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

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

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.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: ZD6474 (Vandetanib); Drug: Bicalutamide; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 95
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Bordeaux Cedex, France
    • Research Site
  • Creteil, France
    • Research Site
  • Paris, France
    • Research Site
  • Reims Cedex, France
    • Research Site
  • Villejuif, France
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Bicalutamide 150mg + ZD6474 300mg	Drug: ZD6474 (Vandetanib); 300mg orally, once daily; Other Names: Zactima; Drug: Bicalutamide; 150mg orally, once daily; Other Names: Casodex
Placebo Comparator: 2; Bicalutamide 150mg + placebo	Drug: Bicalutamide; 150mg orally, once daily; Other Names: Casodex; Drug: Placebo; orally, once daily

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Genzyme, a Sanofi Company

Study record dates

Study Major Dates

• Study Start: February 1, 2008
• Primary Completion (Actual): November 1, 2010
• Study Completion (Actual): July 1, 2011

Study Registration Dates

• First Submitted: April 10, 2008
• First Submitted That Met QC Criteria: April 10, 2008
• First Posted (Estimate): April 16, 2008

Study Record Updates

• Last Update Posted (Estimate): December 5, 2016
• Last Update Submitted That Met QC Criteria: October 11, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Androgen Antagonists; Bicalutamide
• Other Study ID Numbers: D4200C00080; 2007-001891-35 (EudraCT Number)