The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00418886




Registration number
NCT00418886
Ethics application status
Date submitted
4/01/2007
Date registered
5/01/2007
Date last updated
8/03/2017

Titles & IDs
Public title
Efficacy Study Comparing ZD6474 in Combination With Pemetrexed and Pemetrexed Alone in 2nd Line NSCLC Patients
Scientific title
A Phase III, Randomized, Double-blinded, Parallel Group, Multi-centre Study to Assess the Efficacy and Safety of ZD6474 (ZACTIMAâ„¢) in Combination With Pemetrexed (Alimta®) Versus Pemetrexed Alone in Patients With Locally-Advanced or Metastatic NSCLC
Secondary ID [1] 0 0
EUDRACT No. 2006-003695-35
Secondary ID [2] 0 0
D4200C00036
Universal Trial Number (UTN)
Trial acronym
ZEAL
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non Small Cell Lung Cancer 0 0
Lung Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lung - Mesothelioma
Cancer 0 0 0 0
Lung - Non small cell
Cancer 0 0 0 0
Lung - Small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Vandetanib
Treatment: Drugs - Pemetrexed

Placebo Comparator: 1 - Placebo Vandetanib + Pemetrexed

Experimental: 2 - Vandetanib + Pemetrexed


Treatment: Drugs: Vandetanib
oral once daily tablet

Treatment: Drugs: Pemetrexed
intravenous infusion

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Progression-Free Survival (PFS) in the Overall Population - Median time (in weeks) from randomisation until objective disease progression or death (by any cause in the absence of objective progression) provided death is within 3 months from the last evaluable RECIST assessment
Timepoint [1] 0 0
RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomisation until objective progression
Primary outcome [2] 0 0
Progression-Free Survival (PFS) in the Female Population - Median time (in weeks) from randomisation until objective disease progression or death (by any cause in the absence of objective progression) provided death is within 3 months from the last evaluable RECIST assessment
Timepoint [2] 0 0
RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomisation until objective progression
Secondary outcome [1] 0 0
Overall Survival (OS) - Overall survival is defined as the time from date of randomization until death. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive (ie their status must be known at the censored date and should not be lost to follow up or unknown).
Timepoint [1] 0 0
Time to death in months
Secondary outcome [2] 0 0
Objective Response Rate (ORR) - The ORR is the number of patients that are responders ie those patients with a confirmed best objective response of complete response (CR) or partial response (PR) as defined by RECIST criteria.
The categories for best objective response are CR, PR, stable disease (SD)>= 6 weeks, progressive disease (PD) or NE.
Timepoint [2] 0 0
Each patient was assessed for objective response from the sequence of RECIST scan data up to data cut off. RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomisation until objective progression
Secondary outcome [3] 0 0
Disease Control Rate (DCR) - Disease control rate is defined as the number of patients who achieved disease control at 6 weeks following randomisation. Disease control at 6 weeks is defined as a best objective response of complete response (CR), partial response (PR) or stable disease (SD) >= 6 weeks
Timepoint [3] 0 0
RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomisation until objective progression
Secondary outcome [4] 0 0
Duration of Response (DoR) - Response is defined as a confirmed best objective response of CR or PR. Duration of response is defined as time from the date of first documented response until date of documented progression or death in the absence of disease progression (provided death is within 3 months of last RECIST assessment)
Timepoint [4] 0 0
RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomisation until objective progression
Secondary outcome [5] 0 0
Time to Deterioration of Disease-related Symptoms (TDS) by Lung Cancer Symptom Scale (LCSS) Total Score - TDS is the interval from the date of randomization to the first assessment of worsened without an improvement in the next 21 days. A deterioration in symptoms is defined as a single visit assessment of 'worsened' with no visit assessment of 'improved' within the next 21 days. The LCSS scale measures changes in symptoms associated with lung cancer.
Timepoint [5] 0 0
LCSS questionnaires are to be administered every 3 weeks after randomisation
Secondary outcome [6] 0 0
Time to Deterioration of Disease-related Symptoms (TDS) by Average Symptom Burden Index (ASBI) Score - Time to deterioration is defined as the interval from the date of randomization to the first assessment of worsened without an improvement in the next 21 days. A deterioration in symptoms is defined as a single visit assessment of 'worsened' with no visit assessment of 'improved' within the next 21 days. The ASBI is derived from 6 of LCSS's 9 items
Timepoint [6] 0 0
ASBI is a score taken from the LCSS questionnaires which are to be administered every 3 weeks after randomisation
Secondary outcome [7] 0 0
Longitudinal Analysis of Lung Cancer Symptom Scale (LCSS) Total Score - The longitudinal data analysis will include all non-missing visit scores and the model will include only the first 12 weeks of data. LCSS total score is an average of all nine visual analogue patient scales from "none" (0 mm) to "as much as it could be" (100 mm)
Timepoint [7] 0 0
LCSS questionnaires are to be administered every 3 weeks after randomisation
Secondary outcome [8] 0 0
Longitudinal Analysis of Average Symptom Burden Index (ASBI) Score - The longitudinal data analysis will include all non-missing visit scores and the model will include only the first 12 weeks of data. ASBI is an average of the six symptom visual analogue patient scales from "none" (0 mm) to "as much as it could be" (100 mm).
Timepoint [8] 0 0
ASBI is a score taken from the Lung Cancer Symptom Scale (LCSS) questionnaires administered every 3 weeks after randomisation

Eligibility
Key inclusion criteria
- Provision of informed consent

- Female or male aged 18 years or above

- Histologic or cytologic confirmation of locally advanced or metastatic NSCLC (stage
IIIB or IV) on entry into study

- Failure of 1st line anti-cancer therapy (either radiological documentation of disease
progression or due to toxicity) or subsequent relapse of disease following 1st line
therapy

- WHO Performance status 0 - 2

- One or more measurable lesions at least 10 mm in the longest diameter (LD) by spiral
CT scan or 20 mm with conventional techniques according to RECIST criteria. Previously
irradiated lesions will not be considered measurable.

- Life expectancy of 12 weeks or longer

- Negative pregnancy test for women of childbearing potential only
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Mixed small cell and non-small cell lung cancer histology

- Patients have received 2nd-line or subsequent anti-cancer therapy

- Prior treatment with pemetrexed

- Prior treatment with VEGFR TKIs (previous treatment with bevacizumab [Avastin] is
permitted)

- Known or suspected brain metastases or spinal cord compression, unless treated at
least 4 weeks before entry, and stable without steroid treatment for 10 days

- The last radiation therapy within 4 weeks before the start of study therapy, not
including local palliative radiation

- The last dose of prior chemotherapy or other anti-cancer therapy is discontinued less
than 3 weeks before the start of study therapy (6 weeks for nitrosoureas, mitomycin,
and suramin)

- Major surgery within 4 weeks before entry, or incompletely healed surgical incision

- Neutrophils <1.5 x 109/L or platelets <100 x 109/L

- Serum bilirubin >1.5 x the upper limit of reference range (ULRR)

- Creatinine clearance <50 ml/min calculated by either Cockcroft -Gault, 24 hours urine
collection, EDTA scan or other validated methods

- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 x ULRR in the
absence of liver metastases, or > 5 x ULRR in the presence of liver metastases

- Alkaline phosphatase (ALP) >2.5 x ULRR in the absence of liver metastases, or >5 x
ULRR in the presence of liver metastases

- Current active gastrointestinal disease that may affect the ability of the patient to
absorb ZD6474 or tolerate diarrhoea

- Evidence of severe or uncontrolled systemic disease or any concurrent condition which
in the investigator's opinion makes it undesirable for the patient to participate in
the study or which would jeopardize compliance with the protocol

- Any unresolved toxicity greater than CTCAE Grade 2 from previous anti-cancer therapy

- Significant cardiovascular event (e.g., myocardial infarction, superior vena cava
[SVC] syndrome), New York Heart Association [NYHA] classification of heart disease =2
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 (multifocal premature ventricular contractions [PVCs], bigeminy,
trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is
symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained
ventricular tachycardia. Atrial fibrillation, controlled on medication is not excluded

- Congenital long QT syndrome or 1st degree relative with unexplained sudden death under
40 years of age

- QT prolongation with other medications that required discontinuation of that
medication

- Presence of left bundle branch block (LBBB)

- QTc with Bazett's correction unmeasurable or = 480 msec on screening ECG (Note: If a
patient has QTc interval =480 msec on screening ECG, the screen ECG may be repeated
twice [at least 24 hours apart]. The average QTc from the three screening ECGs must be
<480 msec in order for the patient to be eligible for the study) Patients who are
receiving a drug that has a risk of QTc prolongation are eligible if QTc is <460 msec.

- Potassium <4.0 mmol/L despite supplementation; serum calcium (or 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 Torsades de
Pointes or induce CYP3A4 function. Drugs that have a risk of QTc prolongation, that in
the investigator's opinion cannot be discontinued, are allowed, but only of the QTc is
<460 msec

- Hypertension not controlled by medical therapy (systolic blood pressure greater than
160 millimetre of mercury [mmHg] or diastolic blood pressure greater than 100 mmHg)

- 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

- Treatment with a non-approved or investigational drug within 30 days before Day 1 of
study treatment

- Concomitant use of yellow fever vaccine or any live attenuated vaccines

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Research Site - Chermside
Recruitment hospital [2] 0 0
Research Site - Fitzroy
Recruitment hospital [3] 0 0
Research Site - Footscray
Recruitment hospital [4] 0 0
Research Site - Heidelberg
Recruitment hospital [5] 0 0
Research Site - Randwick
Recruitment hospital [6] 0 0
Research Site - St. Leonards
Recruitment hospital [7] 0 0
Research Site - Wodonga
Recruitment postcode(s) [1] 0 0
- Chermside
Recruitment postcode(s) [2] 0 0
- Fitzroy
Recruitment postcode(s) [3] 0 0
- Footscray
Recruitment postcode(s) [4] 0 0
- Heidelberg
Recruitment postcode(s) [5] 0 0
- Randwick
Recruitment postcode(s) [6] 0 0
- St. Leonards
Recruitment postcode(s) [7] 0 0
- Wodonga
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
Connecticut
Country [3] 0 0
United States of America
State/province [3] 0 0
District of Columbia
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Georgia
Country [6] 0 0
United States of America
State/province [6] 0 0
Illinois
Country [7] 0 0
United States of America
State/province [7] 0 0
Iowa
Country [8] 0 0
United States of America
State/province [8] 0 0
Kentucky
Country [9] 0 0
United States of America
State/province [9] 0 0
Maine
Country [10] 0 0
United States of America
State/province [10] 0 0
Maryland
Country [11] 0 0
United States of America
State/province [11] 0 0
Massachusetts
Country [12] 0 0
United States of America
State/province [12] 0 0
Missouri
Country [13] 0 0
United States of America
State/province [13] 0 0
New York
Country [14] 0 0
United States of America
State/province [14] 0 0
North Carolina
Country [15] 0 0
United States of America
State/province [15] 0 0
Ohio
Country [16] 0 0
United States of America
State/province [16] 0 0
South Carolina
Country [17] 0 0
United States of America
State/province [17] 0 0
Texas
Country [18] 0 0
United States of America
State/province [18] 0 0
Utah
Country [19] 0 0
Argentina
State/province [19] 0 0
Avellaneda
Country [20] 0 0
Argentina
State/province [20] 0 0
Buenos Aires
Country [21] 0 0
Argentina
State/province [21] 0 0
Ciudad de Buenos Aires
Country [22] 0 0
Argentina
State/province [22] 0 0
Córdoba
Country [23] 0 0
Argentina
State/province [23] 0 0
La Plata
Country [24] 0 0
Argentina
State/province [24] 0 0
Ramos Mejía
Country [25] 0 0
Argentina
State/province [25] 0 0
Salta
Country [26] 0 0
Argentina
State/province [26] 0 0
Santa Fe
Country [27] 0 0
Belgium
State/province [27] 0 0
Brussels (Woluwé-St-Lambert)
Country [28] 0 0
Belgium
State/province [28] 0 0
Leuven
Country [29] 0 0
Belgium
State/province [29] 0 0
Liège
Country [30] 0 0
Colombia
State/province [30] 0 0
Bogota
Country [31] 0 0
Colombia
State/province [31] 0 0
Medellín
Country [32] 0 0
Colombia
State/province [32] 0 0
Pereira
Country [33] 0 0
Colombia
State/province [33] 0 0
Valledupar
Country [34] 0 0
France
State/province [34] 0 0
Avignon Cedex 09
Country [35] 0 0
France
State/province [35] 0 0
Lyon Cedex 04
Country [36] 0 0
France
State/province [36] 0 0
Paris Cedex 15
Country [37] 0 0
France
State/province [37] 0 0
Pontoise Cedex
Country [38] 0 0
France
State/province [38] 0 0
Strasbourg Cedex
Country [39] 0 0
Germany
State/province [39] 0 0
Hannover
Country [40] 0 0
Germany
State/province [40] 0 0
Karlsruhe
Country [41] 0 0
Germany
State/province [41] 0 0
Kassel
Country [42] 0 0
Germany
State/province [42] 0 0
Köln
Country [43] 0 0
Germany
State/province [43] 0 0
Leipzig
Country [44] 0 0
Greece
State/province [44] 0 0
N. Faliro
Country [45] 0 0
Greece
State/province [45] 0 0
Patras
Country [46] 0 0
Greece
State/province [46] 0 0
Thessaloniki
Country [47] 0 0
Hong Kong
State/province [47] 0 0
Hong Kong
Country [48] 0 0
India
State/province [48] 0 0
Ahmedabad
Country [49] 0 0
India
State/province [49] 0 0
Vellore
Country [50] 0 0
Israel
State/province [50] 0 0
Beer-Sheeva
Country [51] 0 0
Israel
State/province [51] 0 0
Haifa
Country [52] 0 0
Israel
State/province [52] 0 0
Jerusalem
Country [53] 0 0
Israel
State/province [53] 0 0
Kfar Saba
Country [54] 0 0
Israel
State/province [54] 0 0
Petach-Tikva
Country [55] 0 0
Israel
State/province [55] 0 0
Safed
Country [56] 0 0
Israel
State/province [56] 0 0
Tel-Hashomer
Country [57] 0 0
Israel
State/province [57] 0 0
Zerifin
Country [58] 0 0
Italy
State/province [58] 0 0
Genova
Country [59] 0 0
Italy
State/province [59] 0 0
Milano
Country [60] 0 0
Italy
State/province [60] 0 0
Orbassano
Country [61] 0 0
Italy
State/province [61] 0 0
Roma
Country [62] 0 0
Italy
State/province [62] 0 0
S.Andrea delle Fratte
Country [63] 0 0
Mexico
State/province [63] 0 0
Aguascalientes
Country [64] 0 0
Mexico
State/province [64] 0 0
Mexico
Country [65] 0 0
Mexico
State/province [65] 0 0
Puebla
Country [66] 0 0
Philippines
State/province [66] 0 0
Cebu City
Country [67] 0 0
Philippines
State/province [67] 0 0
Manila
Country [68] 0 0
Philippines
State/province [68] 0 0
Pasay City
Country [69] 0 0
Philippines
State/province [69] 0 0
Quezon City
Country [70] 0 0
Portugal
State/province [70] 0 0
Lisboa
Country [71] 0 0
Portugal
State/province [71] 0 0
Santa Maria da Feira
Country [72] 0 0
Portugal
State/province [72] 0 0
Setúbal
Country [73] 0 0
South Africa
State/province [73] 0 0
Cape Town
Country [74] 0 0
South Africa
State/province [74] 0 0
Durban
Country [75] 0 0
South Africa
State/province [75] 0 0
Johannesburg
Country [76] 0 0
South Africa
State/province [76] 0 0
Port Elizabeth
Country [77] 0 0
South Africa
State/province [77] 0 0
Pretoria
Country [78] 0 0
Spain
State/province [78] 0 0
A Coruña
Country [79] 0 0
Spain
State/province [79] 0 0
Lugo
Country [80] 0 0
Spain
State/province [80] 0 0
Majadahonda
Country [81] 0 0
Spain
State/province [81] 0 0
Mataró(Barcelona)
Country [82] 0 0
Spain
State/province [82] 0 0
Málaga
Country [83] 0 0
Spain
State/province [83] 0 0
Orense
Country [84] 0 0
Spain
State/province [84] 0 0
Santiago de Compostela(A Coru
Country [85] 0 0
Spain
State/province [85] 0 0
Vigo(Pontevedra)
Country [86] 0 0
Sweden
State/province [86] 0 0
Lund
Country [87] 0 0
Sweden
State/province [87] 0 0
Sundsvall
Country [88] 0 0
Sweden
State/province [88] 0 0
Umeå
Country [89] 0 0
Sweden
State/province [89] 0 0
Uppsala
Country [90] 0 0
Sweden
State/province [90] 0 0
Västerås
Country [91] 0 0
Taiwan
State/province [91] 0 0
Taipei
Country [92] 0 0
United Kingdom
State/province [92] 0 0
Birmingham
Country [93] 0 0
United Kingdom
State/province [93] 0 0
Edinburgh
Country [94] 0 0
United Kingdom
State/province [94] 0 0
Leeds
Country [95] 0 0
United Kingdom
State/province [95] 0 0
Manchester
Country [96] 0 0
United Kingdom
State/province [96] 0 0
Wolverhampton
Country [97] 0 0
Venezuela
State/province [97] 0 0
Caracas
Country [98] 0 0
Venezuela
State/province [98] 0 0
Valencia

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Genzyme, a Sanofi Company
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Non-small cell lung cancer (NSCLC) can be treated with drugs that kill tumour cells, stop
them from dividing, or stop the growth of the blood supply that cancers need to grow and
spread. Clinical research has shown that drugs that inhibit vascular endothelial growth
factor receptor (VEGFR) or epidermal growth factor receptor (EGFR) signalling can increase
overall survival in patients with advanced non-small cell lung cancer (NSCLC). Preclinical
studies have shown that vandetanib (ZD6474) is an inhibitor of both VEGFR and EGFR
signalling. Giving vandetanib may therefore inhibit the growth of cancer cells by blocking
their blood supply and by stopping them from dividing. This lung cancer study is to
investigate if adding vandetanib to Alimta (pemetrexed) is more effective than Alimta
(pemetrexed) alone.
Trial website
https://clinicaltrials.gov/show/NCT00418886
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Sciences & Operations
Address 0 0
Sanofi
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications