD4054 10 mg     ZD4054 15 mg     ZD4054 22.5 mg  
Number of Participants Analyzed  
[units: participants]
  3     10     2  
Change in Serum Concentration of Bone Alkaline Phosphatase (ALP)  
[units: Percentage Change]
Mean ± Standard Deviation
  -6.161  ± 9.616     -9.197  ± 12.220     -9.182  ± 10.644  

No statistical analysis provided for Change in Serum Concentration of Bone Alkaline Phosphatase (ALP)



5.  Secondary:   Change in Serum Concentration of Procollagen Type I N Propeptide (PINP)   [ Time Frame: Baseline to Day 15. ]

Measure Type Secondary
Measure Title Change in Serum Concentration of Procollagen Type I N Propeptide (PINP)
Measure Description

Percentage change in serum concentration of Procollagen Type I N Propeptide (PINP) (ng/mL) from baseline to Day 15 (14 doses of study treatment per patient – no dose was administered on Day 2).

Percentage change = [(measure at Day 15 – measure at baseline)/measure at baseline]*100

Time Frame Baseline to Day 15.  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The analysis population includes only patients dosed with ZD4054

Reporting Groups
  Description
ZD4054 10 mg ZD4054 10 mg dose: 1 x 10 mg oral tablet once daily
ZD4054 15 mg ZD4054 15 mg dose: 1 x 10 mg + 2 x 2.5 mg oral tablets once daily
ZD4054 22.5 mg ZD4054 22.5 mg dose: 2 x 10 mg + 1 x 2.5 mg oral tablets once daily

Measured Values
    ZD4054 10 mg     ZD4054 15 mg     ZD4054 22.5 mg  
Number of Participants Analyzed  
[units: participants]
  3     10     2  
Change in Serum Concentration of Procollagen Type I N Propeptide (PINP)  
[units: Percentage Change]
Mean ± Standard Deviation
  7.865  ± 14.625     20.681  ± 44.217     113.012  ± 51.302  

No statistical analysis provided for Change in Serum Concentration of Procollagen Type I N Propeptide (PINP)



6.  Secondary:   Change in Serum Concentration of C-Terminal Telopeptide of Type I Collagen (CTx)   [ Time Frame: Baseline to Day 15. ]

Measure Type Secondary
Measure Title Change in Serum Concentration of C-Terminal Telopeptide of Type I Collagen (CTx)
Measure Description Percentage change in serum concentration of C-Terminal Telopeptide of Type I Collagen (CTx) (ng/mL) from baseline to Day 15 (14 doses of study treatment per patient – no dose was administered on Day 2). Percentage change = [(measure at Day 15 – measure at baseline)/measure at baseline]*100
Time Frame Baseline to Day 15.  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The analysis population includes only patients dosed with ZD4054

Reporting Groups
  Description
ZD4054 10 mg ZD4054 10 mg dose: 1 x 10 mg oral tablet once daily
ZD4054 15 mg ZD4054 15 mg dose: 1 x 10 mg + 2 x 2.5 mg oral tablets once daily
ZD4054 22.5 mg ZD4054 22.5 mg dose: 2 x 10 mg + 1 x 2.5 mg oral tablets once daily

Measured Values
    ZD4054 10 mg     ZD4054 15 mg     ZD4054 22.5 mg  
Number of Participants Analyzed  
[units: participants]
  3     10     2  
Change in Serum Concentration of C-Terminal Telopeptide of Type I Collagen (CTx)  
[units: Percentage Change]
Mean ± Standard Deviation
  -13.832  ± 19.003     44.855  ± 94.876     20.386  ± 31.094  

No statistical analysis provided for Change in Serum Concentration of C-Terminal Telopeptide of Type I Collagen (CTx)



7.  Secondary:   Change in Urine Concentration of Type I Collagen-Cross Linked N Telopeptide (NTx)   [ Time Frame: Baseline to Day 15. ]

Measure Type Secondary
Measure Title Change in Urine Concentration of Type I Collagen-Cross Linked N Telopeptide (NTx)
Measure Description Percentage change in urine concentration of Type I Collagen-Cross Linked N Telopeptide (NTx) (nmol BCE/mmol Creatinine) from baseline to Day 15 (14 doses of study treatment per patient – no dose was administered on Day 2). Percentage change = [(measure at Day 15 – measure at baseline)/measure at baseline]*100
Time Frame Baseline to Day 15.  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The analysis population includes only patients dosed with ZD4054

Reporting Groups
  Description
ZD4054 10 mg ZD4054 10 mg dose: 1 x 10 mg oral tablet once daily
ZD4054 15 mg ZD4054 15 mg dose: 1 x 10 mg + 2 x 2.5 mg oral tablets once daily
ZD4054 22.5 mg ZD4054 22.5 mg dose: 2 x 10 mg + 1 x 2.5 mg oral tablets once daily

Measured Values
    ZD4054 10 mg     ZD4054 15 mg     ZD4054 22.5 mg  
Number of Participants Analyzed  
[units: participants]
  3     10     2  
Change in Urine Concentration of Type I Collagen-Cross Linked N Telopeptide (NTx)  
[units: Percentage Change]
Mean ± Standard Deviation
  -25.213  ± 15.389     2.154  ± 41.900     -5.942  ± 34.344  

No statistical analysis provided for Change in Urine Concentration of Type I Collagen-Cross Linked N Telopeptide (NTx)




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
One patient received one dose of 22.5 mg and was dose reduced to 15 mg thereafter. This patient was classified into the 15 mg dose group, except for the single dose pharmacokinetic results (not posted).


  More Information