Efficacy and Safety of Zactima™ in Patients With Castration-refractory Metastatic Prostate Cancer

Study Overview
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Brief Summary
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This randomized, double-blind phase II trial is to assess the efficacy and safety of bicalutamide (Casodex® ) associated to ZD6474 (Zactima™ ) or to placebo in patients with castration-refractory metastatic prostate cancer without any clinical symptom related to disease progression. The study is blinded, and subjects will be randomised (1:1 ratio) to either ZD6474 300 mg or placebo. The blinded design ensures robust, unbiased data collection and assessment. Placebo control is necessary to ensure a robust assessment of PSA PFS, and is acceptable in this subject population where all subjects will also received bicalutamide 150 mg o.d. Subjects will continue study treatment until they reach objective biological disease progression or unacceptable toxicity or withdrawal of consent or until end of trial (which event occurs first). The end of study is fixed 12 months after the last randomised patient's first dose of study treatment.

Official Title
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A Randomized, Double-blind Phase II Trial to Assess the Efficacy and Safety of Bicalutamide (Casodex® ) Associated to ZD6474 (Zactima™ ) or to Placebo in Patients With Castration-refractory Metastatic Prostate Cancer Without Any Clinical Symptom Related to Disease Progression

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: ZD6474 (Vandetanib)
* Drug: Bicalutamide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males presented with a confirmed histological diagnosis of adenocarcinoma of the prostate with evidence of metastases (including bone, lymph nodes, or other site) radiologically or histologically documented and despite a serum testosterone ≤1.73 nmol/L (50 ng/dL) proving castration, evidence of biochemical progression of prostate cancer, documented by a rise in PSA . Exclusion Criteria: Radiotherapy or surgery or antiandrogens (except LHRH analogue) or bilateral orchiectomy within the 30 days preceding Visit 1. Incompletely healed surgical incision. Concomitant anticancer therapy other than surgical castration or continuous medical castration. Biology restriction. Clinical significant cardiovascular event or presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia. History of arrhythmia which is symptomatic or requires treatment (CTCAE grade 3), symptomatic despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled on medication are permitted. Hypertension not controlled by medical therapy ECG /QTc prolongation Presence of left bundle branch block (LBBB).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Bicalutamide 150mg + ZD6474 300mg | Drug: ZD6474 (Vandetanib)<br>* 300mg orally, once daily<br>* Other names: Zactima;Drug: Bicalutamide<br>* 150mg orally, once daily<br>* Other names: Casodex;|
| Placebo Comparator: 2<br>Bicalutamide 150mg + placebo | Drug: Bicalutamide<br>* 150mg orally, once daily<br>* Other names: Casodex;Drug: Placebo<br>* orally, once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prostate Specific Antigen (PSA) Progression Free Rate at 4 Months | To assess the effect of vandetanib on biological progression free rate based on PSA level (assessable set). PSA progression free rate defined as the number of participants with : After decline from baseline: a 25% increase above the nadir No decline from baseline: a 25% increase above the baseline (min. increase of 2 ng/mL) | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) at 4 Months (Instead of Time to PSA Progression) | Due to the difficulties to assess biological progression date when clinical progression has occurred first, and because of the non-assessment of the clinical progression after treatment discontinuation, Time to PSA progression was not evaluated. PFS was evaluated instead, whether biological or clinical progression. | 4 months | 
| Progression Free Survival (PFS) at 4 Months (Instead of Time to Onset of Cancer-related Symptoms) | Due to the difficulties to assess biological progression date when clinical progression has occurred first, and because of the non-assessment of the clinical progression after treatment discontinuation, Time to onset of cancer-related symptoms was not evaluated. PFS was evaluated instead, whether biological or clinical progression. | 4 months | 
| PSA Response Rate | To investigate the effect of vandetanib on the PSA response rate. PSA response rate defined by the number of participants with a PSA decrease relative to baseline of at least 50%. A minimum decrease of 2 ng/mL in absolute value and a confirmation on at least 2 consecutive occasions (at least 4 weeks apart) were requested. | 4 months | 
| Overall Survival (OS) | To investigate the effect of vandetanib on overall survival. Patients alive at the time of the statistical analysis were censored at the time they were last known to be alive. Due to censored data, median overall survival in the placebo group cannot be calculated. OS defined as the number of participants who were alive. | End of study (July 2011) | 
| Progression Rate From the Radionuclide Bone Scanning | To describe the effect of vandetanib on progression rate from the radionuclide bone scanning in a sub-group of patients who had a bone scan within 3 to 6 months after 1st treatment dose. Number of participants with at least 2 new lesions on the radionuclide bone scan compared to baseline assessment were counted for calculation of progression rate. | 4 months | 
| Number of Circulating Tumour Cells (CTC) (in Patients Included in Ile de France Centres Only) | To investigate the effect of vandetanib on CTC. Numbering of CTCs to be performed at baseline, 1 week, 1 and 2 months after randomisation. This study was proposed only to patients followed in a study centre located in Ile de France. Correlation between the number of CTCs and PSA response was to be estimated after 1 week, 1 and 2 months of treatment | 4 months | 
| Number of Circulating Endothelial Cells (CEC) of Tumour Blood Cells (in Patients Included in Ile de France Centres Only) | To investigate the effect of vandetanib on CEC. Numbering of CECs was to be performed at baseline, 1 week, 1 month and 2 months after randomisation. Correlation between the number of CECs and PSA response was to be estimated after 1 week, 1 month and 2 months of treatment. | 4 months | 
| Number of Patients With CECs, CTCs and Gene Signature Profile of CTCs | To investigate the relationship between response to vandetanib, CTCs and CECs. To investigate gene signature profile of antiangiogenic response by gene micro-array analysis of CTCs. Gene signature profile of CTCs was aimed to be compared before and after 2 months of treatment. No blood sample has been taken for the study, and so results on CTCs, CECs of tumour vessels and gene and signature profiles of CTCs were not performed. | 4 months |