| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Non-small cell lung cancer | |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | To demonstrate an improvement in overall survival for ZD6474 (ZACTIMA™ ) plus best supportive care (BSC) compared with placebo plus BSC in patients with locally advanced or metastatic NSCLC after prior therapy with an EGFR TKI | |
| E.2.2 | Secondary objectives of the trial | To demonstrate an improvement in progression-free survival (PFS) for ZD6474(ZACTIMA) plus BSC compared with placebo plus BSC
To demonstrate an improvement in the overall objective response rate (ORR) (complete response [CR] + partial response [PR]), disease control rate (DCR) (CR + PR + Stable Disease [SD] ≥ 8 weeks) and duration of response (DOR) for ZD6474 plus BSC compared with placebo plus BSC using Response Evaluation Criteria in Solid Tumours (RECIST)
To study the safety and tolerability of ZD6474 plus BSC compared with placebo plus BSC
To demonstrate beneficial effects in time to deterioration of disease-relatedsymptoms (TDS) assessed by the combined score of LCS, pain and fatigue for ZD6474 plus BSC compared with placebo plus BSC | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1.Provision of informed consent
2.Female or male aged 18 years and over
3.Histologic or cytologic confirmation of locally advanced or metastatic NSCLC (IIIB-IV) on entry into study. (Sputum cytology alone is not acceptable. Cytology specimens obtained by brushing, washing or needle aspiration are acceptable.)
4.Failure of prior therapy (during or after treatment) with an EGFR TKI (either radiological documentation of disease progression or due to toxicity) in patients who have received at least one but no more than two prior chemotherapy regimens.
5.WHO Performance status 0 – 2
6.Measurable disease defined as - 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
7.Negative pregnancy test for women of childbearing potential
8.Life expectancy of 12 weeks or longer
| |
| E.4 | Principal exclusion criteria | 1.Mixed small cell and non–small-cell lung cancer histology
2.Prior treatment with VEGFR TKIs (prior treatment with bevacizumab [Avastin] is permitted)
3.Chemotherapy or other systemic anti-cancer therapy within 4 weeks (3 weeks for EGFR TKIs) before the start of study therapy (6 weeks for nitrosoureas,
mitomycin and suramin).
4.Three or more prior chemotherapy regimens for advanced disease (one additional regimen allowed for neoadjuvant or adjuvant therapy). Note; chemotherapy or other anti-cancer agents are not allowed during treatment with ZD6474 / Placebo.
5.The last radiation therapy within 4 weeks before the start of study therapy, not including local palliative radiation.
6.Major surgery within 4 weeks, or incompletely healed surgical incision before starting study therapy
7.Any unresolved toxicity > CTCAE grade 2 from previous anti-cancer therapy
8.Serum bilirubin >1.5 x ULRR
9.Creatinine Clearance < 30ml/min (calculated by Cockcroft-Gault formula [see appendix G])
10.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
11.Alkaline phosphatase (ALP) >2.5 x ULRR in the absence of liver metastases, or >5 x ULRR in the presence of liver metastases
12.Significant cardiovascular event (e.g. myocardial infarction, superior vena cava [SVC] syndrome), New York Heart Association [NYHA] classification of heart
disease ≥2 [See Appendix H]) within 3 months before starting study therapy, or presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia
13.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.
14.Congenital long QT syndrome or 1st degree relative with unexplained sudden death under 40 years of age
15.QT prolongation with other medication that required discontinuation of that medication
16.Presence of left bundle branch block (LBBB)
17.QTc with Bazett’s correction unmeasurable or ≥480 msec or greater on screening ECG (Note: If a patient has a QTc interval ≥480 msec on screening ECG, the screening ECG may be repeated twice [at least 24 hrs 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 (see Appendix D, Table 2) are excluded if QTc is ≥ 460 msec.
18.Potassium <4.0 mmol/L despite supplementation; serum calcium (or ionized or adjusted for albumin), or magnesium out of normal range despite supplementation
19.Women who are pregnant or breast feeding
20.Any concomitant medications that may cause QTc prolongation or induce Torsades de Pointes (see Appendix D for the lists of medications in Table 1 & Table 2) or induce CYP3A4 function (see Section 3.6.2) within 2 weeks of start of study
therapy. Drugs listed in Appendix D, Table 2, that in the investigator’s opinion cannot be discontinued, are allowed, provided the precautions outlined in section 3.2.2.1 are adhered to.
21.Known or suspected brain metastases or spinal cord compression, unless treated at least 4 weeks before starting study therapy, and stable without steroid
treatment for 10 days
22.Hypertension not controlled by medical therapy (systolic blood pressure > 160 millimetre of mercury [mmHg] or diastolic blood pressure >100 mmHg)
23.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
24.Evidence of severe or uncontrolled systemic disease or any concurrent condition (e.g. drug or alcohol abuse), 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
25.Previous randomisation in the present study
26.Involvement in the planning and conduct of the study (applies to both AstraZeneca staff, PAREXEL and APEX staff or staff at the investigational site)
27.Participation in a clinical study of any investigational agents within 30 days prior to starting study treatment
| |
| E.5 End points |
| E.5.1 | Primary end point(s) | | The primary outcome variable of this study is overall survival (OS) which is defined as the number of days from randomisation to death from any cause. | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 | The trial involves single site in the Member State concerned | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 19 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | | The end of study will be declared once a program has been established that allows all remaining patients still receiving ZD6474 study treatment to receive open-label supplies after the final analysis of the study has occurred. The end of study will be when all patients have finished study therapy and all sites are closed. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
