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

Lung Cancer Clinical Trial

— ZEAL  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00418886
• Other study ID #: D4200C00036
• Secondary ID: EUDRACT No. 2006
• Status: Completed
• Phase: Phase 3
• Start date: January 2007
• Est. completion date: February 14, 2023

Study information

• Verified date: September 2023
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 698
• Est. completion date: February 14, 2023
• Est. primary completion date: September 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Cancer
• Lung Neoplasms
• Non Small Cell Lung Cancer

Intervention

Drug:
• Vandetanib
oral once daily tablet
• Pemetrexed
intravenous infusion

Locations

Country	Name	City	State
Argentina	Research Site	Avellaneda
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Ciudad de Buenos Aires
Argentina	Research Site	Córdoba
Argentina	Research Site	La Plata
Argentina	Research Site	Ramos Mejía
Argentina	Research Site	Salta
Argentina	Research Site	Santa Fe
Australia	Research Site	Chermside
Australia	Research Site	Fitzroy
Australia	Research Site	Footscray
Australia	Research Site	Heidelberg
Australia	Research Site	Randwick
Australia	Research Site	St. Leonards
Australia	Research Site	Wodonga
Belgium	Research Site	Brussels (Woluwé-St-Lambert)
Belgium	Research Site	Leuven
Belgium	Research Site	Liège
Colombia	Research Site	Bogota
Colombia	Research Site	Medellín
Colombia	Research Site	Pereira
Colombia	Research Site	Valledupar
France	Research Site	Avignon Cedex 09
France	Research Site	Lyon Cedex 04
France	Research Site	Paris Cedex 15
France	Research Site	Pontoise Cedex
France	Research Site	Strasbourg Cedex
Germany	Research Site	Hannover
Germany	Research Site	Karlsruhe
Germany	Research Site	Kassel
Germany	Research Site	Köln
Germany	Research Site	Leipzig
Greece	Research Site	N. Faliro
Greece	Research Site	Patras
Greece	Research Site	Thessaloniki
Hong Kong	Research Site	Hong Kong
India	Research Site	Ahmedabad
India	Research Site	Vellore
Israel	Research Site	Beer-Sheeva
Israel	Research Site	Haifa
Israel	Research Site	Jerusalem
Israel	Research Site	Kfar Saba
Israel	Research Site	Petach-Tikva
Israel	Research Site	Safed
Israel	Research Site	Tel-Hashomer
Israel	Research Site	Zerifin
Italy	Research Site	Genova
Italy	Research Site	Milano
Italy	Research Site	Orbassano
Italy	Research Site	Roma
Italy	Research Site	S.Andrea Delle Fratte
Mexico	Research Site	Aguascalientes
Mexico	Research Site	Mexico
Mexico	Research Site	Puebla
Philippines	Research Site	Cebu City
Philippines	Research Site	Manila
Philippines	Research Site	Pasay City
Philippines	Research Site	Quezon City
Portugal	Research Site	Lisboa
Portugal	Research Site	Santa Maria da Feira
Portugal	Research Site	Setúbal
South Africa	Research Site	Cape Town
South Africa	Research Site	Durban
South Africa	Research Site	Johannesburg
South Africa	Research Site	Port Elizabeth
South Africa	Research Site	Pretoria
Spain	Research Site	A Coruña
Spain	Research Site	Lugo
Spain	Research Site	Majadahonda
Spain	Research Site	Málaga
Spain	Research Site	Mataró(Barcelona)
Spain	Research Site	Orense
Spain	Research Site	Santiago De Compostela(A Coru
Spain	Research Site	Vigo(Pontevedra)
Sweden	Research Site	Lund
Sweden	Research Site	Sundsvall
Sweden	Research Site	Umeå
Sweden	Research Site	Uppsala
Sweden	Research Site	Västerås
Taiwan	Research Site	Taipei
United Kingdom	Research Site	Birmingham
United Kingdom	Research Site	Edinburgh
United Kingdom	Research Site	Leeds
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Wolverhampton
United States	Research Site	Austin	Texas
United States	Research Site	Baltimore	Maryland
United States	Research Site	Boston	Massachusetts
United States	Research Site	Casa Grande	Arizona
United States	Research Site	Chandler	Arizona
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Farmington	Connecticut
United States	Research Site	Gainesville	Georgia
United States	Research Site	Hilton Head Island	South Carolina
United States	Research Site	Middletown	Ohio
United States	Research Site	Mineola	New York
United States	Research Site	Mount Sterling	Kentucky
United States	Research Site	Orlando	Florida
United States	Research Site	Portland	Maine
United States	Research Site	Rochester	New York
United States	Research Site	Rockville	Maryland
United States	Research Site	Saint Louis	Missouri
United States	Research Site	Salt Lake City	Utah
United States	Research Site	Sioux City	Iowa
United States	Research Site	Skokie	Illinois
United States	Research Site	Stamford	Connecticut
United States	Research Site	Washington	District of Columbia
United States	Research Site	Winston-Salem	North Carolina
Venezuela	Research Site	Caracas
Venezuela	Research Site	Valencia

Sponsors (1)

Lead Sponsor	Collaborator
Genzyme, a Sanofi Company

Countries where clinical trial is conducted

United States,  Venezuela,  Argentina,  Australia,  Belgium,  Colombia,  France,  Germany,  Greece,  Hong Kong,  India,  Israel,  Italy,  Mexico,  Philippines,  Portugal,  South Africa,  Spain,  Sweden,  Taiwan,  United Kingdom, 

References & Publications (1)

de Boer RH, Arrieta O, Yang CH, Gottfried M, Chan V, Raats J, de Marinis F, Abratt RP, Wolf J, Blackhall FH, Langmuir P, Milenkova T, Read J, Vansteenkiste JF. Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomisation until objective progression
Primary	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	RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomisation until objective progression
Secondary	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).	Time to death in months
Secondary	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.	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	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	RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomisation until objective progression
Secondary	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)	RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomisation until objective progression
Secondary	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.	LCSS questionnaires are to be administered every 3 weeks after randomisation
Secondary	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	ASBI is a score taken from the LCSS questionnaires which are to be administered every 3 weeks after randomisation
Secondary	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)	LCSS questionnaires are to be administered every 3 weeks after randomisation
Secondary	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).	ASBI is a score taken from the Lung Cancer Symptom Scale (LCSS) questionnaires administered every 3 weeks after randomisation

External Links

•   CSR-D4200C00036.pdf
•   Related Info
•   Vandetanib_study_36_ZEAL_CSP_redacted_SECURE