Efficacy Study Comparing ZD6474 in Combination With Pemetrexed and Pemetrexed Alone in 2nd Line NSCLC Patients - Full Text View

Purpose

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.

Condition	Intervention	Phase
Non Small Cell Lung Cancer Lung Cancer	Drug: Vandetanib Drug: Pemetrexed	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	A Phase III, Randomized, Double-blinded, Parallel Group, Multi-centre Study to Assess the Efficacy and Safety of ZD6474 (ZACTIMA™) in Combination With Pemetrexed (Alimta®) Versus Pemetrexed Alone in Patients With Locally-Advanced or Metastatic NSCLC

Resource links provided by NLM:

MedlinePlus related topics: Cancer Lung Cancer

Drug Information available for: Pemetrexed Pemetrexed disodium Vandetanib

U.S. FDA Resources

Further study details as provided by AstraZeneca:

Primary Outcome Measures:

Progression-Free Survival (PFS) in the Overall Population [ Time Frame: RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomisation until objective progression ] [ Designated as safety issue: No ]
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
Progression-Free Survival (PFS) in the Female Population [ Time Frame: RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomisation until objective progression ] [ Designated as safety issue: No ]
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

Secondary Outcome Measures:

Overall Survival (OS) [ Time Frame: Time to death in months ] [ Designated as safety issue: No ]
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).
Objective Response Rate (ORR) [ Time Frame: 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 ] [ Designated as safety issue: No ]
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.
Disease Control Rate (DCR) [ Time Frame: RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomisation until objective progression ] [ Designated as safety issue: No ]
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
Duration of Response (DoR) [ Time Frame: RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomisation until objective progression ] [ Designated as safety issue: No ]
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)
Time to Deterioration of Disease-related Symptoms (TDS) by Lung Cancer Symptom Scale (LCSS) Total Score [ Time Frame: LCSS questionnaires are to be administered every 3 weeks after randomisation ] [ Designated as safety issue: No ]
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.
Time to Deterioration of Disease-related Symptoms (TDS) by Average Symptom Burden Index (ASBI) Score [ Time Frame: ASBI is a score taken from the LCSS questionnaires which are to be administered every 3 weeks after randomisation ] [ Designated as safety issue: No ]
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
Longitudinal Analysis of Lung Cancer Symptom Scale (LCSS) Total Score [ Time Frame: LCSS questionnaires are to be administered every 3 weeks after randomisation ] [ Designated as safety issue: No ]
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)
Longitudinal Analysis of Average Symptom Burden Index (ASBI) Score [ Time Frame: ASBI is a score taken from the Lung Cancer Symptom Scale (LCSS) questionnaires administered every 3 weeks after randomisation ] [ Designated as safety issue: No ]
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).

Enrollment:	510
Study Start Date:	January 2007
Estimated Study Completion Date:	December 2012
Primary Completion Date:	September 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Placebo Comparator: 1 Placebo Vandetanib + Pemetrexed	Drug: Pemetrexed intravenous infusion Other Names: Pemetrexed disodium Alimta®
Experimental: 2 Vandetanib + Pemetrexed	Drug: Vandetanib oral once daily tablet Other Names: ZACTIMA™ ZD6474 Drug: Pemetrexed intravenous infusion Other Names: Pemetrexed disodium Alimta®

Detailed Description:

This randomized phase III non-small cell lung cancer clinical trial is studying the effect of Alimta (pemetrexed) plus vandetanib to see how well the combination works compared to Alimta (pemetrexed) alone in patients who have previously been treated for non-small cell lung cancer (NSCLC).

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00418886

Show 104 Study Locations

Sponsors and Collaborators

AstraZeneca

Investigators

Study Director:	Peter Langmuir, MD	AstraZeneca
Principal Investigator:	Richard de Boer, MD	Western Hospital Footscray

More Information

No publications provided

Responsible Party:	AstraZeneca
ClinicalTrials.gov Identifier:	NCT00418886 History of Changes
Other Study ID Numbers:	D4200C00036, EUDRACT No. 2006-003695-35
Study First Received:	January 4, 2007
Results First Received:	April 27, 2011
Last Updated:	September 24, 2012
Health Authority:	United States: Food and Drug Administration Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica Australia: Department of Health and Ageing Therapeutic Goods Administration Belgium: Directorate general for the protection of Public health: Medicines France: Ministry of Health Germany: Federal Institute for Drugs and Medical Devices Greece: Ministry of Health and Welfare Hong Kong: Department of Health Israel: Ministry of Health Italy: Ministry of Health Mexico: Ministry of Health Spain: Spanish Agency of Medicines Sweden: Medical Products Agency Taiwan: Department of Health

Keywords provided by AstraZeneca:

NSCLC
Non Small Cell Lung Cancer

Additional relevant MeSH terms:

Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases

Pemetrexed
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Antimetabolites, Antineoplastic
Antimetabolites

ClinicalTrials.gov processed this record on May 23, 2013

Efficacy Study Comparing ZD6474 in Combination With Pemetrexed and Pemetrexed Alone in 2nd Line NSCLC Patients (ZEAL)