Informations générales (source: ClinicalTrials.gov)
A Phase II, Multi-centre Study, to Evaluate the Efficacy and Safety of Osimertinib Treatment for Patients with EGFR-mutated Non-small Cell Lung Cancer (NSCLC) with Brain or Leptomeningeal Metastases (ORBITAL)
Interventional
Phase 2
Intergroupe Francophone de Cancerologie Thoracique (Voir sur ClinicalTrials)
juillet 2020
décembre 2024
17 octobre 2024
Treatment of non-small cell lung cancer (NSCLC) with Epidermal Growth Factor Receptor
(EGFR) mutation is mainly based on tyrosine kinase inhibitors (TKIs) targeting EGFR. 1st
or 2nd generation inhibitors have been shown to be superior to chemotherapy in terms of
Progression-Free Survival (PFS) when used as 1st line treatment.
In case of progression at several metastatic sites, systemic treatment will be considered
and will depend on the presence of the TKI resistance mutation, the T790M mutation. In
the presence of the T790M mutation, osimertinib is superior to chemotherapy in terms of
progression-free survival, while in the absence of the T790M mutation, platinum salt
chemotherapy is recommended. In case of local progression, treatment of the site in
progression by radiotherapy and/or surgery is considered. As these local treatments can
cause long-term adverse effects, systemic treatments are increasingly being considered in
this indication.
Brain and leptomeningeal metastases are the most frequent isolated site of progression in
EGFR mutated patients treated with TKI. The high frequency of isolated cerebral and
leptomeningeal progression is a consequence of the lower diffusion of 1st and 2nd
generation TKIs in the central nervous system (CNS). Osimertinib is a 3rd generation TKI
that has the particularity of overcoming the T790M mutation and having greater brain
penetration than 1st or 2nd generation TKIs, which could make it an attractive
therapeutic option in the event of brain progression or leptomeningeal progression.
However, its efficacy in patients with cerebral or leptomeningeal metastases is still
poorly understood.
Etablissements
| Les établissements d'Île-de-France ayant mis à jour leurs données Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CHI DE CRETEIL | Isabelle MONNET | 29/03/2024 01:28:58 | Contacter | ||
| CLCC INSTITUT GUSTAVE ROUSSY | David PLANCHARD | 18/03/2024 11:06:11 | Contacter | ||
| Les établissements d'Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| AP-HP - Hôpital Bichat | Contact (sur clinicalTrials) | ||||
| AP-HP - Hôpital Cochin | Contact (sur clinicalTrials) | ||||
| HOPITAL FOCH | Contact (sur clinicalTrials) | ||||
| IFSI AP-HP DU CH AMBROISE PARÉ | Contact (sur clinicalTrials) | ||||
| Les établissements hors Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Centre Hospitalier de la Côte Basque - 64100 - Bayonne - France | Contact (sur clinicalTrials) | ||||
| Centre Hospitalier de Villefranche-sur-Saône - 69655 - Villefranche-sur-Saône - France | Contact (sur clinicalTrials) | ||||
| Centre Hospitalier Général - Pau - 64000 - Pau - France | Contact (sur clinicalTrials) | ||||
| Centre Hospitalier Régional - Hôpital de la Source - 45000 - Orléans - France | Contact (sur clinicalTrials) | ||||
| Centre Paul Papin - 49055 - Angers - France | Contact (sur clinicalTrials) | ||||
| CHU Amiens - Groupe Hospitalier Sud - 80054 - Amiens - France | Contact (sur clinicalTrials) | ||||
| CHU Bretonneau - 37044 - Tours - France | Contact (sur clinicalTrials) | ||||
| CHU Côte de Nacre - 14000 - Caen - France | Contact (sur clinicalTrials) | ||||
| CHU de la Réunion - Site Felix Guyon - 97400 - Saint-Denis - France | Contact (sur clinicalTrials) | ||||
| CHU de La Réunion-Site Sud - 97448 - Saint-Pierre - France | Contact (sur clinicalTrials) | ||||
| CHU Dupuytren - 87042 - Limoges - France | Contact (sur clinicalTrials) | ||||
| Chu Grenoble - 38043 - Grenoble - France | Contact (sur clinicalTrials) | ||||
| CHU Hôpital du Bocage - 21079 - Dijon - France | Contact (sur clinicalTrials) | ||||
| Groupe Hospitalier Saint André - 33075 - Bordeaux - France | Contact (sur clinicalTrials) | ||||
| HIA Sainte-Anne - 83800 - Toulon - France | Contact (sur clinicalTrials) | ||||
| Hôpital Calmette - 59037 - Lille - France | Contact (sur clinicalTrials) | ||||
| Hôpital Larrey - 31059 - Toulouse - France | Contact (sur clinicalTrials) | ||||
| Hôpital Louis Pasteur - 68024 - Colmar - France | Contact (sur clinicalTrials) | ||||
| Marseille Hôpital Nord - 13915 - Marseille - France | Contact (sur clinicalTrials) | ||||
| Nouvel Hôpital Civil - Hôpitaux Universitaires de Strasbourg - 67091 - Strasbourg - France | Contact (sur clinicalTrials) | ||||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Centre Hospitalier Aix-Pertuis - 13616 - Aix-en-Provence - France | Contact (sur clinicalTrials) | ||||
| Centre Hospitalier Général - 72037 - Le Mans - France | Contact (sur clinicalTrials) | ||||
| CHU Besançon - Hôpital J. MINJOZ - 25030 - Besançon - France | Contact (sur clinicalTrials) | ||||
| CHU Montpellier - 34295 - Montpellier - France | Contact (sur clinicalTrials) | ||||
| Hôpital privé d'Antony - 92166 - Antony - France | Contact (sur clinicalTrials) | ||||
| Institut de Cancérologie de l'Ouest - René Gauducheau - 44805 - Saint-Herblain - France | Contact (sur clinicalTrials) | ||||
| Institut Paoli Calmettes - 13273 - Marseille - France | Contact (sur clinicalTrials) | ||||
| Institut Sainte Catherine - 84918 - Avignon - France | Contact (sur clinicalTrials) | ||||
| Lyon - URCOT Centre Hospitalier Universitaire - 69310 - Pierre-Bénite - France | Contact (sur clinicalTrials) | ||||
| Valenciennes Clinique PRIV - 59300 - Valenciennes - France | Contact (sur clinicalTrials) | ||||
Critères
Tous
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
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
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).