| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-small cell lung cancer with ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) gene rearrangements |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-small cell lung cancer is a disease in which malignant (cancer) cells form in the tissues of the lung |
|
| 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 | 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 efficacy of entrectinib compared with crizotinib in patients who have ROS1 rearrangement-positive NSCLC with CNS metastases at baseline |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate the efficacy of entrectinib compared with crizotinib in patients who have ROS1 rearrangement-positive NSCLC in the whole study population (ITT)
•To evaluate the efficacy of entrectinib compared with crizotinib in patients who have ROS1 rearrangement-positive NSCLC with CNS metastases at baseline
•To evaluate the safety of entrectinib compared with crizotinib in patients who have ROS1 rearrangement-positive NSCLC
•To evaluate health status utility scores of patients treated with entrectinib to inform pharmacoeconomic modeling using the EuroQol 5-Dimension Questionnaire (5-level version; EQ-5D-5L) index-based and visual analog scale (VAS) scores |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Age ≥ 18 years
•Histologically- or cytologically-confirmed diagnosis of advanced or recurrent (Stage IIIB/C, not amenable for radical treatment) or metastatic (Stage IV) NSCLC that harbors a documented ROS1 gene rearrangement
•No prior treatment with a ROS1 tyrosine kinase inhibitor, chemotherapy or other systemic therapy for advanced or recurrent (Stage IIIB/C not amenable for radical treatment) or metastatic (Stage IV) NSCLC
•Prior radiotherapy is allowed if more than 14 days have elapsed between the end of treatment and randomization. Patients who received brain irradiation must have completed whole brain radiotherapy at least 14 days prior and/or stereotactic radiosurgery at least 7 days prior to the start of entrectinib treatment
•Measurable systemic disease according to RECIST v1.1
•Patients with measurable and non-measurable CNS lesions per RECIST v1.1, including leptomeningeal carcinomatosis, are eligible, provided that the patient is neurologically stable for at least 1 week prior to the first dose of study treatment.Note: Previously irradiated CNS lesions cannot be selected as target (measurable) lesions
•Life expectancy of at least 12 weeks
•Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
•Adequate hematologic, renal, liver function
•Recovery from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment
•Patients must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment
•Ability to comply with the study protocol, in the investigator’s judgment
•Ability to swallow entrectinib and crizotinib intact without chewing, crushing, or opening the capsules
•For women of childbearing potential: agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs
during the treatment period and for up to 5 weeks after the final dose of entrectinib or for at least 90 days after the final dose of crizotinib
•For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm |
|
| E.4 | Principal exclusion criteria |
•Current participation in another therapeutic clinical trial
•Prior treatment with a ROS1 tyrosine kinase inhibitor, chemotherapy or other systemic therapy for advanced or recurrent (Stage IIIB/C not amenable for radical treatment) or metastatic (Stage IV) NSCLC
•NCI-CTCAE v5.0 Grade 3 or higher toxicities due to any prior therapy (excluding alopecia, fatigue, nausea and lack of appetite), which have not shown improvement and are strictly considered to interfere with current study drug
•History of recent (within the past 3 months) symptomatic congestive heart failure or ejection fraction ≤ 50% observed during screening for the study
•History of prolonged corrected QT interval
•History of additional risk factors for torsades de pointes
•Grade ≥2 peripheral sensory neuropathy
•Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis
•Previous malignancy within the past 3 years (other than curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is considered to have no impact on PFS and OS for the current NSCLC)
•Incomplete recovery from any surgery prior to the start of study treatment that would interfere with the determination of safety or efficacy
•Active GI disease or other malabsorption syndrome that would reasonably impact drug absorption
•History of prior therapy-induced pneumonitis
•Any condition (in the past 3 months) that would interfere with the determination of safety or efficacy of study treatments
•Known active infections that would interfere with the assessment of safety or efficacy of study treatments (bacterial, fungal or viral) , with the exceptions of HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) infections
•History of hypersensitivity to any of the additives in the entrectinib and/or crizotinib drug formulations
•Pregnant or breastfeeding, or intending to become pregnant during the study or within 3 months after the final dose of entrectinib or crizotinib
•Known human immunodeficiency virus (HIV) positivity or acquired immunodeficiency syndrome (AIDS)-related illness
•Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the patient in this study
•Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the patient before trial entry |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1.Progression-free survival (PFS) in patients with CNS metastases at baseline, defined as the time from randomization to the first documented disease progression (extracranial or intracranial) or death from any cause, whichever occurs first, as determined by a blinded independent review committee (BIRC) using RECIST v1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1.Progression-free survival in the CNS (CNS-PFS), defined as the time from randomization to the first documented disease progression in the CNS or death from any cause, whichever occurs first, as determined by the BIRC using RECIST v1.1
2.Overall response rate (ORR), defined as the percentage of patients who attain CR or PR, as assessed by the BIRC and the investigator per RECIST v1.1
3.Duration of response (DOR), defined as the time from when response (CR or PR) is first documented to disease progression or death, whichever occurs first, as assessed by the BIRC and the investigator per RECIST v1.1
4.Progression-free survival (PFS), defined as the time from randomization to the first documented disease progression (extracranial or intracranial) or death from any cause, whichever occurs first, as determined by the BICR and investigator using RECIST v1.1
5.Overall survival (OS), defined as the time from randomization to death from any cause
6.Impact on functioning, including health-related quality of life, using the Global Health Status/Quality of Life (GHS/QoL), the Physical Functioning (PF) and Role Function (RF) scores, as assessed by the EORTC QLQ-C30 and analyzed as a time to first and confirmed clinically meaningful deterioration
7.Impact on lung cancer-specific symptoms, as assessed by the EORTC QLQ-LC13
8.Objective response rate in the CNS (CNS-ORR), defined as the percentage of patients who attain CR or PR for lesions in the CNS, as determined by the BICR per RECIST v1.1
9.Duration of response in the CNS (CNS-DOR), defined as the time from when a CNS response (CR or PR) is first documented to disease progression in the CNS, as determined by the BICR per RECIST v1.1
10.Incidence, type, timing, relatedness and severity of adverse events,, including serious adverse events and adverse events leading to dose modifications/interruptions, study drug withdrawal or death, as assessed by the investigator according to the National Cancer Institute Common Terminology
Criteria for Adverse Events, Version 5.0
11.Health utility from the EQ-5D-5L and pharmacoeconomic model |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-10.Up to 7 years
11.Baseline (Day 1), Week 4, Week 8, all subsequent visits (every 8 weeks), Post-progression visits on treatment in case of isolated CNS progression (every 8 weeks), Post-Treatment Visit / Safety Follow Up Visit (4 weeks after permanent treatment discontinuation) |
|
| 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 | 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 | 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) | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 47 |
| 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 |
| Colombia |
| Guatemala |
| Iraq |
| Switzerland |
| Brazil |
| China |
| Croatia |
| France |
| Germany |
| Greece |
| India |
| Italy |
| Jordan |
| Lebanon |
| Mexico |
| Netherlands |
| Romania |
| Russian Federation |
| Slovakia |
| Spain |
| Sweden |
| Turkey |
|
| 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
|
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the date at which the last data point required for statistical analysis or safety follow-up is received from the last patient, whichever occurs later. The end of the study is expected to occur approximately 24 months after the last patient is enrolled.
The total length of the study, from screening of the first patient to the end of the study, is expected to be approximately 7 years. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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