Clinical Trials /

Local Ablative Therapy for Treatment of Oligoprogressive, EGFR-Mutated, Non-Small Cell Lung Cancer After Treatment With Osimertinib

NCT02759835

Description:

Background: Some non-small-cell lung cancers (NSCLC) have a mutation in a gene that makes a protein called EGFR. This particular cancer can be treated with certain drugs such as Erlotinib (Tarceva), Gefitinib (Iressa) and Osimertinib (Tagrisso). But many tumors become resistant to these drugs because of a second mutation. Researchers want to test if adding local ablative therapy (LAT) extends the benefits of the drug, Osimertinib. LAT can include techniques such as surgery, radiofrequency ablation, cryotherapy or radiation therapy. Objective: To test if re-taking osimertinib after LAT is safe, tolerable, and effective for people whose NSCLC has progressed after initial treatment with osimertinib. Eligibility: Adults ages 18 and older with certain types of NSCLC. Participants will be divided into various groups as described below. Design: Participants will be screened with: Medical history Physical exam Blood, urine, and heart tests Tumor scans Eye exam Review of tumor sample. Participants will take the study drug by mouth once a day. They will continue until they can no longer tolerate it or their disease worsens. They will keep a dosage diary. All participants will start each 21-day course with physical exam; blood, urine, and saliva tests; and electrocardiogram. They will have scans every 6 weeks and echocardiogram every 3 months. Groups 1 and 2 will: Start osimertinib right away. Have LAT if their disease gets worse and is suitable for LAT. If LAT cannot be performed or LAT consists of a procedure other than surgery, a tumor biopsy will be performed. Re-start osimertinib after LAT, or other treatments if not suitable for LAT. Group 3 will: Have LAT. If LAT consists of a procedure other than surgery, a tumor biopsy will be performed. Start osimertinib after LAT. After participants stop taking the drugs, they will have a final visit. This will include: Medical history Physical exam Heart and blood tests Participants will be called every year for follow-up.

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

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Local Ablative Therapy for Treatment of Oligoprogressive, EGFR-Mutated, Non-Small Cell Lung Cancer After Treatment With Osimertinib
  • Official Title: A Pilot Study of Local Ablative Therapy for Treatment of Oligoprogressive, EGFR-mutated, Non-Small Cell Lung Cancer (NSCLC) After Treatment With Osimertinib (AZD9291, Tagrisso)

Clinical Trial IDs

  • ORG STUDY ID: 160092
  • SECONDARY ID: 16-C-0092
  • NCT ID: NCT02759835

Conditions

  • Lung Adenocarcinoma
  • Lung Neoplasms

Interventions

DrugSynonymsArms
osimertinibArm 1

Purpose

Background: Some non-small-cell lung cancers (NSCLC) have a mutation in a gene that makes a protein called EGFR. This particular cancer can be treated with certain drugs such as Erlotinib (Tarceva), Gefitinib (Iressa) and Osimertinib (Tagrisso). But many tumors become resistant to these drugs because of a second mutation. Researchers want to test if adding local ablative therapy (LAT) extends the benefits of the drug, Osimertinib. LAT can include techniques such as surgery, radiofrequency ablation, cryotherapy or radiation therapy. Objective: To test if re-taking osimertinib after LAT is safe, tolerable, and effective for people whose NSCLC has progressed after initial treatment with osimertinib. Eligibility: Adults ages 18 and older with certain types of NSCLC. Participants will be divided into various groups as described below. Design: Participants will be screened with: Medical history Physical exam Blood, urine, and heart tests Tumor scans Eye exam Review of tumor sample. Participants will take the study drug by mouth once a day. They will continue until they can no longer tolerate it or their disease worsens. They will keep a dosage diary. All participants will start each 21-day course with physical exam; blood, urine, and saliva tests; and electrocardiogram. They will have scans every 6 weeks and echocardiogram every 3 months. Groups 1 and 2 will: Start osimertinib right away. Have LAT if their disease gets worse and is suitable for LAT. If LAT cannot be performed or LAT consists of a procedure other than surgery, a tumor biopsy will be performed. Re-start osimertinib after LAT, or other treatments if not suitable for LAT. Group 3 will: Have LAT. If LAT consists of a procedure other than surgery, a tumor biopsy will be performed. Start osimertinib after LAT. After participants stop taking the drugs, they will have a final visit. This will include: Medical history Physical exam Heart and blood tests Participants will be called every year for follow-up.

Detailed Description

      Background:

        -  EGFR tyrosine kinase inhibitors (TKI) have significantly improved the response rate (RR)
           and survival in patients with tumors harboring EGFR-sensitizing mutations.

        -  An invariable consequence of treatment with EGFR-TKIs is the development of acquired
           resistance. The most common mechanism of resistance observed in approximately 50% of all
           cases is the emergence of a secondary mutation (T790M) in exon 20.

        -  Osimertinib is a third-generation EGFR-TKI designed to target the T790M mutation, which
           has shown impressive responses in both first- and second-line settings.

        -  Despite these developments, it is almost certain that selection pressure will lead to
           the emergence of newer clones that are resistant to treatment with osimertinib. In fact,
           a newly identified EGFR mutation (C797S) that results in acquired resistance to
           osimertinib has been reported recently.

        -  The use of local ablative therapies for patients who develop limited metastatic disease
           oligoprogressive disease) on EGFR-TKI therapy is promising.

        -  We hypothesize that following local ablative therapy to treat oligoprogressive disease
           after emergence of resistance to AZD9291, osimertinib can be resumed safely and
           reinitiation of osimertinib results in additional progression-free survival benefits.

      Objectives:

        -  Determine the safety, tolerability, and efficacy (as assessed by PFS) of re-initiation
           of osimertinib following local ablative therapy (LAT) for patients with oligoprogressive
           disease after treatment with osimertinib

        -  Assess mechanisms of acquired resistance to osimertinib

      Eligibility:

        -  Histologically confirmed advanced lung adenocarcinoma with EGFR-sensitizing somatic
           mutations or a germline T790M mutation and no prior EGFR tyrosine kinase inhibitor (TKI)
           therapy (Cohort 1); OR progressive disease after 1st or 2nd generation EGFR TKI therapy
           harboring somatic T790M mutation (Cohort 2); or patients with progressive disease after
           treatment with osimertinib who are eligible for local ablative therapy (Cohort 3). If
           biopsy for EGFR mutation status confirmation is not clinically feasible, EGFR mutations
           may be confirmed by ctDNA analysis using a CLIA certified assay.

        -  Presence of measurable disease per RECIST version 1.1

        -  ECOG performance status 0-2

        -  Adequate end organ function

        -  If patients are not eligible for LAT, they will be referred for standard of care
           chemotherapy as per treating physicians discretion. These patients may also be
           considered for other clinical trials.

      Design:

        -  This is a single-institution, open-label phase II trial of osimertinib.

        -  Eligible patients not previously treated with osimertinib will be treated with
           osimertinib daily until disease progression. At the time of progression, patients with
           oligoprogressive disease (no more than 5 sites of progressive disease) will be assessed
           for LAT.

        -  If patients are eligible for LAT, osimertinib will be resumed after LAT and they will be
           followed for second progression on osimertinib (PFS2).

        -  If patients progress at the same site where LAT has been performed before, the
           progression will be considered to be a result of inadequate ablation and they will be
           considered for repeat LAT and again re-challenged with osimertinib if clinically
           feasible.

        -  Tumor samples will be obtained at baseline by a mandatory biopsy. At the time of first
           progression on osimertinib if a patient is eligible for surgery as a form of LAT, then a
           tissue sample will be obtained for genomic and proteomic studies to identify mechanisms
           of acquired resistance. For patients who are not eligible for LAT or a form of LAT that
           is not surgery (radiation, radiofrequency ablation, cryoablation), then a mandatory
           biopsy will be performed, if clinically safe, to obtain tissue for above studies.

        -  Re-treatment will be allowed for a small number of subjects.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1Experimentalosimertinib followed by LAT followed by osimertinib
  • osimertinib
Arm 2ExperimentalLAT followed by osimertinib
  • osimertinib

Eligibility Criteria

        -  INCLUSION CRITERIA:

        For inclusion in the study subjects should fulfill the following criteria:

          -  Provision of informed consent prior to any study specific procedures

          -  Patients (male/female) must be greater than or equal to 18 years of age.

          -  Patients with histologically confirmed, by the NCI Laboratory of Pathology or by
             CLIA-certified Next Generation Sequencing or cobas EGFR Mutation Test v1/2 at an
             outside institution, advanced lung adenocarcinoma with EGFR-sensitizing somatic
             mutations or a germline T790M mutation (detected histologically or via ctDNA analysis
             using a CLIA assay) with:

               -  No prior EGFR tyrosine kinase inhibitor (TKI) therapy (Cohort 1)

        OR

        -- Progressive disease after 1st or 2nd generation EGFR TKI therapy harboring somatic T790M
        mutation (Cohort 2)

        OR

          -  Progressive disease after treatment with osimertinib who are eligible for local
             ablative therapy (Cohort 3)

               -  Presence of measurable disease per RECIST version 1.1.

               -  In patients with suspected leptomeningeal disease, the diagnosis of
                  leptomeningeal disease should be confirmed by the presence of neurological or
                  imaging signs and/or positive CSF cytology.

               -  ECOG performance status 0-2.

               -  No uncontrolled arrhythmia; no myocardial infarction in the last 6 months.

               -  Females should not be breast feeding and must have a negative pregnancy test
                  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 sterilization by hysterectomy, bilateral
             oophorectomy or bilateral salpingectomy but not tubal ligation

               -  Females of child-bearing potential should use reliable methods of contraception
                  from the time of screening until 3 months after discontinuing osimertinib.
                  Acceptable methods of contraception include total and true sexual abstinence,
                  tubal ligation, hormonal contraceptives that are not prone to drug-drug
                  interactions (IUS Levonorgestrel Intra Uterine System (Mirena),
                  Medroxyprogesterone injections (Depo-Provera), copper-banded intra-uterine
                  devices, and vasectomized partner. All hormonal methods of contraception should
                  be used in combination with the use of a condom by their male sexual partner for
                  intercourse.

               -  Male patients should be willing to use barrier contraception. Male patients
                  should be asked to use barrier contraceptives (i.e., by use of condoms) during
                  sex with all of their female partners during the trial and for a washout period
                  of 3 months. Patients should refrain from donating sperm from the start of dosing
                  until 6 months after discontinuing osimertinib treatment. If male patients wish
                  to father children they should be advised to arrange for freezing of sperm
                  samples prior to the start of osimertinib treatment.

               -  Patient is willing and able to comply with the protocol for the duration of the
                  study including undergoing treatment and scheduled visits and examinations
                  including follow up.

        EXCLUSION CRITERIA:

        Subjects should not enter the study if any of the following exclusion criteria are
        fulfilled:

          -  Any unresolved toxicities from prior therapy greater than Common Terminology Criteria
             for Adverse Events (CTCAE) grade 1 at the time of starting study treatment with the
             exception of alopecia and grade 2, prior platinum-therapy related neuropathy.

          -  Treatment with an investigational drug within five half-lives of the compound.

          -  Major thoracic or abdominal surgery from which the patient has not sufficiently
             recovered yet.

          -  Untreated and uncontrolled second tumor in the past 2 years.

          -  Patients currently receiving (or unable to stop use prior to receiving the first dose
             of study treatment) medications or herbal supplements known to be potent inhibitors of
             CYP3A4 (at least 1 week prior) and potent inducers of CYP3A4 (at least 3 week prior)
             will only be eligible at the PI s discretion.

          -  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 jeopardize
             compliance with the protocol. Screening for chronic conditions is not required.

          -  Patients with CNS metastases who are neurologically unstable.

          -  Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation
             pneumonitis requiring 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 <1 x 10(9)/L

               -  Platelet count <100 x 10(9)/L

               -  Hemoglobin <90 g/L

               -  Alanine aminotransferase >2.5 times the 2.1.2.9.4 upper limit of normal (ULN) if
                  no demonstrable liver metastases or >5 times ULN in the presence of liver
                  metastases

               -  Aspartate aminotransferase >2.5 times ULN if no demonstrable liver metastases or
                  >5 times ULN in the presence of liver metastases

               -  Total bilirubin >1.5 times ULN if no liver metastases or >3 times ULN in the
                  presence of documented Gilbert s Syndrome (unconjugated hyperbilirubinemia) or
                  liver metastases

               -  Creatinine >1.5 times ULN concurrent with creatinine clearance <30 ml/min
                  (measured or calculated by Cockcroft and Gault equation); confirmation of
                  creatinine clearance is only required when creatinine is >1.5 times ULN

          -  Any of the following cardiac criteria

               -  Resting corrected QT interval (QTc using Fredericia s formula) > 480 msec

               -  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)

               -  Any factors that increase the risk of QTc prolongation or risk of arrhythmic
                  events such as heart failure, hypokalemia, 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

               -  Significant symptomatic congestive heart failure, per PI judgement.

          -  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 osimertinib (or drugs with a similar chemical structure
             or class to osimertinib) or any excipients of these agents

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:determine PFS in patients with oligoprogressive disease after treatment with LAT followed by osimertinib
Time Frame:progression of disease
Safety Issue:
Description:progression-free survival (PFS)

Secondary Outcome Measures

Measure:response rate
Time Frame:end of treatment
Safety Issue:
Description:response rate
Measure:overall survival
Time Frame:death
Safety Issue:
Description:overall survival
Measure:feasibility of evaluating EGFR mutation status using liquid biopsies
Time Frame:end of treatment
Safety Issue:
Description:EGFR mutation status using liquid biopsies

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • EGFR Tyrosine Kinase Inhibitors
  • T790M Mutation
  • Local Ablative Therapies
  • Oligoprogressive Disease
  • Acquired Resistance

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