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Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Osimertinib

Mitogens

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Cohort 1 - Osimertinib followed by LAT followed by osimertinib. Single daily dose of osimertinib until progression. The starting dose of osimertinib will be 80 mg per day for participants without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline.

\*including germline T790M mutation

Cohort 2 - Osimertinib followed by LAT followed by osimertinib. Participants may undergo 1 of 3 local ablative procedures after initial progression on osimertinib: surgery, radiotherapy, or radiofrequency ablation.

Cohort 3 - LAT followed by Osimertinib. Participants may undergo 1 of 3 local ablative procedures after initial progression on Osimertinib: surgery, radiotherapy, radiofrequency ablation. The starting dose of Osimertinib will be 80 mg per day for participants without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline. Single daily dose of Osimertinib until progression.

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.

osimertinib

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

Local Ablative Therapy (LAT)

Azam Ghafoor, M.D.

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.

Background:

* Epidermal growth factor receptor (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 in patients treated with 1st and 2nd generation EGFR-TKIs is the emergence of a secondary mutation (T790M) in exon 20.
* Osimertinib is a 3rd-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. One common mechanism of acquired resistance to osimertinib is the generation of EGFR C797S mutation.
* The use of local ablative therapies for patients who develop limited metastatic disease or oligoprogressive disease on EGFR-TKI therapy is promising.
* We hypothesize that following local ablative therapy to treat oligoprogressive disease after emergence of resistance, osimertinib can be resumed safely and re-initiation of osimertinib results in additional progression-free survival benefits.

Objectives:

* Determine the safety, tolerability, and efficacy (as assessed by progression free survival (PFS) upon 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 circulating tumor deoxyribonucleic acid (ctDNA) analysis using a Clinical Laboratory Improvement Amendments of 1988 (CLIA) certified assay.
* Presence of measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
* Eastern Cooperative Oncology Group (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 physician's discretion. These patients may also be considered for other clinical trials.

Design:

* This is a single-institution, open-label phase II trial of osimertinib treatment in EGFR mutant lung cancer.
* 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.

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

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)

All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

PFS1 = time from initiation of osimertinib to first progression of disease or clinical progression, or death any cause. Progression was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and reported using the Kaplan Meier curve. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progression).

PFS2 = time from osimertinib re-challenge after LAT following first progression on osimertinib until second progression on osimertinib. Progression was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and reported using the Kaplan Meier curve. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progression).

Adverse events were assessed by the by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse events.

Whole-exome sequencing (WES), targeted sequencing and ribonucleic acid (RNA)-seq was performed on tumors to identify Osimertinib acquired resistant mechanisms. Sequencing can help identify mutations/heterogeneity that may impact a participant prognosis.

Whole-exome sequencing (WES), targeted sequencing and ribonucleic acid (RNA)-seq was performed on tumors for first and second line Osimertinib treatment to identify Osimertinib acquired resistant mechanisms. Sequencing can help identify mutations (i.e., NE-differentiation, ribonucleic acid (RNA), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), other amps, etc.)/heterogeneity that may impact a participant prognosis.

Best Overall Response is defined as a Complete Response (CR) + Partial Response (PR) and is recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The participant's best response assignment will depend on the achievement of both measurement and confirmation criteria. Response was evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete Response (CR) is disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. Any pathological lymph nodes must have reduction in short axis to \<10 mm. Partial Response (PR) is at least a 30% decrease in the sum of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions.

Overall survival is defined as the duration of time from start of treatment to death from any cause.

DCR is defined as a Complete Response (CR) + Partial Response (PR) + Stable Disease (SD). Response was evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete Response (CR) is disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. Any pathological lymph nodes must have reduction in short axis to \<10 mm. Partial Response (PR) is at least a 30% decrease in the sum of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD), taking as reference the smallest sum diameters while on study. PD is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progression.

National Cancer Institute (NCI)

Principal Investigator

COHORT 1: Osimertinib followed by LAT followed by osimertinib. Single daily dose of Osimertinib until progression. The starting dose of Osimertinib will be 80 mg per day for participants without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline. Participants may undergo 1 of 3 local ablative procedures after initial progression on Osimertinib: surgery, radiotherapy, radiofrequency ablation.

\*including germline T790M mutation

Tyrosine Kinase Inhibitor Naïve Epidermal Growth Factor Receptor *Mutated Non Small Cell Lung Cancer

Cohort 2 - Osimertinib followed by LAT followed by osimertinib. Participants may undergo 1 of 3 local ablative procedures after initial progression on osimertinib: surgery, radiotherapy, or radiofrequency ablation. The starting dose of Osimertinib will be 80 mg per day for participants without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline. Single daily dose of Osimertinib until progression.

EGFR Mutated NSCLC Progressed on Prior 1st/2nd Generation EGFR TKI Therapy &Acquired T790M Mutation

Epidermal Growth Factor Receptor Mutated Non Small Cell Lung Cancer Progressed on Osimertinib

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Azam Ghafoor

All Participants in Cohort 1

All Participants in Cohort 2

Cohort 3 is not applicable for this outcome measure because these participants enrolled in the study after getting Osimertinib at an outside institution. One participant in Cohort 1 was not evaluable.

Progression Free Survival 1 (PFS 1) for ALL Participants Who Started Osimertinib on Trial Until First Progression of Disease or Clinical Progression, or Death Any Cause

COHORT 1: Osimertinib followed by LAT followed by osimertinib. Single daily dose of Osimertinib until progression. The starting dose of Osimertinib will be 80 mg per day for participants without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline. Participants may undergo 1 of 3 local ablative procedures after initial progression on Osimertinib: surgery, radiotherapy, radiofrequency ablation.

\*including germline T790M mutation

Cohort 2 - Osimertinib followed by LAT followed by osimertinib. Participants may undergo 1 of 3 local ablative procedures after initial progression on osimertinib: surgery, radiotherapy, or radiofrequency ablation. The starting dose of Osimertinib will be 80 mg per day for participants without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline. Single daily dose of Osimertinib until progression.

Cohort 3 - LAT followed by Osimertinib. Participants may undergo 1 of 3 local ablative procedures after initial progression on Osimertinib: surgery, radiotherapy, radiofrequency ablation. The starting dose of Osimertinib will be 80 mg per day for participants without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline. Single daily dose of Osimertinib until progression.

All Participants in Cohorts 1, 2, and 3

Progression Free Survival 2 (PFS 2) - Local Ablative Therapy (LAT Eligible Only)

This outcome measure reports data for LAT eligible participants only.

Progression Free Survival 2 (PFS 2) - Local Ablative Therapy (LAT Eligible Only) - Cohort 1, Cohort 2, and Cohort 3

Anemia - Possibly Related

Lung Infection - Possibly Related

Peripheral Sensory Neuropathy Possibly Related

Pleural Effusion - Possibly Related

Thromboembolic Event - Definitely Related

Serious Adverse Events Possibly, Probably, and/or Definitely Related to Treatment

Abdominal pain - Grade 3

Alanine aminotransferase increased - Grade 1

Alanine aminotransferase - increased - Grade 2

Alanine aminotransferase - increased - Grade 3

Alkaline phosphatase increased - Grade 1

Anemia -Grade 1

Anemia - Grade 2

Anorexia - Grade 1

Arthralgia - Grade 2

Aspartate aminotransferase increased - Grade 1

Aspartate aminotransferase increased - Grade 2

Aspartate aminotransferase increased - Grade 3

Atelectasis - Grade 1

Bloating - Grade 2

Blurred vision - Grade 1

CPK increased - Grade 2

Cough - Grade 1

Cough - Grade 2

Dizziness - Grade 1

Dry mouth - Grade 1

Dysgeusia - Grade 1

Dyspnea - Grade 1

Dyspnea - Grade 2

Electrocardiogram QT corrected interval prolonged - Grade 2

Eyelid function disorder - Grade 1

Fall - Grade 1

Fever - Grade 1

Hypokalemia - Grade 1

Hypophosphatemia - Grade 2

Hypophosphatemia - Grade 3

Hypotension - Grade 1

Hypotension - Grade 2

Hypoxia - Grade 3

Localized edema - Grade 1

Lymphocyte count decreased - Grade 2

Lymphocyte count decreased - Grade 3

Muscle weakness upper limb - Grade 1

Muscle weakness lower limb - Grade 2

Muscle weakness lower limb - Grade 3

Nausea - Grade 1

Non-cardiac chest pain - Grade 1

Non-cardiac chest pain - Grade 2

Pain - Grade 1

Pain - Grade 2

Pain - Grade 3

Pain in extremity - Grade 2

Paresthesia - Grade 1

Pericardial effusion - Grade 2

Peripheral sensory neuropathy - Grade 1

Pleural effusion - Grade 1

Pleural effusion - Grade 2

Pleural effusion - Grade 3

Pneumothorax - Grade 1

Pneumothorax - Grade 2

Respiratory, thoracic and mediastinal disorders - Other, Hydropneumothorax - Grade 1

Respiratory, thoracic and mediastinal disorders - Hydropneumothorax - Grade 2

Respiratory, thoracic and mediastinal disorders - Other, Subcutaneous emphysema - Grade 1

Sore throat - Grade 1

Sinus tachycardia - Grade 2

Surgical and medical procedures - Other, incision site pain - Grade 1

Surgical and medical procedures - Other, incision site pain - Grade 2

Tinnitus - Grade 1

Urinary retention - Grade 2

Vomiting - Grade 2

Wheezing - Grade 1

Wheezing - Grade 2

COHORT 1: Osimertinib followed by LAT followed by osimertinib. Single daily dose of Osimertinib until progression. The starting dose of Osimertinib will be 80 mg per day for participants without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline. Participants may undergo 1 of 3 local ablative procedures after initial progression on Osimertinib: surgery, radiotherapy, radiofrequency ablation.

\*including germline T790M mutation

Adverse events possibly related to LAT.

Cohort 1: Possibly Related

COHORT 1: Osimertinib followed by LAT followed by osimertinib. Single daily dose of Osimertinib until progression. The starting dose of Osimertinib will be 80 mg per day for participants without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline. Participants may undergo 1 of 3 local ablative procedures after initial progression on Osimertinib: surgery, radiotherapy, radiofrequency ablation.

\*including germline T790M mutation

Adverse events probably related to LAT.

Cohort 1: Probably Related

COHORT 1: Osimertinib followed by LAT followed by osimertinib. Single daily dose of Osimertinib until progression. The starting dose of Osimertinib will be 80 mg per day for participants without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline. Participants may undergo 1 of 3 local ablative procedures after initial progression on Osimertinib: surgery, radiotherapy, radiofrequency ablation.

\*including germline T790M mutation.

Adverse events definitely related to LAT.

Cohort 1: Definitely Related

Cohort 2 - Osimertinib followed by LAT followed by osimertinib. Participants may undergo 1 of 3 local ablative procedures after initial progression on osimertinib: surgery, radiotherapy, or radiofrequency ablation. The starting dose of Osimertinib will be 80 mg per day for participants without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline. Single daily dose of Osimertinib until progression.

Adverse events possibly related to LAT.

Cohort 2: Possibly Related

Cohort 2 - Osimertinib followed by LAT followed by osimertinib. Participants may undergo 1 of 3 local ablative procedures after initial progression on osimertinib: surgery, radiotherapy, or radiofrequency ablation. The starting dose of Osimertinib will be 80 mg per day for participants without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline. Single daily dose of Osimertinib until progression.

Adverse events probably related to LAT.

Cohort 2: Probably Related

Cohort 2 - Osimertinib followed by LAT followed by osimertinib. Participants may undergo 1 of 3 local ablative procedures after initial progression on osimertinib: surgery, radiotherapy, or radiofrequency ablation. The starting dose of Osimertinib will be 80 mg per day for participants without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline. Single daily dose of Osimertinib until progression.

Adverse events definitely related to LAT.

Cohort 2: Definitely Related

Cohort 3 - LAT followed by Osimertinib. Participants may undergo 1 of 3 local ablative procedures after initial progression on Osimertinib: surgery, radiotherapy, radiofrequency ablation. The starting dose of Osimertinib will be 80 mg per day for participants without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline. Single daily dose of Osimertinib until progression.

Adverse events possibly related to LAT.

Cohort 3: Possibly Related

Cohort 3 - LAT followed by Osimertinib. Participants may undergo 1 of 3 local ablative procedures after initial progression on Osimertinib: surgery, radiotherapy, radiofrequency ablation. The starting dose of Osimertinib will be 80 mg per day for participants without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline. Single daily dose of Osimertinib until progression.

Adverse events probably related to LAT.

Cohort 3: Probably Related

Cohort 3 - LAT followed by Osimertinib. Participants may undergo 1 of 3 local ablative procedures after initial progression on Osimertinib: surgery, radiotherapy, radiofrequency ablation. The starting dose of Osimertinib will be 80 mg per day for participants without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline. Single daily dose of Osimertinib until progression.

Adverse events definitely related to LAT.

Cohort 3: Definitely Related

All Grades 1, Grade 2, Grade 3, Grade 4, and/or Grade 5 Adverse Events Possibly, Probably, and/or Definitely Related to Local Ablative Therapy (LAT)

Alanine aminotransferase increased - Grade 3

Alopecia - Grade 1

Anemia - Grade 1

Anemia - Grade 1*

Anemia - Grade 3

Arthralgia - Grade 1

Bloating - Grade 1

Blurred vision - Grade 1*

Buttock pain - Grade 1

CPK increased - Grade 1

CPK increased - Grade 3

CPK increased - Grade 4

Constipation - Grade 1

Diarrhea - Grade 1

Diarrhea - Grade 2

Dry eye - Grade 1

Dry skin - Grade 1

Dry skin - Grade 2

Dyspepsia - Grade 1

Dyspepsia - Grade 2

Edema face - Grade 1

Edema limbs - Grade 1

Electrocardiogram QT corrected interval prolonged - Grade 1

Electrocardiogram QT corrected interval prolonged - Grade 2*

Esophagitis - Grade 2

Eye pain - Grade 1

Fatigue - Grade 1

Fatigue - Grade 2

Floaters - Grade 1

Gastritis - Grade 2

Gastroesophageal reflux disease - Grade 1

Gastroesophageal reflux disease - Grade 2

Gastrointestinal disorders - Other, stomatitis - Grade 1

Gastrointestinal disorders - Other, stomatitis - Grade 2

Headache - Grade 1

Headache - Grade 2

Hyperglycemia - Grade 2

\*Because this adverse event has attribution to local ablative therapy (LAT) as well.

All Grades 1, Grade 2, Grade 3, Grade 4, and/or Grade 5 Adverse Events Possibly, Probably, and/or Definitely Related to Osimertinib

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Local Ablative Therapy for Treatment of Oligoprogressive, EGFR-Mutated, Non-Small Cell Lung Cancer After Treatment With Osimertinib	NCT02759835	Lung Adenocarci... Lung Neoplasms	osimertinib Local Ablative ...	18 Years -	National Institutes of Health Clinical Center (CC)
Local Ablative Therapy for Treatment of Oligoprogressive, EGFR-Mutated, Non-Small Cell Lung Cancer After Treatment With Osimertinib	NCT02759835	Lung Adenocarci... Lung Neoplasms	osimertinib Local Ablative ...	18 Years -	National Institutes of Health Clinical Center (CC)
Longitudinal Study of Local Ablative Therapy in Oligometastatic Disease	NCT06356779	Oligometastatic... Metastases Ablation Techni... Radiotherapy Stereotactic Ra... Surgery	Local ablative ...	18 Years -	Herlev Hospital

Spots Global Cancer Trial Database for local ablative therapy (lat)