| Eligibility |
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 1) detection of cancer cell or EGFR mutation
in the CSF, or 2) 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:
- For Cohort 1, patients could have been previously treated with maximum 3 lines of
anti-cancer treatment.
- For cohort 2, patients could have been previously treated with maximum 1 line of
anti-cancer treatment.
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).
8. Presence of at least one evaluable lesion not previously irradiated according to RECIST
1.1. For cohort 2, presence of one CNS evaluable lesion not previously irradiated according
to RECIST 1.1.The radiological assessment has to be done within the timelines indicated.
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.
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:
- Post-menopausal defined as aged more than 50 years and amenorrheic for at least
12 months following cessation of all exogenous hormonal treatments
- 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
- Documentation of irreversible surgical sterilisation by hysterectomy, bilateral
oophorectomy or bilateral salpingectomy but not tubal ligation 20. Male subjects
should be willing to use highly effective barrier contraception during the study
and for 4 months after discontinuing osimertinib
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).Active infection will include any patients
receiving treatment for infection. Participants with a resolved or chronic infection
HBV are eligible if they are:
- Negative for HBsAg and positive for hepatitis B core antibody [anti-HBc IgG] or
- Positive for HBsAg, negative for HBeAg but for > 6 months have had transaminases
levels below ULN and HBV DNA levels below 2000 IU/mL (i.e., are in an inactive
carrier state).
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 who is subject to legal protection or who is unable to express his will.
21. Patient with a deficiency preventing complete understanding of the study requirements.
22. Patient having already been included and treated in this study or in another clinical
trial (except for biological trials consisting of taking samples only).
23. 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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