MEchanisms of Resistance in EGFR Mutated Nonpretreated Advanced Lung Cancer Receiving OSimErtib

NCT03865511 | Active Not Recruiting Phase 2

• 1 other identifier: RC18_0287
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 17

Brief Summary

Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The AURA 3 study (T790M-positive advanced non-small-cell lung cancer in progression after first-line EGFR-TKI therapy, shown that the median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months p\<0.001). In addition, clinical data show that patients with mutated EGFR NSCLC receiving osimertinib in first line, presented an objective response rate of 77 % with a disease control rate of 98 % and a median PFS was 19.3 months. Finally, The FLAURA study randomized phase 3 study clearly demonstrated the superiority of osimertinib compared with erlotinib or gefitinib in EGFR mutated nonpretreated NSCLC (median PFS of 18.9 months versus 10.2 months). However, several issues remain unknown or debated :

• What are the mechanisms of resistance to osimertinib prescribed in first-line?
• What are the consequences of prolonged exposure to osimertinib on the expression of markers of response to immunotherapy?
• Is there an association between kinetic parameters of ctDNA (circulating tumor DNA) and prediction of response to osimertinib and/ or and prediction of therapeutic escape under osimertinib? In order to respond to all these questions, this phase II trial will be the first to systemically analyze the mechanisms of resistance to Osimertinib based on the analysis of biopsy, and collection of plasma from all patients during the course of treatment.

Conditions

Non-small Cell Lung Cancer

Outcome Measures

Primary Outcomes (1)

• Examination of the genetic profile at the point of disease progression in EGFRm+ (mutated Epidermal Growth Factor Receptor) patients receiving osimertinib as first-line EGFR TKI therapy compared to baseline.

  Analyze of the proportion of patients with a given genetic marker on tumor biopsy (including, but not limited to, EGFR mutations, HER2 (Human Epidermal Growth factor receptor 2), and cMET expression and/or amplification) at the point of clinical disease progression.

  At clinical disease progression (approximately 22 months)

Secondary Outcomes (14)

• Clinical objective : To assess efficacy of Osimertinib

  Every 3 months up to one year after first study dose

• Clinical objective : To assess efficacy of Osimertinib

  Every 3 months until radiological disease progression (approximately 22 months)

• Clinical objective : To assess efficacy of Osimertinib

  Every month until clinical disease progression (approximately 22 months)

• Clinical objective : To assess efficacy of Osimertinib

  From first dose to end of study or date of death from any cause, whicheever comes first, assessed every 3 months (approximately 48 months)

• Clinical objective : To assess efficacy of Osimertinib

  every 3 months until radiological disease progression (approximately 22 months)

Study Arms (1)

TAGRISSO® 80mg (Osimertinib)

EXPERIMENTAL

Oral administration of TAGRISSO® 80mg (Osimertinib) as a single daily dose until disease progression or unacceptable toxicity. Tumor biopsies performed at baseline and clinical progression. ctDNA analysis by Collection of plasma (two 10-ml Streck tubes) at each time point indicated in the trial.

Drug: TAGRISSO® 80mg (Osimertinib); Genetic: Tumor biopsies; Genetic: ctDNA analysis

Interventions

TAGRISSO® 80mg (Osimertinib) DRUG

Oral administration of TAGRISSO® 80mg (Osimertinib) as a single daily dose until disease progression or unacceptable toxicity.

TAGRISSO® 80mg (Osimertinib)

Tumor biopsies GENETIC

Tumor biopsies performed at baseline and clinical progression will be processed (fixed) on site, and sent to Nantes University Hospital for analysis. The following analysis will be performed: 1. Analyses performed on a regular basis, in order to allow subsequent inclusion in other clinical trials : * C797S testing (digital PCR) * MET amplification (dPCR/FISH) * Histological examination of the tissue sample (to identify small cell transformation) * Expression of proteins by immunohistochemistry: PD-L1 (Ventana SP263 antibody); CD73 ; CD4; CD8. 2. At the end of inclusions, deep sequencing analysis to identify acquired mutations and copy number variations (amplifications).

TAGRISSO® 80mg (Osimertinib)

ctDNA analysis GENETIC

ctDNA analysis by Collection of plasma (two 10-ml Streck tubes) at each time point indicated in the trial. These samples will be sent at room temperature by courier to the central laboratory (Nantes University Hospital). There they will be centrifuged, and plasma will be frozen (-80°C). Analyses : * Detection of the EGFR activating mutation in plasma at baseline By dPCR (characterization of patients enrolled) * Detection of the EGFR activating mutation at d7 and m1 by dPCR (early detection of response to osimertinib) * Analysis of the plasma samples collected at clinical progression in order to identify acquired mechanisms of resistance by NGS (and comparison with analysis of the biopsies). * Kinetics studies of the alterations

TAGRISSO® 80mg (Osimertinib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female, aged at least 18 years.
• Informed consent signed prior to any study specific procedures, sampling, and analyses.
• Pathologically confirmed 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 first-line treatment with osimertinib
• Subjects affiliated to an appropriate health insurance
• World Health Organization Performance Status of 0 to 1 with no clinically significant 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 first dose of study drug; or female patients must have an 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 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

You may not qualify if:

• 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 first dose of study drug.
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug.
• Treatment with an investigational drug within five 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 first 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 immunodeficiency virus (HIV). Screening for chronic conditions is not required.
• 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.
• 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.

Sponsors & Collaborators

• Nantes University Hospital: lead
• AstraZeneca: collaborator

Study Sites (17)

CHU d'ANGERS

Angers, 49033, France

Location

Crlcc Francois Baclesse

Caen, 14000, France

Location

CH de Cholet

Cholet, 49300, France

Location

C H I Créteil

Créteil, 94000, France

Location

CHD Vendée

La Roche-sur-Yon, 85925, France

Location

Chu Grenoble

La Tronche, 38700, France

Location

CH Le Mans

Le Mans, 72000, France

Location

Hôpital Calmette CHRU de Lille

Lille, 59037, France

Location

AP-HM Hôpital Nord Marseille

Marseille, 13915, France

Location

CH DU MOENCHSBERG - Hôpital Emile Muller

Mulhouse, 68051, France

Location

CHU de Nantes

Nantes, 44000, France

Location

Institut Curie

Paris, 75005, France

Location

AP-HP Hôpital Tenon

Paris, 75970, France

Location

Chru Pontchaillou

Rennes, 35033, France

Location

Chru Strasbourg

Strasbourg, 67091, France

Location

Chits Ch Sainte Musse

Toulon, 83056, France

Location

Chu Tours

Tours, 37044, France

Location

Related Publications (1)

• Bennouna J, Girard N, Audigier-Valette C, le Thuaut A, Gervais R, Masson P, Marcq M, Molinier O, Cortot A, Debieuvre D, Cadranel J, Lena H, Moro-Sibilot D, Chouaid C, Mennecier B, Urban T, Sagan C, Perrier L, Barlesi F, Denis MG. Phase II Study Evaluating the Mechanisms of Resistance on Tumor Tissue and Liquid Biopsy in Patients With EGFR-mutated Non-pretreated Advanced Lung Cancer Receiving Osimertinib Until and Beyond Radiologic Progression: The MELROSE Trial. Clin Lung Cancer. 2020 Jan;21(1):e10-e14. doi: 10.1016/j.cllc.2019.09.007. Epub 2019 Oct 1.

  PMID: 31648999 DERIVED

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

osimertinib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Jaafar BENNOUNA, MD,PhD

  Nantes University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 27, 2019
• First Posted: March 7, 2019
• Study Start: April 9, 2019
• Primary Completion: January 1, 2025
• Study Completion: January 1, 2025
• Last Updated: February 28, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

FR (17)