| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
ALK positive Locally Advanced or Metastatic Non-small Cell Lung Cancer
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic or locally advanced non-small cell lung cancer |
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| 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 | 21.1 |
| 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 |
The objective of the study is to compare the efficacy and safety of brigatinib to that of crizotinib in ALK+ locally advanced or metastatic NSCLC patients naive to ALK inhibitors, as evidenced by PFS.
|
|
| E.2.2 | Secondary objectives of the trial |
1. To compare the efficacy of brigatinib to that of crizotinib, as evidenced by confirmed ORR, time to/duration of response, disease control rate (DCR), and Overall Survival (OS)
2. To compare the efficacy in the CNS of brigatinib to that of crizotinib, as evidenced by intracranial response and intracranial PFS in those patients with intracranial CNS metastases at baseline
3. To assess the safety and tolerability of brigatinib in comparison with crizotinib
4. To determine pharmacokinetic (PK) parameters of brigatinib through population PK modeling
5. To assess patient-reported symptoms and health-related quality of life (HRQoL) with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 (v3.0), and its lung cancer module, QLQ-LC13 (v3.0) in patients treated with brigatinib compared to those treated with crizotinib. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have histologically or cytologically confirmed stage IIIB (locally advanced or recurrent and not a candidate for definitive multimodality therapy) or stage IV NSCLC.
2. Must have prior positive test results from an ALK test.
3. Have sufficient tumor tissue available for central analysis.
4. Have at least 1 measurable (i.e., target) lesion per RECIST v1.1.
5. Recovered from toxicities related to prior anticancer therapy to NCI CTCAE v 4.0 grade ≤1. Note: treatment-related alopecia or peripheral neuropathy that are grade >1 are allowed if deemed irreversible.
6. Are a male or female patient ≥18 years old.
7. Have adequate organ function, as defined by the study protocol.
8. Have Eastern Cooperative Oncology Group (ECOG) performance status <2.
9. Have normal QT interval on screening ECG evaluation, defined as QT interval corrected (Fridericia) (QTcF) of ≤450 milliseconds (msec) in males or ≤470 msec in females.
10. For female patients of childbearing potential, have a negative pregnancy test documented prior to randomization.
11. For female and male patients who are fertile, agree to use a highly effective form of contraception with their sexual partners during the dosing period and for a period of at least 4 months after the end of treatment with brigatinib and at least 3 months after the end of treatment with crizotinib.
12. Provide signed and dated informed consent indicating that the patient has been informed of all pertinent aspects of the study, including the potential risks, and is willingly participating.
13. Have the willingness and ability to comply with scheduled visit and study procedures. |
|
| E.4 | Principal exclusion criteria |
1. Previously received an investigational antineoplastic agent for NSCLC.
2. Previously received any prior TKI, including ALK-targeted TKIs.
3. Previously received more than 1 regimen of systemic anticancer therapy for locally advanced or metastatic disease.
4. Received chemotherapy or radiation within 14 days of first dose of study drug, except stereotactic radiosurgery (SRS) or stereotactic body radiation therapy (SBRT).
5. Received anti-neoplastic monoclonal antibodies within 30 days of the first dose of study drug.
6. Had major surgery within 30 days of the first dose of study drug, minor surgical procedures such as catheter placement or minimally invasive biopsies are allowed.
7. Have been diagnosed with another primary malignancy other than NSCLC, except for adequately treated non-melanoma skin cancer or cervical cancer in situ; definitively treated non-metastatic prostate cancer; or patients with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary malignancy.
8. Have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening or asymptomatic disease requiring an increasing dose of corticosteroids to control symptoms within 7 days prior to randomization.
9. Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Patients with leptomeningeal disease and without cord compression are allowed.
10. Be pregnant, planning a pregnancy, or breastfeeding
11. Have significant, uncontrolled, or active cardiovascular disease, as defined by the study protocol.
12. Have uncontrolled hypertension.
13. Have a history or the presence at baseline of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis.
14. Have an ongoing or active infection.
15. Have a known history of human immunodeficiency virus (HIV) infection.
16. Have a known or suspected hypersensitivity to brigatinib or its excipients and/or crizotinib or its excipients.
17. Have malabsorption syndrome or other gastrointestinal (GI) illness or condition.
18. Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of the study drug. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS) as assessed by a blinded Independent Review Committee (bIRC) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. ORR
2. Intracranial ORR
3. Intracranial PFS
4. OS
5. Duration of response
6. Time to response
7. DCR
8. Safety and tolerability
9. Change from baseline scores in global health status/quality of life (QOL) assessed with the EORTC QLQ-C30 (v3.0) , and time-to-deterioration in dyspnea assessed with the EORTC QLQ-LC13 (v3.0). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-8. At least upto 36 months
9. Until 30 days after the last dose of study treatment. |
|
| 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 | Yes |
| 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 |
| To evaluate exploratory biomarkers |
|
| 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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 82 |
| 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 |
| Canada |
| Denmark |
| Finland |
| France |
| Germany |
| Hong Kong |
| Italy |
| Korea, Democratic People's Republic of |
| Luxembourg |
| Netherlands |
| Norway |
| Singapore |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| United Kingdom |
| United States |
|
| 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
|
Last visit after treatment with interventional therapy is completed prior
to entering long term follow-up for survival.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| 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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