Clinical trial NCT00418886: Efficacy Study Comparing ZD6474 in Combination With Pemetrexed and Pemetrexed Alone in 2nd Line NSCLC Patients
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Non Small Cell Lung Cancer
Lung Cancer
Keywords: NSCLC
Non Small Cell Lung Cancer
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2007-01-05
Enrollment: 698
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 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

Primary outcomes:
measure: Progression-Free Survival (PFS) in the Overall Population
timeFrame: RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression
measure: Progression-Free Survival in the Female Population
timeFrame: RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Time to death in months
measure: Objective Response Rate (ORR)
timeFrame: Each participant 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 randomization until objective progression
measure: Disease Control Rate (DCR)
timeFrame: RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression
measure: Duration of Response (DoR)
timeFrame: RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression
measure: Time to Deterioration of Disease-Related Symptoms (TDS) by Lung Cancer Symptom Scale (LCSS) Total Score
timeFrame: LCSS questionnaires are to be administered every 3 weeks after randomization
measure: Time to Deterioration of Disease-Related Symptoms by Average Symptom Burden Index (ASBI) Score
timeFrame: ASBI is a score taken from the LCSS questionnaires which are to be administered every 3 weeks after randomization
measure: Longitudinal Analysis of Lung Cancer Symptom Scale Total Score
timeFrame: LCSS questionnaires are to be administered every 3 weeks after randomization
measure: Longitudinal Analysis of Average Symptom Burden Index Score
timeFrame: ASBI is a score taken from the LCSS questionnaires administered every 3 weeks after randomization
Other outcomes:
Locations:
city: Casa Grande
country: United States
facility: Research Site
state: Arizona
city: Chandler
country: United States
facility: Research Site
state: Arizona
city: Farmington
country: United States
facility: Research Site
state: Connecticut
city: Stamford
country: United States
facility: Research Site
state: Connecticut
city: Washington
country: United States
facility: Research Site
state: District of Columbia
city: Orlando
country: United States
facility: Research Site
state: Florida
city: Gainesville
country: United States
facility: Research Site
state: Georgia
city: Skokie
country: United States
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state: Illinois
city: Sioux City
country: United States
facility: Research Site
state: Iowa
city: Mount Sterling
country: United States
facility: Research Site
state: Kentucky
city: Portland
country: United States
facility: Research Site
state: Maine
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Rockville
country: United States
facility: Research Site
state: Maryland
city: Boston
country: United States
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state: Massachusetts
city: Saint Louis
country: United States
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state: Missouri
city: Mineola
country: United States
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state: New York
city: Rochester
country: United States
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state: New York
city: Winston-Salem
country: United States
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state: North Carolina
city: Cincinnati
country: United States
facility: Research Site
state: Ohio
city: Middletown
country: United States
facility: Research Site
state: Ohio
city: Hilton Head Island
country: United States
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state: South Carolina
city: Austin
country: United States
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state: Texas
city: Salt Lake City
country: United States
facility: Research Site
state: Utah
city: Avellaneda
country: Argentina
facility: Research Site
city: Buenos Aires
country: Argentina
facility: Research Site
city: Ciudad de Buenos Aires
country: Argentina
facility: Research Site
city: Córdoba
country: Argentina
facility: Research Site
city: La Plata
country: Argentina
facility: Research Site
city: Ramos Mejía
country: Argentina
facility: Research Site
city: Salta
country: Argentina
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city: Santa Fe
country: Argentina
facility: Research Site
city: Chermside
country: Australia
facility: Research Site
city: Fitzroy
country: Australia
facility: Research Site
city: Footscray
country: Australia
facility: Research Site
city: Heidelberg
country: Australia
facility: Research Site
city: Randwick
country: Australia
facility: Research Site
city: St. Leonards
country: Australia
facility: Research Site
city: Wodonga
country: Australia
facility: Research Site
city: Brussels (Woluwé-St-Lambert)
country: Belgium
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Liège
country: Belgium
facility: Research Site
city: Bogota
country: Colombia
facility: Research Site
city: Medellín
country: Colombia
facility: Research Site
city: Pereira
country: Colombia
facility: Research Site
city: Valledupar
country: Colombia
facility: Research Site
city: Avignon Cedex 09
country: France
facility: Research Site
city: Lyon Cedex 04
country: France
facility: Research Site
city: Paris Cedex 15
country: France
facility: Research Site
city: Pontoise Cedex
country: France
facility: Research Site
city: Strasbourg Cedex
country: France
facility: Research Site
city: Hannover
country: Germany
facility: Research Site
city: Karlsruhe
country: Germany
facility: Research Site
city: Kassel
country: Germany
facility: Research Site
city: Köln
country: Germany
facility: Research Site
city: Leipzig
country: Germany
facility: Research Site
city: N. Faliro
country: Greece
facility: Research Site
city: Patras
country: Greece
facility: Research Site
city: Thessaloniki
country: Greece
facility: Research Site
city: Hong Kong
country: Hong Kong
facility: Research Site
city: Ahmedabad
country: India
facility: Research Site
city: Vellore
country: India
facility: Research Site
city: Beer-Sheeva
country: Israel
facility: Research Site
city: Haifa
country: Israel
facility: Research Site
city: Jerusalem
country: Israel
facility: Research Site
city: Kfar Saba
country: Israel
facility: Research Site
city: Petach-Tikva
country: Israel
facility: Research Site
city: Safed
country: Israel
facility: Research Site
city: Tel-Hashomer
country: Israel
facility: Research Site
city: Zerifin
country: Israel
facility: Research Site
city: Genova
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Orbassano
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: S.Andrea Delle Fratte
country: Italy
facility: Research Site
city: Aguascalientes
country: Mexico
facility: Research Site
city: Mexico
country: Mexico
facility: Research Site
city: Puebla
country: Mexico
facility: Research Site
city: Cebu City
country: Philippines
facility: Research Site
city: Manila
country: Philippines
facility: Research Site
city: Pasay City
country: Philippines
facility: Research Site
city: Quezon City
country: Philippines
facility: Research Site
city: Lisboa
country: Portugal
facility: Research Site
city: Santa Maria da Feira
country: Portugal
facility: Research Site
city: Setúbal
country: Portugal
facility: Research Site
city: Cape Town
country: South Africa
facility: Research Site
city: Durban
country: South Africa
facility: Research Site
city: Johannesburg
country: South Africa
facility: Research Site
city: Port Elizabeth
country: South Africa
facility: Research Site
city: Pretoria
country: South Africa
facility: Research Site
city: A Coruña
country: Spain
facility: Research Site
city: Lugo
country: Spain
facility: Research Site
city: Majadahonda
country: Spain
facility: Research Site
city: Mataró(Barcelona)
country: Spain
facility: Research Site
city: Málaga
country: Spain
facility: Research Site
city: Orense
country: Spain
facility: Research Site
city: Santiago De Compostela(A Coru
country: Spain
facility: Research Site
city: Vigo(Pontevedra)
country: Spain
facility: Research Site
city: Lund
country: Sweden
facility: Research Site
city: Sundsvall
country: Sweden
facility: Research Site
city: Umeå
country: Sweden
facility: Research Site
city: Uppsala
country: Sweden
facility: Research Site
city: Västerås
country: Sweden
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Birmingham
country: United Kingdom
facility: Research Site
city: Edinburgh
country: United Kingdom
facility: Research Site
city: Leeds
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Wolverhampton
country: United Kingdom
facility: Research Site
city: Caracas
country: Venezuela
facility: Research Site
city: Valencia
country: Venezuela
facility: Research Site
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: 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: a randomized, double-blind phase III trial. J Clin Oncol. 2011 Mar 10;29(8):1067-74. doi: 10.1200/JCO.2010.29.5717. Epub 2011 Jan 31.
citation: Platt A, Morten J, Ji Q, Elvin P, Womack C, Su X, Donald E, Gray N, Read J, Bigley G, Blockley L, Cresswell C, Dale A, Davies A, Zhang T, Fan S, Fu H, Gladwin A, Harrod G, Stevens J, Williams V, Ye Q, Zheng L, de Boer R, Herbst RS, Lee JS, Vasselli J. A retrospective analysis of RET translocation, gene copy number gain and expression in NSCLC patients treated with vandetanib in four randomized Phase III studies. BMC Cancer. 2015 Mar 23;15:171. doi: 10.1186/s12885-015-1146-8.