| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutation(s) and have never been treated with an EGFR-TKI |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutation(s) and have never been treated with an EGFR-TKI |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 evaluate the safety, tolerability and efficacy of afatinib in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutation(s) and have never been treated with an EGFR-TKI. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients with:
1) locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC)
2) Epidermal Growth Factor Receptor (EGFR) mutation-positive result per the institution’s testing methodology.
3) male or female patients age ≥18 years
4) Adequate organ function, defined as all of the following:
a. Left Ventricular Ejection Fraction (LVEF) >50% or within institution normal values
b. Absolute Neutrophil Count (ANC) > 1500/mm3. (ANC >1000/mm3 may be considered in special circumstances such as benign cyclical neutropenia as judged by the investigator and in discussion with the sponsor).
c. Platelet count >75,000/mm3
d. Serum creatinine 1.5 times of the upper limit of normal
e. Total Bilirubin < 1.5 times upper limit of (institutional) normal (Patients with Gilbert’s syndrome total bilirubin must be <4 times institutional upper limit of normal).
f. Aspartate Amino Transferase (AST) or Alanine Amino Transferase (ALT) < three times the upper limit of (institutional) normal (ULN) (if related to liver metastases < five times ULN).
5) ECOG score between 0 - 2
6) written informed consent by patient or guardian prior to admission into the trial that is consistent with International Conference on Harmonisation (ICH)- Good Clinical Practice (GCP) guidelines and local law.
|
|
| E.4 | Principal exclusion criteria |
Patients who or with:
1) prior treatment with an EGFR tyrosine kinase inhibitor (TKI)
2) anti-cancer treatment within 2 weeks prior to start of trial treatment (continued use of anti-androgens and/or gonadorelin analogues for treatment of prostate cancer permitted)
3) radiotherapy within 14 days prior to drug administration, except as follows:
a. Palliative radiation to organs other than chest may be allowed up to 2 weeks prior to drug administration, and
b. Single dose palliative treatment for symptomatic metastasis outside above allowance to be discussed with sponsor prior to enrolling.
4) major surgery within 4 weeks before starting trial treatment or scheduled for surgery during the projected course of the trial
5) known hypersensitivity to afatinib or any of its excipients (see Section 4.1.1)
6) history or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3 (Refer to Appendix 10.2), unstable angina or poorly controlled arrhythmia as determined by the investigator. Myocardial infarction within 6 months prior to starting trial treatment.
7) are Women of Child-Bearing Potential (WOCBP) and men who are able to father a child, unwilling to use adequate contraception prior to trial entry, for the duration of trial participation and for at least 2 weeks after treatment has ended. Adequate methods of contraception and Women of Child-Bearing Potential described in Section 4.2.3.
8) are WOCBP childbearing potential (see Section 4.2.3) who are nursing or are pregnant or do not agree to submit to pregnancy testing required by this protocol
9) any history of or concomitant condition that, in the opinion of the investigator, would compromise the patient’s ability to comply with the trial or interfere with the evaluation of safety for the trial drug
10) previous or concomitant malignancies at other sites, except effectively treated non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or effectively treated malignancy that has been in remission for more than 3 years and is considered to be cured.
11) requiring treatment with any of the prohibited concomitant medications listed in Section 4.2.2 that can not be stopped for the duration of trial participation
12) known pre-existing interstitial lung disease
13) presence of poorly controlled gastrointestinal disorders that could affect the absorption of the trial drug (e.g. Crohn’s disease, ulcerative colitis, malabsorption, or CTC grade ≥2 diarrhoea of any aetiology) based on investigator assessment.
14) active hepatitis B infection (defined as presence of Hepatitis B (HepB) sAg and/or HepB DNA), active Hepatitis C (HEP C) infection (defined as presence of Hep C RNA) and/or known Human Immunodeficiency Virus (HIV) carrier.
15) meningeal carcinomatosis
16) symptomatic brain metastases (patients with asymptomatic brain metastases, who were previously treated, are eligible provided they have had Stable Disease (SD) for at least 4 weeks on stable doses of medication)
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is the safety assessment. Safety will primarily be assessed by adverse events according to Common Terminology Criteria (CTCAE Version 3) in a descriptive fashion. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Disease Assessment will be based on the assessment of cancer related symptoms and, if available, radiologic assessments as per standard of care at the site.
Data regarding tumour assessments that are performed according to local standard of care for NSCLC may contribute to:
- Time to symptomatic progression (TTSP) is defined as the time from first administration of afatinib to the date of first documented clinically significant symptomatic progression that required change in or stopping anti-cancer treatment according to investigator’s assessment.
Data regarding tumour assessments that are performed according to local standard of care for NSCLC may contribute to Progression-Free Survival (PFS), defined as time from the date of the first administration of afatinib to the date of progression or to the date of death, whichever occurs first.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 107 |
| 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 | No |
| 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 |
| Australia |
| Austria |
| Czech Republic |
| Greece |
| Hungary |
| Israel |
| Italy |
| Poland |
| Russian Federation |
| Spain |
| Switzerland |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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