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

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ClinicalTrials.gov Identifier: NCT02759835
Recruitment Status : Recruiting
First Posted : May 3, 2016
Last Update Posted : April 11, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief 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 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.


Condition or disease Intervention/treatment Phase
Lung Adenocarcinoma Lung Neoplasms Drug: osimertinib Other: LAT Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : April 13, 2016
Estimated Primary Completion Date : February 1, 2021
Estimated Study Completion Date : September 1, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
Drug Information available for: Osimertinib

Arm Intervention/treatment
Experimental: Arm 1
osimertinib followed by LAT followed by osimertinib
Drug: osimertinib
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.

Other: LAT
local ablative therapy. Subjects may undergo 1 of 3 local ablative procedures after initial progression on osimertinib: surgery, radiotherapy, radiofrequency ablation

Experimental: Arm 2
LAT followed by osimertinib
Drug: osimertinib
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.

Other: LAT
local ablative therapy. Subjects may undergo 1 of 3 local ablative procedures after initial progression on osimertinib: surgery, radiotherapy, radiofrequency ablation




Primary Outcome Measures :
  1. determine PFS in patients with oligoprogressive disease after treatment with LAT followed by osimertinib [ Time Frame: progression of disease ]
    progression-free survival (PFS)

  2. 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) [ Time Frame: progression of disease ]
    time to second progression (PFS2)


Secondary Outcome Measures :
  1. response rate [ Time Frame: end of treatment ]
    response rate

  2. overall survival [ Time Frame: death ]
    overall survival

  3. feasibility of evaluating EGFR mutation status using liquid biopsies [ Time Frame: end of treatment ]
    EGFR mutation status using liquid biopsies



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02759835


Contacts
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Contact: Elizabeth Q Akoth (240) 858-3154 elizabeth.akoth@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Udayan Guha, M.D. National Cancer Institute (NCI)

Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02759835     History of Changes
Other Study ID Numbers: 160092
16-C-0092
First Posted: May 3, 2016    Key Record Dates
Last Update Posted: April 11, 2019
Last Verified: March 22, 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
EGFR Tyrosine Kinase Inhibitors
T790M Mutation
Local Ablative Therapies
Oligoprogressive Disease
Acquired Resistance

Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Adenocarcinoma
Lung Neoplasms
Adenocarcinoma of Lung
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Osimertinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action