| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
EGFR-mutated Non-small cell lung cancer (NSCLC) with Brain or Leptomeningeal metastases
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| E.1.1.1 | Medical condition in easily understood language |
| lung cancer with Brain or Leptomeningeal metastases with harboring a EGFR mutation |
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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 | 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) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10071975 |
| E.1.2 | Term | EGFR gene mutation |
| E.1.2 | System Organ Class | 10018065 - General disorders and administration site conditions |
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| 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 determine efficacy of osimertinib in EGFR-mutated NSCLC patients with brain or leptomeningeal metastasis. |
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| E.2.2 | Secondary objectives of the trial |
To determine OS and PFS in EGFR-mutated NSCLC patients with brain or leptomeningeal metastasis treated with osimertinib.
To determine safety and quality of life in EGFR-mutated NSCLC patients with brain or leptomeningeal metastasis treated with osimertinib.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient with NSCLC (histological or cytological diagnosis) stage IV (8th UICC TNM edition, 2017).
2. Patients with brain and/or leptomeningeal metastases.
For cohort 1, the diagnosis of leptomeningeal metastasis requires either detection of cancer cell or EGFR mutation in the CSF, or presence of both clinical and neuro-imaging findings typical of LM, according to EANO-ESMO criteria.
3. Presence of an activating EGFR mutation. The following mutations are considered to be activating: L858R, exon 19 deletions, exon 19 insertions, L861Q, G719X. The inclusion of patients with other mutations should be discussed on a case-by-case basis with IFCT.
The presence of co-mutations on an oncogenic driver should be discussed with the IFCT before inclusion of the patient.
4. Testing for T790M mutation in circulating tumour DNA or tumour tissue sample at progression on the last treatment received before inclusion.
5. Maximum lines of anti-cancer treatment received before inclusion:
o For Cohort 1, patients could have been previously treated with maximum 3 lines of anti-cancer treatment.
o For cohort 2, patients could have been previously treated with maximum 1 line of anti-cancer treatment.
o For cohorts 3 and 4, patients could have been previously treated with maximum 2 lines of anti-cancer treatment. The line just before enrolment must be an EGFR TKI.
In case of previous chemotherapy, a wash-out period of 28 days will be applied. If there was any prior therapy with an investigational agent, a washout period of five half-lives of the compound or 3 months, whichever is greater, is needed.
6. Patient having recovered from all grade ≤ 1 toxicities related to previous anticancer therapies (CTCAE v 5.0) except for alopecia, platinum-therapy-related neuropathy (where ≤2 is allowed).
7. For cohorts 3 and 4, documented tumour progression after previous therapy according to RECIST 1.1 :
- Cohort 3: patients must have progressive brain metastases but no extra-CNS progression.
- Cohort 4: patients must have progressive brain metastases and extra-CNS progression.
8. Presence of at least one evaluable lesion not previously irradiated according to RECIST 1.1. For cohort 2, 3 and 4, presence of one CNS evaluable lesion not previously irradiated according to RECIST 1.1.
9. Age of at least 18 years old.
10. Performance status (PS) 0 to 2 (ECOG) except for patients with leptomeningeal carcinomatosis (cohort 1) a PS 3 is authorised.
11. Patient with a life expectancy of ≥ 6 weeks for cohort 1 and ≥ 12 weeks for cohort 2, 3 and 4.
12. Haematological function:
- Absolute number of neutrophils ≥ 1.5 x 109/L;
- Platelets ≥ 100 x 109/L;
- Haemoglobin ≥ 9 g/dL (transfusions to maintain or exceed this value are accepted).
13. Hepatic function:
- Total bilirubin ≤ 1.5 x UNL (Upper Normal Limit) or ≤ 3 x UNL in case of documented Gilbert’s syndrome or liver metastases;
- AST / ALT < 2.5 x UNL if no liver metastases or < 5 x UNL in case of liver metastases.
14. Renal function: Creatinine ≤1.5 x UNL. If creatinine > 1.5 x UNL, Creatinine clearance must be ≥ 50 mL/min (Cockroft or MDRD or CKD-epi)
15. Coagulation:
- International Normalized Ratio (INR) ≤ 1.5 ;
- Prothrombin Ratio (PR) ≤ 1.5 x UNL.
16. Patient having signed an informed consent form prior to any study specific procedure
17. Patient able, according to the investigator, to comply with study requirements,
18. Patient covered by a national health insurance
19. Female subjects should be using highly effective contraceptive measures during the study and 2 months after discontinuing osimertinib (highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly), and must have a negative pregnancy test and not be breast-feeding prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
o Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments
o Women under 50 years old would be consider postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution
o Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
20. Male subjects should be willing to use barrier contraception during the study and for 4 months after discontinuing osimertinib
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| E.4 | Principal exclusion criteria |
1. Small cell lung cancer histology (SCLC) or tumours with mixt histology including a SCLC component.
2. Previous treatment with osimertinib or another 3rd generation EGFR inhibitor.
3. Previous treatment with any EGFR TKI (cohort 2 only)
4. Brain progression requiring whole brain radiation without delay.
5. Local treatments (neurosurgical or stereotactic treatment) for brain metastases performed less than 2 weeks prior to enrolment.
6. Local brain treatment scheduled during study treatment.
7. Patient who received radiotherapy including the lung fields ≤ 4 weeks before enrolment or patient who has not recovered from radiotherapy-induced toxicities. For all other body sites (including radiotherapy on thoracic vertebrae and ribs), radiotherapy ≤ 2 weeks before enrolment or who have not recovered from radiotherapy-induced toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks before enrolment is authorised.
8. Any of the following cardiac criteria:
- Mean resting corrected QT interval (QTc) > 470 msec using the screening clinic ECG machine derived QTc value
- Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g. complete left bundle branch block, third degree heart block and second degree heart block).
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, electrolyte abnormalities (including: Serum/plasma potassium < LLN; Serum/plasma magnesium < LLN; Serum/plasma calcium < LLN), congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause Torsades de Pointes.
9. Active malignant disease other than NSCLC.
10. Previous or active cancer within the previous 3 years (except for treated carcinoma in situ of the cervix or basal cell skin cancer).
11. Others on-going anti-cancer treatment (including hormone therapy).
12. Major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic) during the 4 weeks before enrolment or patient who has not recovered from the side effects of such as procedure.
13. Current severe infectious disease or fever > 38.5°C or evidence of any other pathology, degradation of organic or neurological functions, result of the physical examination or laboratory tests leading to suspect disease or a condition contra-indicating the use of the study treatment, which can impair the patient’s compliance to the protocol conditions or expose to any possible risk of complications related to treatment.
14. Clinically significant heart disease (e.g. active): stroke or myocardial infarction in the 6 months prior to inclusion, unstable angina, congestive heart failure grade > II according to New York Heart Association (NYHA) parameters, or cardiac arrhythmia requiring specific treatment during the study which could interfere with study compliance or which is not controlled by a treatment.
15. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV).
16. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib
17. History of hypersensitivity to any of the active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib.
18. Currently receiving (or unable to stop use at least 3 week prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of CYP3A4 (see Appendix 2). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4.
19. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
20. Patient with a deficiency preventing complete understanding of the study requirements.
21. Patient having already been included and treated in this study or in another clinical trial (except for biological trials consisting of taking samples only).
22. Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
- Progression free survival (PFS)
- Overall survival (OS)
- Safety (CTCAE v5.0), tolerance
- Quality of life evaluation (EORTC QLQ-C30, QLQ LC13, QLQ BN20): time to symptom deterioration
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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) | 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 | 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.8.3 |
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 | 40 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | 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
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| The end of the study is defined as 6 months after the last visit of the last treated patient. |
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| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
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