| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced or metastatic non-small cell lung cancer (NSCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic or locally advanced 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 | 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 investigate the efficacy and safety of BI 1482694 versus standard platinum doublet chemotherapy as a second line treatment for patients with locally advanced or metastatic NSCLC whose disease progressed on or after one prior 1st line EGFR-TKI therapy and whose tumours carry at least one EGFR activating mutation and a T790M mutation versus standard platinum doublet chemotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Pathologically confirmed diagnosis of adenocarcinoma of the lung. Patients with mixed histology are eligible if adenocarcinoma is the predominant histology.
2. Locally Advanced Stage IIIb or metastatic stage IV NSCLC.
3. At least one documented EGFR mutation known to be associated with EGFR TKI sensitivity e.g. exon 19 deletion, L858R, L861Q, G719X.
4. Presence of T790M mutation confirmed by central laboratory analysis of tumor tissue obtained after disease progression on, or after first-line treatment with an approved EGFR-TKI.
5. Radiologically confirmed progression or recurrence of disease during or following first-line treatment with an approved 1st or 2nd generation EGFR -TKI.
6. At least one target lesion (excluding the brain), that can be accurately measured per RECIST version 1.1.
7. Eligible to receive treatment with the selected doublet-chemotherapy (i.e. cisplatin/pemetrexed or carboplatin/ pemetrexed) in accordance with SmPC/PI.
8. Patients aged at least 18 years or over the legal age of consent in countries where that is greater than 18 years.
9. Eastern Cooperative Oncology Group (ECOG) score: 0 or 1 (R01-0787).
10. Adequate organ function.
|
|
| E.4 | Principal exclusion criteria |
1. More than one line of prior therapy for locally advanced stage IIIb or metastatic stage IV NSCLC.
a. Radiotherapy alone is not counted as a line of therapy;
b. Radiosensitisers and/or intrapleural administration of anti-cancer agents are not counted as a line of therapy.
2. Previous treatment with BI 1482694, or other 3rd generation EGFR inhibiting drugs that target T790M-positive mutant EGFR (e.g. AZD9291, CO-1686).
3. Previous treatment with an approved 1st or 2nd generation EGFR-TKI i.e. erlotinib, gefitinib, and afatinib within 8 days or 5 half-lives, whichever is longer, prior to randomisation. Treatment with an approved 1st or 2nd generation EGFR-TKI during screening is allowed as long as the washout period of 8 days or 5 half-lives is guaranteed.
4. Previous chemotherapy and experimental anticancer therapy within 4 weeks, anticancer immunotherapy within 2 weeks, or anticancer hormonal treatment within 2 weeks, of the first administration of study drug.
5. Radiotherapy within 4 weeks prior to randomisation except as follows:
a. Palliative radiotherapy to regions other than the chest is allowed up to 2 weeks prior to randomization;
b. Single dose palliative radiotherapy for symptomatic metastasis within 2 weeks prior to randomisation may be allowed but must be discussed with the sponsor.
6. Major surgery within 4 weeks prior to randomisation or scheduled during the projected course of the study.
7. Known history of hypersensitivity to BI 1482694 or any of its excipients or drugs with a chemical structure similar to BI 1482694.
8. Known history of hypersensitivity to cisplatin, carboplatin or pemetrexed or any of their excipients.
9. History or presence of cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of ≥ 3, unstable angina or poorly controlled arrhythmia which are considered as clinically relevant by the investigator. Myocardial infarction within 6 months prior to randomisation.
10. Female patients of childbearing potential (see Section 4.2.2.3) who are nursing or pregnant or do not agree to submit to pregnancy testing required by this protocol.
11. 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 the efficacy and safety of the test drug.
12. Previous or concomitant malignancies at other sites, except:
a. effectively treated non-melanoma skin cancers;
b. effectively treated carcinoma in situ of the cervix;
c. effectively treated ductal carcinoma in situ;
d. other effectively treated malignancy that has been in remission for more than 3 years and is considered to be cured.
13. Known pre-existing interstitial lung disease.
14. Any history or presence of uncontrolled gastrointestinal disorders that could affect the intake and/or absorption of the study drug (e.g. nausea, vomiting, Crohn’s disease, ulcerative colitis, chronic diarrhoea, malabsorption) in the opinion of the investigator.
15. Known active hepatitis B infection (defined as presence of HepB sAg and/or Hep B DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV carrier.
16. Left ventricular ejection fraction (LVEF) < 50%.
17. Leptomeningeal carcinomatosis.
18. Presence or history of uncontrolled or symptomatic brain or subdural metastases, unless considered stable by the investigator and local therapy was completed. Use of corticosteroids is allowed if the dose was stable for at least 4 weeks. Of note:Inclusion of patients with newly identified brain metastasis/es at screening will be allowed if patients
are asymptomatic.
19. Previous randomisation in this trial.
20. Concurrent participation in another clinical trial with an investigational device or drug.
21. Active infectious disease which puts the patient at increased risk in the opinion of the investigator.
22. Concomitant yellow fever vaccination.
23. Current tumour bleeding. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint:
- Progression free survival (PFS) according to RECIST 1.1 by independent review. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every 6 weeks up until Week 60 and every 12 weeks thereafter until PD or start of subsequent anti-cancer therapy. |
|
| E.5.2 | Secondary end point(s) |
- Overall Survival (OS)
- Objective response (OR) according to RECIST 1.1 by independent review
- Time to and duration of OR according to RECIST 1.1 by independent review
- Disease Control (DC) and tumour shrinkage (according to RECIST 1.1 by independent review)
- Time to deterioration in Patient Reported Outcomes (PROs) of:
cough (EORTC QLQ-LC13: Q1);
dyspnoea (EORTC QLQ-LC13: Q3-5 and EORTC QLQC30:Q8);
chest pain (EORTC QLQ-LC13: Q10);
NSCLC specific symptoms of NSCLC SAQ (R99-1213, R07-2064; R12-5607; R07-2060).
- Deterioration of NSCLC specific symptoms (NSCLC-SAQ). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
OS – every 3 weeks until PD/start of subsequent anti-cancer therapy and then every 60 days until death.
OR – imaging visits, - all RECIST endpoints as imaging visits frequency;
QoL questionnaires – every 3 weeks until death or PD/start of subsequent anti-cancer therapy. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| The crossover part only occurs in one arm. |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Pemetrexed, Cisplatin, Carboplatin |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 165 |
| 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 |
| Belgium |
| Canada |
| China |
| France |
| Germany |
| Hong Kong |
| India |
| Italy |
| Korea, Republic of |
| Malaysia |
| Philippines |
| Poland |
| Portugal |
| Russian Federation |
| Serbia |
| Singapore |
| Spain |
| Taiwan |
| Thailand |
| United Kingdom |
| United States |
| Vietnam |
|
| 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 at least two-thirds of randomized patients have died and those alive have been followed up for approximately 23 months. |
|
| 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 | 5 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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