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

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

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.

Study Overview

• Status: Completed
• Conditions: Lung Cancer; Non Small Cell Lung Cancer
• Intervention / Treatment: Drug: Pemetrexed; Drug: Vandetanib

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).

• Study Type: Interventional
• Enrollment (Actual): 698
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 1; Placebo Vandetanib + Pemetrexed	Drug: Pemetrexed; intravenous infusion; Other Names: Alimta®; Pemetrexed disodium
Experimental: 2; Vandetanib + Pemetrexed	Drug: Pemetrexed; intravenous infusion; Other Names: Alimta®; Pemetrexed disodium; Drug: Vandetanib; oral once daily tablet; Other Names: ZD6474; ZACTIMA™; SAR390530

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Genzyme, a Sanofi Company
• Investigators: Study Director: Clinical Sciences & Operations, Sanofi

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• Related Info
• CSR-D4200C00036.pdf
• Vandetanib_study_36_ZEAL_CSP_redacted_SECURE

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2007
• Primary Completion (Actual): September 1, 2008
• Study Completion (Actual): February 14, 2023

Study Registration Dates

• First Submitted: January 4, 2007
• First Submitted That Met QC Criteria: January 4, 2007
• First Posted (Estimated): January 5, 2007

Study Record Updates

• Last Update Posted (Actual): September 28, 2023
• Last Update Submitted That Met QC Criteria: September 19, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: NSCLC; Non Small Cell Lung Cancer
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Folic Acid Antagonists; Pemetrexed
• Other Study ID Numbers: D4200C00036; EUDRACT No. 2006-003695-35; LPS15296 (Other Identifier: Sanofi)