Locally advanced or metastatic Non-small-cell lung carcinoma
Conditions
Interventions
Trade Name: Tagrisso 40mg
Product Name: osimertinib
Pharmaceutical Form: Film-coated tablet
Trade Name: Tagrisso 80mg
Product Name: osimertinib
Pharmaceutical Form: Film-coated tablet
Sponsors
CHU de Nantes
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Male or female, aged at least 18 years. • Informed consent signed prior to any study speci?c procedures, sampling, and analyses. • Pathologically con?rmed adenocarcinoma of the lung (e.g., this may occur as systemic recurrence after prior surgery for early stage disease or patients may be newly diagnosed with Stage lIIB/ IV disease). Patients with mixed histology are eligible if adenocarcinoma is the predominant histology. • Locally advanced or metastatic NSCLC (Non-small-cell lung carcinoma), not amenable to curative surgery or radiotherapy. • The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19 deletions, L858R), either alone or in combination with other EGFR mutations. • Patients must be treatment-naive for advanced NSCLC and eligible to receive ?rst-line treatment with osimertinib • Subjects affiliated to an appropriate health insurance • World Health Organization Performance Status of 0 to 1 with no clinically signi?cant deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks. • At least one lesion, not previously irradiated and not chosen for biopsy during the study screening period, that can be accurately measured at baseline as 10 mm in the longest diameter (except lymph nodes which must have a short axis of 15 mm) with computerized tomography (CT) or magnetic resonance imaging (MRI), and which is suitable for accurate repeated measurements. • Female patients should be using adequate contraceptive measures, should not be breast feeding, and must have a negative pregnancy test prior to ?rst dose of study drug; or female patients must have an evidence of non-child-bearing potential by ful?lling one of the following criteria at screening: ~ Post-menopausal de?ned 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 luteinizing hormone (LH) and follicle-stimulating hormone (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. • Male patients should be willing to use barrier contraception, i.e., condoms Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 40 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 26
Exclusion criteria
Exclusion criteria: • Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site) • Previous enrolment in the present study • Treatment with any of the following: * Prior treatment with any systemic anti-cancer therapy for advanced NSCLC including standard chemotherapy, biologic therapy, immunotherapy, or any investigational drug. * Prior treatment with an EGFR-TKI. including osimertinib * Major surgery (excluding placement of vascular access) within 4 weeks of the ?rst dose of study drug. * Radiotherapy treatment to more than 30% of the bone marrow or with a wide ?eld of radiation within 4 weeks of the ?rst dose of study drug. * Treatment with an investigational drug within ?ve half-lives of the compound or any of its related material, if known. • Any concurrent and/or other active malignancy that has required systemic treatment within 2 years of ?rst dose of study drug. • Any unresolved toxicities from prior systemic therapy (e. g., adjuvant chemotherapy) greater than CTCAE grade l at the time of starting study drug with the exception of alopecia, prior platinum-therapy related neuropathy grade 2. • Spinal cord compression, symptomatic and unstable brain metastases except for those patients who have completed definitive therapy, and have had a stable neurological status for at least 2 weeks after completion of definitive therapy. Patients may be on corticosteroids to control brain metastases if they have been on a stable dose for 2 weeks (14 days) prior to the start of study treatment and are clinically asymptomatic. • 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 immunode?ciency virus (HIV). Screening for chronic conditions is not required. • Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous signi?cant bowel resection that would preclude adequate absorption of osimertinib. • Any of the following cardiac criteria: * Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs, 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, second-degree heart block, PR interval >250 msec. * Any factors that increase the risk of QTc prolongation or risk of arrhythmic events suchas heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in ?rst-degree relatives or any concomitant medication known to prolong the QT interval. • Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD. • Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values. *Absolute neutrophil count 2.5x the upper limit of normal (ULN) if no demonstrable liver metastases or >5 x ULN in the presence of liver metastases. *Aspartate aminotran
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To examine the genetic profile at the point of disease progression in patients receiving osimertinib as first-line EGFR TKI therapy for EGFRm+ locally advanced or metastatic NSCLC compared to the profile prior to initiation of treatment;Secondary Objective: Clinical objectives: ?To assess efficacy of osimertinib To assess the safety Biological objectives: ? To evaluate the consequence of osimertinib treatment on the expression of targets of immune check point inhibitors ? To evaluate diagnostic accuracy of ctDNA to detect mutation ? To observe if the presence of ctDNA at baseline is a prognostic factor of clinical progression disease? ? To demonstrate that the early kinetics of ctDNA is an indicator of response to osimertinib To measure the biological progression (bPFS) in patients treated with osimertinib ? To compare the genetic profile of the ctDNA and the tumor biopsy ? To compare the kinetic of appearance of EGFR mutation and radiological and clinical progression disease ;Primary end point(s): Proportion of patients with a given genetic marker on tumor biopsy (including, but not limited to, EGFR mutations, HER2, and cMET expression and/or amplification) at the point of clinical disease progression.;Timepoint(s) of evaluation of this end point: clinical disease progression | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Clinical endpoints 1. Progression free survival rate at one year defined by time from first study dose to first event between Radiological Progression Disease or death, or one year if no event. The rPFS is defined according to RECIST 1.1. 2. Radiological Progression Free Survival (rPFS): Time from first study dose to first event between rPFS or death. The rPFS is defined according to RECIST 1.1. 3. Clinical Progression Free Survival (cPFS): Time from first study dose to off-osimertinib. 4. Overall survival : Time from first study dose to death or end of the study 5. Objective Response Rate (ORR): Sum of CR (complete response) and PR (partial response). 6. Duration of Response (DoR): Time from tumor response to disease progression. 7. Disease Control Rate (DCR): Sum of CR (complete response) PR, (partial response) and SD (stable disease) defined according to RECIST 1.1 criteria. ? Adverse events (grade 3 and 4) Biological endpoints: ? Expression of molecules involved in the efficacy of check point inhibitors determined by immunohistochemistry (PD-L1; CD73; CD4; CD8) on tumor tissue collected at progression ? Mutations collected at progression on tumor tissue and ctDNA. ? Presence of tumors ctDNA at baseline, clinical progression disease ? Absolute quantities of ctDNA molecules presenting the EGFR mutation identified in the tumor, clinical progression disease ? Serial monitoring in ctDNA of molecular alterations identified in tissues collected at progression ? The EGFR mutation identified in the tumor biopsy and in the ctDNA ? Absolute quantities of ctDNA molecules presenting the EGFR mutation monthly, radiological and clinical progression disease;Timepoint(s) of evaluation of this end point: refer to détails indicated in E.5.2, depending the secondary end point. | — |
Countries
France
Contacts
Public ContactDirection recherche, CHU de Nantes
CHU de Nantes
Outcome results
None listed