Local Ablative Therapy for Treatment of Oligoprogressive, EGFR-Mutated, Non-Small Cell Lung Cancer After Treatment With Osimertinib
Condition: Lung Adenocarcinoma; Lung Neoplasms
MeSH terms: Lung Neoplasms; Adenocarcinoma of Lung
Intervention: osimertinib; Local Ablative Therapy (LAT)
Intervention description: Single daily dose of osimertinib until progression. The starting dose of osimertinib will be 80 mg per day for patients without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline.; local ablative therapy. Subjects may undergo 1 of 3 local ablative procedures after initial progression on osimertinib: surgery, radiotherapy, radiofrequency ablation
Intervention MeSH terms: Osimertinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 37.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: EGFR Tyrosine Kinase Inhibitors; T790M Mutation; Local Ablative Therapies; Oligoprogressive Disease; Acquired Resistance

Summary:

      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 progresses 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

      Blood tests

      Participants will be called every year for follow-up.
    

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 National Cancer Institute (NCI)
             Laboratory of Pathology or by Clinical Laboratory Improvement Amendments of 1988
             (CLIA)-certified Next Generation Sequencing or Cobas estimated Epidermal Growth Factor
             Receptor (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 circulating tumor deoxyribonucleic acid (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 Response Evaluation Criteria in Solid Tumors
                  (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 cerebrospinal fluid (CSF) cytology.

               -  Eastern Cooperative Oncology Group (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 luteinizing Hormone (LH) and follicle stimulating hormone (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 cytochrome P450 3A4 (CYP3A4) (at
             least 3 weeks 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 central nervous system (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 (corrected QT interval (QTc) using Fredericia's
                  formula) > 480 msec

               -  Any clinically important abnormalities in rhythm, conduction or morphology of
                  resting electrocardiogram (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 principal investigator (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