ORBITAL: Study of Osimertinib in Patients With a Lung Cancer With Brain or Leptomeningeal Metastases With EGFR Mutation

Sponsor

Intergroupe Francophone de Cancerologie Thoracique (Other)

Overall Status

Recruiting

CT.gov ID

NCT04233021

Collaborator

(none)

Enrollment

Locations

Arm

42.5

Anticipated Duration (Months)

1.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Non Small Cell Lung Cancer Metastatic Leptomeningeal Metastasis Brain Metastases EGFR Activating Mutation	Drug: Osimertinib	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

69 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jul 16, 2020

Anticipated Primary Completion Date :

Apr 1, 2023

Anticipated Study Completion Date :

Feb 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Osimertinib Osimertinib 80 mg/d	Drug: Osimertinib Osimertinib 80 mg/d

Arm

Intervention/Treatment

Experimental: Osimertinib

Osimertinib 80 mg/d

Drug: Osimertinib

Osimertinib 80 mg/d

Outcome Measures

Primary Outcome Measures

Objective Response Rate [6 months]
Objective Response Rate at 6 months using EANO-ESMO criteria (cohort 1) and RECIST1.1 criteria (cohorts 2)

Secondary Outcome Measures

Overall Survival [About 24 months]
Time from enrollment until death due to any cause
Progression-free survival [About 24 months]
Time from enrollment to first observation of progression (EANO-ESMO criteria (cohort 1) and RECIST1.1 criteria (cohorts 2) or date of death (from any cause)
CNS Progression-free survival [About 24 months]
Time between the date of randomization and the first date of documented CNS progression, or death in the absence of progression due to any cause, whichever occurs first.
Incidence, type and severity of adverse event [From time of informed consent through treatment period and up to 30 days post last dose of study treatment (about 24 months)]
Descriptive statistics of safety will be presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
Evaluate the Quality of life [From time of randomisation through treatment period (about 24 months)]
EORTC QLQ-C30-LC13 (Qualify of Life Questionnaire C30 and Lung Cancer 13) questionnaire
Evaluate the Quality of life [From time of randomisation through treatment period (about 24 months)]
QLQ BN20 (Brain Neoplasm N20) questionnaire
CNS Overall response Rate (ORR) [6 months]
the percentage of subjects who have a best overall CNS response of Complete CNS Response (CR) or Partial CNS Response (PR) at 6 months.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patient with NSCLC (histological or cytological diagnosis) stage IV (8th UICC TNM edition, 2017).
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.
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.

Testing for T790M mutation in circulating tumour DNA or tumour tissue sample at progression on the last treatment received before inclusion.
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.

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).
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.
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.
Patient with a life expectancy of ≥ 6 weeks for cohort 1 and ≥ 12 weeks for cohort 2.
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).

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.

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

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:

Small cell lung cancer histology (SCLC) or tumours with mixt histology including a SCLC component.
Previous treatment with osimertinib or another 3rd generation EGFR inhibitor.
Previous treatment with any EGFR TKI (cohort 2 only)
Brain progression requiring whole brain radiation without delay.
Local treatments (neurosurgical or stereotactic treatment) for brain metastases performed less than 2 weeks prior to enrolment.
Local brain treatment scheduled during study treatment.
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.
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.

Active malignant disease other than NSCLC.
Previous or active cancer within the previous 3 years (except for treated carcinoma in situ of the cervix or basal cell skin cancer).
Others on-going anti-cancer treatment (including hormone therapy).
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.
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.
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.
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).

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
History of hypersensitivity to any of the active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib.
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.
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.
Patient who is subject to legal protection or who is unable to express his will.
Patient with a deficiency preventing complete understanding of the study requirements.
Patient having already been included and treated in this study or in another clinical trial (except for biological trials consisting of taking samples only).
Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site).

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Centre Hospitalier Aix-Pertuis	Aix-en-Provence	France	13616
2	CHU Amiens - Groupe Hospitalier Sud	Amiens	France	80054
3	Centre Paul Papin	Angers	France	49055
4	Hôpital privé d'Antony	Antony	France	92166
5	Institut Sainte Catherine	Avignon	France	84918
6	Centre Hospitalier de la Côte Basque	Bayonne	France	64100
7	CHU Besançon - Hôpital J. MINJOZ	Besançon	France	25030
8	Groupe Hospitalier Saint André	Bordeaux	France	33075
9	AP-HP Hôpital Ambroise Paré	Boulogne	France	92104
10	CHU Côte de Nacre	Caen	France	14000
11	Hôpital Louis Pasteur	Colmar	France	68024
12	Centre Hospitalier Intercommunal de Créteil	Créteil	France	94000
13	Centre Georges-François Leclerc	Dijon	France	21079
14	CHU Hôpital du Bocage	Dijon	France	21079
15	Chu Grenoble	Grenoble	France	38043
16	Centre Hospitalier Général	Le Mans	France	72037
17	Hôpital Calmette	Lille	France	59037
18	CHU Dupuytren	Limoges	France	87042
19	Institut Paoli Calmettes	Marseille	France	13273
20	Marseille Hôpital Nord	Marseille	France	13915
21	CHU Montpellier	Montpellier	France	34295
22	Centre Hospitalier Régional - Hôpital de la Source	Orléans	France	45000
23	AP-HP Hôpital Cochin	Paris	France	75014
24	AP-HP Hôpital Bichat	Paris	France	75877
25	Centre Hospitalier Général - Pau	Pau	France	64000
26	Lyon - URCOT Centre Hospitalier Universitaire	Pierre-Bénite	France	69310
27	CHU de la Réunion - Site Felix Guyon	Saint-Denis	France	97400
28	Institut de Cancérologie de l'Ouest - René Gauducheau	Saint-Herblain	France	44805
29	CHU de La Réunion-Site Sud	Saint-Pierre	France	97448
30	Nouvel Hôpital Civil - Hôpitaux Universitaires de Strasbourg	Strasbourg	France	67091
31	Hôpital Foch	Suresnes	France	92151
32	HIA Sainte-Anne	Toulon	France	83800
33	Hôpital Larrey	Toulouse	France	31059
34	CHU Bretonneau	Tours	France	37044
35	Valenciennes Clinique PRIV	Valenciennes	France	59300
36	Centre Hospitalier de Villefranche-sur-Saône	Villefranche-sur-Saône	France	69655
37	Gustave Roussy	Villejuif	France	94805

Sponsors and Collaborators

Intergroupe Francophone de Cancerologie Thoracique

Investigators

Principal Investigator: David PLANCHARD, Intergroupe Francophone de Cancerologie Thoracique
Study Director: Franck MORIN, Intergroupe Francophone de Cancerologie Thoracique