| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with stage IIIB or IV metastatic non-small-cell lung cancer with somatic EGFR mutation |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with metastatic non-small-cell lung cancer |
|
| 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 | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029521 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIB |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| 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 compare the efficacy of afatinib maintenance with pemetrexed maintenance following induction therapy with platinum/ pemetrexed in patients with metastatic EGFR mutated non-small-cell lung cancer progressing after treatment with afatinib as first tyrosine kinase inhibitor with respect to progression-free survival |
|
| E.2.2 | Secondary objectives of the trial |
To compare afatinib maintenance with pemetrexed maintenance after induction therapy with platinum/pemetrexed with respect to
• Overall survival
• Objective response rate, Clinical benefit rate (RECIST1.1)
• Safety / toxicity
• Quality of Life
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically or cytologically confirmed diagnosis of non-small-cell lung cancer (NSCLC) with no curative therapeutic option. Patients with Stage IV (UICC 7th edition) disease or Stage IIIB disease not amenable to curative intent surgery or radiotherapy are enrolled. Patients with mixed histology are eligible if NSCLC is the predominant histology
2. Documented somatic EGFR mutation as determined by medically accepted assay technology
3. Patients with documented progression after response (CR/PR) or stable disease (SD) for at least 6 months of treatment with afatinib as first tyrosine kinase inhibitor (either given as first-line therapy or being switched to afatinib after up to 4 courses of platinum-based chemotherapy)
4. Patients who have completed 3 or 4 cycles of cisplatin or carboplatin plus pemetrexed induction chemotherapy prior to randomization leading to documented response (CR/PR) or SD according to RECIST 1.1
5. At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
6. Male or female patient with age ≥18 years
7. ECOG performance status ≤ 2
8. Adequate organ and bone marrow function, defined as all of the following:
Before the last cycle of induction chemotherapy or after hematopoietic recovery from the last cycle of induction chemotherapy:
+ Absolute neutrophil count (ANC) ≥ 1,500 / mm3
+ Platelet count ≥ 100,000 / mm3
+ Creatinine clearance ≥ 45 ml / min (calculated according to Cockroft and Gault, or Tc99m-DPTA clearance or similar methodology). Patients
with creatinine clearance of 45 to 79 ml/min should refrain from using NSAID at least 2 days before and 2 days after infusion of pemetrexed.
Long-acting NSAID should be terminated 5 days before pemetrexed infusion.
+ Total serum bilirubin ≤ 1.5 times upper limit of institutional normal (ULN)
+ Serum aspartate amino transferase (AST) and serum alanine amino transferase (ALT) ≤ 3 times the upper limit of institutional normal (ULN)
( ≤ 5 times ULN if liver function abnormalities are due to underlying malignancy)
9. Recovered from any previous therapy related toxicity to ≤ Grade 1 at study entry (except for stable sensory neuropathy ≤ Grade 2 and alopecia)
10. Written informed consent
11. Ability to comply with the protocol for the duration of the study, including hospital/office visits for treatment and scheduled follow-up visits and examinations
|
|
| E.4 | Principal exclusion criteria |
1. Systemic therapy for metastatic disease or relapse other than (a) first-line treatment with afatinib or (b) afatinib given as first EGFR-targeting agent following up to 4 courses of platinum-based chemotherapy with no disease progression between first-line chemotherapy and initiation of afatinib (prior adjuvant chemotherapy is allowed) and 3 to 4 cycles of induction chemotherapy with cisplatin or carboplatin and pemetrexed following afatinib failure
2. Prior treatment with erlotinib, gefitinib or other investigational or approved EGFR-targeting small molecules or antibodies
3. Known EGFR T790M mutation (analysis not mandatory)
4. Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study
5. Extended radiotherapy within 4 weeks prior to randomization, except as follows:
a. Palliative, limited local radiation to non-target lesions (e.g. isolated bone metastases) may be allowed up to 2 weeks prior to randomization, and
b. single dose palliative treatment for symptomatic metastasis outside above allowance to be discussed with sponsor prior to enrolling
6. Active brain metastases except for the followings:
Asymptomatic brain metastases incidentally found during screening process which do not require local treatment in the opinion of the
investigator.
Asymptomatic brain metastases for which local treatment has been given: stable for at least 4 weeks of lower dose corticosteroids (e.g.,
dexamethasone up to 4 mg/d) and/or non-enzyme-inducing anti-convulsants treatment before study randomization.
Brain metastases controlled after surgery and/or radiotherapy
7. Meningeal carcinomatosis
8. Previous or concomitant malignancies at other sites, except effectively treated non-melanoma skin cancers, carcinoma in situ of the cervix,
non-invasive bladder cancer, ductal carcinoma in situ of the breast, or effectively treated malignancy that has been in remission for more than 3
years and is considered to be cured. Definitively treated localized low/intermediate risk prostate cancer (Gleason score ≤ 7) is allowed when a rise in
serum PSA level by ≥ 2 ng/mL above the nadir is excluded
9. Known pre-existing interstitial lung disease
10. Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the study drug in the opinion of the
investigator (e.g. Crohn’s disease, ulcerative colitis, chronic diarrhea, and malabsorption)
11. Clinically relevant cardiovascular abnormalities as judged by the investigator such as uncontrolled hypertension, congestive heart failure ≥ NYHA
grade III, unstable angina or myocardial infarction within the past 6 months, or poorly controlled cardiac arrhythmia in the opinion of investigator
12. Any history of or concomitant condition that, in the opinion of the investigator, would compromise the patient’s ability to comply with the study or
interfere with the evaluation of the efficacy and safety of the test drug, or renders the patient at high risk of treatment complications
13. Women of child-bearing potential and men who are able to father a child, unwilling to be abstinent or use adequate contraception prior to study
entry, for the duration of study participation and for at least 2 weeks after treatment has ended
14. Female patient pregnant or breast-feeding
15. Known active infection with HBV, HCV or HIV
16. Any contraindications for therapy with pemetrexed
17. Known hypersensitivity to afatinib or the excipients of any of the trial drugs
18. Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 60 days prior to
treatment start
19. Pleurocentesis or paracentesis should be considered in patients with clinically significant pleural effusions or ascites if clinically indicated. However,
per SmPC of pemetrexed the presence of effusion is not an exclusion criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (RECIST 1.1) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every 6 weeks until 24 weeks after randomization and then every 9 weeks |
|
| E.5.2 | Secondary end point(s) |
To compare afatinib maintenance with pemetrexed maintenance after induction therapy with platinum/pemetrexed with respect to
• Overall survival
• Objective response rate, Clinical benefit rate (RECIST1.1)
• Safety / toxicity
• Quality of Life
|
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| QoL and translational research |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 25 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| When the last patient on treatment has completed the first follow-up visit after discontinuation of treatment or 12 months after "last patient randomized", whichever comes first |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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