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:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Local Ablative Therapy for Treatment of Oligoprogressive, <span class="go-doc-concept go-doc-biomarker">EGFR</span>-<span class="go-doc-concept go-doc-keyword">Mutated</span>, Non-Small Cell Lung Cancer After Treatment With <span class="go-doc-concept go-doc-intervention">Osimertinib</span>

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

    NCT ID: NCT02759835

    ORG ID: 160092

    NCI ID: 16-C-0092

    Trial Conditions

    Lung Adenocarcinoma

    Lung Neoplasms

    Trial Interventions

    Drug Synonyms Arms
    osimertinib cohort 1, cohort 2, cohort 3

    Trial 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 or progressive disease after 1st or 2nd generation EGFR TKI therapy
    harboring somatic T790M mutation.

    - Patients with acquired resistance to osimertinib and harboring EGFR T790M mutation.

    - Presence of measurable disease per RECIST version 1.1

    - ECOG performance status 0-2

    - Adequate end organ function

    - Patients with leptomeningeal disease, a second malignancy, or uncontrolled systemic
    diseases (hypertension, cardiac disease, diabetes) are excluded.

    Design:

    - This is a single-arm, 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.

    Trial Arms

    Name Type Description Interventions
    cohort 2 Experimental Patients with progressive disease after 1st or 2nd generation EGFR tyrosine kinase inhibitor therapy osimertinib
    cohort 1 Experimental Patients with EGFR sensitizing mutation or germline T790M mutation and no prior EGFR tyrosine kinase inhibitor therapy osimertinib
    cohort 3 Experimental Patients with acquired resistance to osimertinib amenable to local ablative therapy 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, 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

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

    - Presence of measurable disease per RECIST version 1.1, defined as at least one
    lesion, not previously irradiated, that can be accurately measured at baseline
    as greater than or equal to 10 mm in the longest diameter (except lymph nodes
    which must have short axis greater than or equal to 15 mm) with computed
    tomography (CT) or magnetic resonance imaging (MRI).

    - 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). All patients must avoid concomitant use of any medications, herbal
    supplements and/or ingestion of foods with known inducer/inhibitory effects on
    CYP3A4.

    - 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 symptomatic 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 < 1.5 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

    - Mean 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

    - Symptomatic congestive heart failure or LVEF< 50%

    - 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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: 100 Years

    Eligible Gender: Both

    Primary Outcome Measures

    determine PFS in patients with oligoprogressive disease after treatment with LAT followed by osimertinib

    Patients who progress on their initial treatment with osimertinib and receive LAT therapy (surgery, radiation therapy, or RFA) followed by osimertinib will be evaluated for their time to second progression (PFS2)

    Secondary Outcome Measures

    response rate

    overall survival

    feasibility of evaluating EGFR mutation status using liquid biopsies

    Trial Keywords

    EGFR Tyrosine Kinase Inhibitors

    T790M Mutation

    Local Ablative Therapies

    Oligoprogressive Disease

    Acquired Resistance