Clinical Trials /

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

NCT03865511

Description:

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.

Related Conditions:
  • Lung Adenocarcinoma
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: MEchanisms of Resistance in EGFR Mutated Nonpretreated Advanced Lung Cancer Receiving OSimErtib
  • Official Title: MELROSE: Phase 2 Study Evaluating MEchanisms of Resistance on Tumor Tissue and Liquid Biopsy in Patients With EGFR Mutated Nonpretreated Advanced Lung Cancer Receiving OSimErtinib Until and Beyond Radiological Progression : the MELROSE Trial

Clinical Trial IDs

  • ORG STUDY ID: RC18_0287
  • NCT ID: NCT03865511

Conditions

  • Non-small Cell Lung Cancer

Interventions

DrugSynonymsArms
TAGRISSO® 80mg (Osimertinib)TAGRISSO® 80mg (Osimertinib)

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
TAGRISSO® 80mg (Osimertinib)ExperimentalOral 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.
  • TAGRISSO® 80mg (Osimertinib)

Eligibility Criteria

        Inclusion Criteria :

          1. Male or female, aged at least 18 years.

          2. Informed consent signed prior to any study specific procedures, sampling, and analyses.

          3. 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.

          4. Locally advanced or metastatic NSCLC (Non-small-cell lung carcinoma), not amenable to
             curative surgery or radiotherapy.

          5. 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.

          6. Patients must be treatment-naive for advanced NSCLC and eligible to receive first-line
             treatment with osimertinib

          7. Subjects affiliated to an appropriate health insurance

          8. 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.

          9. 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.

         10. 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.

         11. Male patients should be willing to use barrier contraception, i.e., condoms

        Exclusion Criteria :

          1. Involvement in the planning and/or conduct of the study (applies to both Investigator
             staff and/or staff at the study site)

          2. Previous enrolment in the present study

          3. 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.

          4. Any concurrent and/or other active malignancy that has required systemic treatment
             within 2 years of first dose of study drug.

          5. 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.

          6. 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.

          7. 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.

          8. 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.

          9. 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
                  first-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.

         10. Inadequate bone marrow reserve or organ function as demonstrated by any of the
             following laboratory values.

               -  Absolute neutrophil count <1.5 x 109/L.

               -  Platelet count <100 x 109/L.

               -  Haemoglobin <90 g/L.

               -  Alanine aminotransferase (ALT) >2.5x the upper limit of normal (ULN) if no
                  demonstrable liver metastases or >5 x ULN in the presence of liver metastases

               -  Aspartate aminotransferase (AST) >2.5 x ULN if no demonstrable liver metastases
                  or >5xULN in the presence of liver metastases.

               -  Total bilirubin >1.5 x ULN if no liver metastases or >3 x ULN in the presence of
                  documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver
                  metastases.

               -  Creatinine >1.5 x ULN concurrent with creatinine clearance <50 mL/min (measured
                  or calculated by Cockcroft and Gault equation); confirmation of creatinine
                  clearance is only required when creatinine is >1.5 x ULN.

         11. Women who are breast feeding

         12. History of hypersensitivity to active or inactive excipients of osimertinib or drugs
             with a similar chemical structure or class to osimertinib

         13. Judgment by the Investigator that the patient should not participate in the study if
             the patient is unlikely to comply with study procedures, restrictions, and
             requirements.

         14. Adults under a legal protection regime (guardianship, trusteeship, judicial safeguard)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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.
Time Frame:At clinical disease progression (approximately 22 months)
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Clinical objective : To assess efficacy of Osimertinib
Time Frame:Every 3 months up to one year after first study dose
Safety Issue:
Description:Progression free survival rate at one year defined by time from first study dose to first event between Radiological Progression Disease and death, or one year if no event. The rPFS is defined according to RECIST 1.1.
Measure:Clinical objective : To assess efficacy of Osimertinib
Time Frame:Every 3 months until radiological disease progression (approximately 22 months)
Safety Issue:
Description: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.
Measure:Clinical objective : To assess efficacy of Osimertinib
Time Frame:Every month until clinical disease progression (approximately 22 months)
Safety Issue:
Description:Clinical Progression Free Survival (cPFS): Time from first study dose to off-osimertinib.
Measure:Clinical objective : To assess efficacy of Osimertinib
Time Frame:From first dose to end of study or date of death from any cause, whicheever comes first, assessed every 3 months (approximately 48 months)
Safety Issue:
Description:Overall survival
Measure:Clinical objective : To assess efficacy of Osimertinib
Time Frame:every 3 months until radiological disease progression (approximately 22 months)
Safety Issue:
Description:Objective Response Rate (ORR)
Measure:Clinical objective : To assess efficacy of Osimertinib: Duration of Response (DoR): Disease Control Rate (DCR)
Time Frame:every 3 months until radiological disease progression (approximately 22 months)
Safety Issue:
Description:Duration of Response (DoR): Disease Control Rate (DCR)
Measure:Clinical objective : To assess safety of Osimertinib with Monitoring of Adverse events (grade 3 and 4)
Time Frame:monthly from first study dose until 15 days after last study dose
Safety Issue:
Description:Monitoring of Adverse events (grade 3 and 4)
Measure:Biological objective : To evaluate the consequence of osimertinib treatment on the expression of targets of immune check point inhibitors
Time Frame:At baseline and at clinical disease progression (approximately 22 months)
Safety Issue:
Description:By the study of the 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
Measure:Biological objective : To evaluate diagnostic accuracy of ctDNA to detect mutation
Time Frame:At baseline and monthly until clinical disease progression (approximately 22 months)
Safety Issue:
Description:Analyze of mutation at progression on tumor tissue and ctDNA
Measure:Biological objective : To observe if the presence of ctDNA at baseline is a prognostic factor of clinical progression disease
Time Frame:At baseline and monthly until clinical disease progression (approximately 22 months)
Safety Issue:
Description:Analyze of the presence of tumors ctDNA at baseline, clinical progression disease
Measure:Biological objective : To demonstrate that the early kinetics of ctDNA is an indicator of response to osimertinib
Time Frame:At baseline and monthly until clinical disease progression (approximately 22 months)
Safety Issue:
Description:Analyze of absolute quantities of ctDNA molecules presenting the EGFR mutation identified in the tumor, clinical progression disease
Measure:Biological objective : To measure the biological progression (bPFS) in patients treated with osimertinib
Time Frame:At baseline and monthly until clinical disease progression (approximately 22 months)
Safety Issue:
Description:Serial monitoring in ctDNA of molecular alterations identified in tissues collected at progression
Measure:Biological objective : To compare the genetic profile of the ctDNA and the tumor biopsy
Time Frame:At baseline and at clinical disease progression (approximately 22 months)
Safety Issue:
Description:Analyze of the EGFR mutation identified in the tumor biopsy and in the ctDNA
Measure:Biological objective : To compare the kinetic of appearance of EGFR mutation and radiological and clinical progression disease
Time Frame:At baseline and monthly until clinical disease progression (approximately 22 months)
Safety Issue:
Description:Analyze of the absolute quantities of ctDNA molecules presenting the EGFR mutation monthly, radiological and clinical progression disease

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Nantes University Hospital

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