Phase I Efficacy On Vascular Permeability In Patients With Advanced Colorectal Cancer
Primary Purpose
Colorectal Cancer
Status
Completed
Phase
Phase 1
Locations
Germany
Study Type
Interventional
Intervention
ZD6474 (Zactima) 100mg
Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MR)
Biomarker Draws
ZD6474 (Zactima) 300mg
Sponsored by
About this trial
This is an interventional treatment trial for Colorectal Cancer focused on measuring ZD6474, Colorectal Cancer, Liver Metastases, Biomarkers
Eligibility Criteria
Inclusion Criteria:
- Histologically confirmed metastatic colorectal adenocarcinoma (stage IV) with at least 1 measurable hepatic lesion of 20 mm or more on MRI and for whom no standard therapy is available.
- WHO Performance status 0 - 2.
- Life expectancy of at least 12 weeks
Exclusion Criteria:
- Brain metastases or spinal cord compression, unless treated at least 4 weeks before entry and stable without steroid treatment for 10 days or greater.
- Last dose of prior chemotherapy must be discontinued at least 4 weeks before the start of study treatment.
- Last dose of radiotherapy received within 4 weeks before the start of study treatment excluding palliative radiotherapy.
- Prior treatment with VEGFR TKIs
- Serum bilirubin . 1.5 x the upper limit of reference range.
- Serum creatinine >1.5 x ULRR or Creatinine clearance (as determined by the Cockcroft - Gault method) less than or equal to 50 mL/min.
- ALT or AST >5 x ULRR
- ALP >5 x ULRR
- Evidence of severe or uncontrolled systemic disease or any concurrent conditions which in the investigators opinion make it undesirable for the patient to participate in the study or would jeopardize compliance with the protocol.
- Any unresolved toxicity greater than CTCAE Grade 2 for previous anti-cancer therapy.
- Significant cardiovascular event within 3 months before entry, 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) or asymptomatic sustained ventricular tachycardia. Atrial fibrillation, controlled by medication is not excluded.
- Congenital long QT syndrome or 1st degree relative with sudden unexplained death under of 40 years of age.
- Presence of Left Bundle Branch Block.
- QTc with Bazett's correction unmeasurable or greater than or equal to 480 msec or greater of screening ECG.
- Potassium <4.0 mmol/L despite supplementation, serum calcium (ionized or adjusted for albumin), or magnesium out of normal range despite supplementation.
- Women who are pregnant or breast feeding.
- Any concomitant medications that may cause QTc prolongation or induce or induce Torsades de Pointes or induce CTP3A4 function.
- Hypotension not controlled by medical therapy.
- Participation in a clinical study of any investigational pharmaceutical agent within 30 days prior to commencing study treatment.
- Major surgery within 4 weeks or incompletely healed surgical incision.
- Previous or current malignancies of other histologies within the last 5 years, with the exception of in situ carcinoma of the cervix and adequately treated basal cell or Squamous cell carcinoma of the skin.
- Any contraindications to MRI scans.
- Involvement in the planning or conduct of the study.
- Previous enrollment or randomization of treatment in the present study.
Sites / Locations
- Research Site
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
ZD6474 (vandetanib) 100mg
ZD6474 (vandetanib) 300mg
Arm Description
Outcomes
Primary Outcome Measures
Assess by dynamic contrast-enhanced magnetic resonance imaging the effect of once daily dosing with ZD6474 on tumour perfusion and vascular permeability in patients with advanced colorectal cancer and liver metastases.
Secondary Outcome Measures
Assessment of appropriate Pharmacokinetic parameters
The exposure to ZD6474 in patients with advanced colorectal cancer and liver metastases by assessment of: maximum plasma concentration after single and at steady state (C max and Css, max); time to reach C max and Css, max (tmax); minimum plasma concentration before and at steady state (Cmin and Css, min); area under plasma concentration-time curve from zero to 24 h and at steady state (AUC(0-24) and AUCss); total body clearance of drug from plasma after an oral dose (CL/F): accumulation ratio (Rac) and fraction of ZD6474 unbound (fu).
Determine the population PK of ZD6474 and assess the relationship between both free and total plasma PK and measures of Pharmacological activity
Determination of the population PK of ZD6474 and the assessment of the relationship between both free and total plasma PK and measures of pharmacological activity by assessment of individual predicted plasma concentrations, individual predicted CL/F, AUCss, Css, max, and AUC to the point up to the scan.
Assessment of the effectiveness of ZD6474 as measured by objective response rate and progression free survival based on RECIST.
Full Information
NCT ID
NCT00496509
First Posted
July 3, 2007
Last Updated
August 25, 2016
Sponsor
Genzyme, a Sanofi Company
1. Study Identification
Unique Protocol Identification Number
NCT00496509
Brief Title
Phase I Efficacy On Vascular Permeability In Patients With Advanced Colorectal Cancer
Official Title
A Phase I, Open-Label Study To Assess The Effect of ZD6474 (ZACTIMA) On Vascular Permeability In Patients With Advanced Colorectal Cancer and Liver Metastases
Study Type
Interventional
2. Study Status
Record Verification Date
August 2016
Overall Recruitment Status
Completed
Study Start Date
August 2006 (undefined)
Primary Completion Date
October 2007 (Actual)
Study Completion Date
October 2007 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Genzyme, a Sanofi Company
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
A Phase I, Open-Label Study To Assess The Effect of ZD6474 (ZACTIMA) On Vascular Permeability In Patients with Advanced Colorectal Cancer and Liver Metastases.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Cancer
Keywords
ZD6474, Colorectal Cancer, Liver Metastases, Biomarkers
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
24 (Actual)
8. Arms, Groups, and Interventions
Arm Title
ZD6474 (vandetanib) 100mg
Arm Type
Experimental
Arm Title
ZD6474 (vandetanib) 300mg
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
ZD6474 (Zactima) 100mg
Intervention Type
Procedure
Intervention Name(s)
Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MR)
Intervention Type
Procedure
Intervention Name(s)
Biomarker Draws
Intervention Type
Drug
Intervention Name(s)
ZD6474 (Zactima) 300mg
Primary Outcome Measure Information:
Title
Assess by dynamic contrast-enhanced magnetic resonance imaging the effect of once daily dosing with ZD6474 on tumour perfusion and vascular permeability in patients with advanced colorectal cancer and liver metastases.
Time Frame
Up to 57 days.
Secondary Outcome Measure Information:
Title
Assessment of appropriate Pharmacokinetic parameters
Description
The exposure to ZD6474 in patients with advanced colorectal cancer and liver metastases by assessment of: maximum plasma concentration after single and at steady state (C max and Css, max); time to reach C max and Css, max (tmax); minimum plasma concentration before and at steady state (Cmin and Css, min); area under plasma concentration-time curve from zero to 24 h and at steady state (AUC(0-24) and AUCss); total body clearance of drug from plasma after an oral dose (CL/F): accumulation ratio (Rac) and fraction of ZD6474 unbound (fu).
Time Frame
Predetermined timepoints after dose administration
Title
Determine the population PK of ZD6474 and assess the relationship between both free and total plasma PK and measures of Pharmacological activity
Description
Determination of the population PK of ZD6474 and the assessment of the relationship between both free and total plasma PK and measures of pharmacological activity by assessment of individual predicted plasma concentrations, individual predicted CL/F, AUCss, Css, max, and AUC to the point up to the scan.
Time Frame
Predetermined timepoints after dose administration
Title
Assessment of the effectiveness of ZD6474 as measured by objective response rate and progression free survival based on RECIST.
Time Frame
Every 8 weeks during the study
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Histologically confirmed metastatic colorectal adenocarcinoma (stage IV) with at least 1 measurable hepatic lesion of 20 mm or more on MRI and for whom no standard therapy is available.
WHO Performance status 0 - 2.
Life expectancy of at least 12 weeks
Exclusion Criteria:
Brain metastases or spinal cord compression, unless treated at least 4 weeks before entry and stable without steroid treatment for 10 days or greater.
Last dose of prior chemotherapy must be discontinued at least 4 weeks before the start of study treatment.
Last dose of radiotherapy received within 4 weeks before the start of study treatment excluding palliative radiotherapy.
Prior treatment with VEGFR TKIs
Serum bilirubin . 1.5 x the upper limit of reference range.
Serum creatinine >1.5 x ULRR or Creatinine clearance (as determined by the Cockcroft - Gault method) less than or equal to 50 mL/min.
ALT or AST >5 x ULRR
ALP >5 x ULRR
Evidence of severe or uncontrolled systemic disease or any concurrent conditions which in the investigators opinion make it undesirable for the patient to participate in the study or would jeopardize compliance with the protocol.
Any unresolved toxicity greater than CTCAE Grade 2 for previous anti-cancer therapy.
Significant cardiovascular event within 3 months before entry, 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) or asymptomatic sustained ventricular tachycardia. Atrial fibrillation, controlled by medication is not excluded.
Congenital long QT syndrome or 1st degree relative with sudden unexplained death under of 40 years of age.
Presence of Left Bundle Branch Block.
QTc with Bazett's correction unmeasurable or greater than or equal to 480 msec or greater of screening ECG.
Potassium <4.0 mmol/L despite supplementation, serum calcium (ionized or adjusted for albumin), or magnesium out of normal range despite supplementation.
Women who are pregnant or breast feeding.
Any concomitant medications that may cause QTc prolongation or induce or induce Torsades de Pointes or induce CTP3A4 function.
Hypotension not controlled by medical therapy.
Participation in a clinical study of any investigational pharmaceutical agent within 30 days prior to commencing study treatment.
Major surgery within 4 weeks or incompletely healed surgical incision.
Previous or current malignancies of other histologies within the last 5 years, with the exception of in situ carcinoma of the cervix and adequately treated basal cell or Squamous cell carcinoma of the skin.
Any contraindications to MRI scans.
Involvement in the planning or conduct of the study.
Previous enrollment or randomization of treatment in the present study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Sciences & Operations
Organizational Affiliation
Sanofi
Official's Role
Principal Investigator
Facility Information:
Facility Name
Research Site
City
Freiberg
Country
Germany
12. IPD Sharing Statement
Citations:
PubMed Identifier
19946413
Citation
Mross K, Fasol U, Frost A, Benkelmann R, Kuhlmann J, Buchert M, Unger C, Blum H, Hennig J, Milenkova TP, Tessier J, Krebs AD, Ryan AJ, Fischer R. DCE-MRI assessment of the effect of vandetanib on tumor vasculature in patients with advanced colorectal cancer and liver metastases: a randomized phase I study. J Angiogenes Res. 2009 Sep 21;1:5. doi: 10.1186/2040-2384-1-5.
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Phase I Efficacy On Vascular Permeability In Patients With Advanced Colorectal Cancer
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