| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-small cell lung cancer |
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| 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 |
| The primary objective of this study is to demonstrate an improvement in Progression Free Survival (PFS) for ZD6474 (ZACTIMA™ ) Versus Erlotinib (Tarceva®) in patients with locally advanced or metastatic NSCLC after failure of at least one but no more than two, prior cytotoxic chemotherapy regimens. |
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| E.2.2 | Secondary objectives of the trial |
1. To demonstrate an improvement in overall survival (OS) for ZD6474 compared with Erlotinib
2. To demonstrate an improvement in the objective response rate (ORR), disease control rate (DCR), and duration of response (DOR) for ZD6474 compared with Erlotinib
3. To demonstrate an improvement in the time-to-deterioration of pain, dyspnoea, cough in patients treated with ZD6474, compared with Erlotinib, based on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) plus lung cancer module (QLQ-LC13)
4. To study the safety and tolerability of ZD6474 compared with Erlotinib
5. To investigate the population pharmacokinetics (PK) of ZD6474 and assess the relationship between PK and QTc, measures of safety and efficacy and pharmacodynamic (PD) biomarkers.
6. To investigate plasma levels of the N-desmethyl and N-oxide metabolites of ZD6474 in this patient population
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| 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). Sputum cytology alone is not acceptable. Cytology specimens obtained by brushing, washing, or needle aspiration are acceptable.
4. Failure of at least one, but no more than two, prior cytotoxic chemotherapy regimens (either radiological documentation of disease progression or due to toxicity).
5. WHO Performance status 0 – 2
6. 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
7. Negative pregnancy test for women of childbearing potential
8. Life expectancy of 12 weeks or longer.
9. Able to read and write
For inclusion in the genetic research part of the study, patients must fulfil the following criterion:
10. Provision of informed consent for genetic research and tissue sampling
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|
| E.4 | Principal exclusion criteria |
1. Mixed small cell and non small-cell lung cancer histology
2. Prior treatment with EGFR TKIs or VEGFR TKIs (prior treatment with cetuximab [Erbitux] or bevacizumab [Avastin] is permitted)
3. Chemotherapy or other systemic anti-cancer therapy within 4 weeks before the start of study therapy (6 weeks for nitrosoureas, mitomycin and suramin)
4. Radiation therapy within 4 weeks before the start of study therapy, not including local palliative radiation. Lesions that have received radiation in the advanced setting cannot be included as target lesions unless clear tumour progression has been documented in the lesions since the end of radiation therapy
5. Major surgery within 4 weeks, or incompletely healed surgical incision before starting study therapy
6. Any unresolved toxicity > CTCAE grade 2 from previous anti-cancer therapy
7. Serum bilirubin greater than 1.5x upper limit of reference range (ULRR)
8. Serum creatinine greater than 1.5 x ULRR or creatinine clearance ≤30 ml/min (calculated by Cockcroft-Gault formula) See Appendix G.
9. ALT or AST > 2.5 x ULRR if no demonstrable liver metastases, or > 5 x ULRR if judged by the Investigator to be related to liver metastases
10. Alkaline phosphatase (ALP) > 2.5 x ULRR if no demonstrable liver metastases, or > 5 x ULRR if judged by the Investigator to be related to liver metastases
11. Significant cardiovascular event (e.g. myocardial infarction, superior vena cava [SVC] syndrome, New York Heart Association [NYHA] classification of heart disease (see appendix I of protocol) ≥2 within 3 months before entry, or presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia
12. 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 4) or asymptomatic sustained ventricular tachycardia. Atrial fibrillation, controlled on medication, is not excluded.
13. Congenital long QT syndrome or 1st degree relative with unexplained sudden death under 40 years of age
14. QT prolongation with other medications that required discontinuation of that medication
15. Presence of left bundle branch block (LBBB)
16. QTc with Bazett’s correction unmeasurable or ≥ 480 msec or greater on screening ECG. (Note: If a patient has QTc ≥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 QT prolongation (see Appendix D, Table 2) are excluded if QTc is ≥ 460 msec.
17. Potassium <4.0 mmol/L despite supplementation; serum calcium (or ionized or adjusted for albumin), or magnesium out of normal range despite supplementation
18. Women who are pregnant or breast feeding
19. Concomitant medications that may cause QTc prolongation or induce Torsades de Pointes (see appendix D). Drugs listed in Appendix D, Table 2, that in the Investigator's opinion cannot be discontinued, are allowed.
20. Concomitant medications that are potent inhibitors (ketoconazole, itraconazole, atanazavir, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO) and voriconazole) or inducers (rifampicin, rifabutin, phenytoin, carbamazepine, phenobarbital and St. John's Wort) of CYP3A4 function
21. Brain metastases or spinal cord compression, unless treated at least 4 weeks before entry, and stable without steroid treatment for 10 days
22. Hypertension not controlled by medical therapy (systolic blood pressure greater than 160 millimeter of mercury [mmHg] or diastolic blood pressure greater than 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 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. Any significant ophthalmologic abnormality, especially severe dry eye syndrome, keratoconjunctivitis sicca, Sjögren syndrome, severe exposure keratopathy or any other disorder likely to increase the risk of corneal epithelial lesion such as bullous keratopathy, aniridia, severe chemical burns or neutrophilic keratitis
26. Previous randomisation of treatment in the present study or other ZD6474 studies
27. Involvement in the planning and conduct of the study (applies to both AstraZeneca staff or staff at the investigational site)
28. Receipt of any investigational agents within 30 days prior to starting study treatment
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival |
|
| 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 | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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.8.5 | 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 |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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 for remaining patients still receiving ZD6474 study treatment after the final analysis of this trial has occurred. |
|
| 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 | 2 |
| 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 | 2 |
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