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

NCT02759835 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 16009216-C-0092
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 1

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 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.

Conditions

Lung Adenocarcinoma; Lung Neoplasms

Keywords

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

Outcome Measures

Primary Outcomes (8)

• 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

  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).

  Cycle 1 Day 1 (each cycle is 28 days) to progression of disease, range 36-1231 days

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

  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).

  Retreatment Cycle 1 Day 1 (cycle is 28 days) to progression of disease, range 29-721 days

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

  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).

  Retreatment Cycle 1 Day 1 (cycle is 28 days) to progression of disease, range 29-721 days

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

  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.

  Date treatment consent signed to date off study, approximately 74 months and 16 days, 65 months and 16 days, and 40 months and 4 days for the first, second and third group respectively.

• 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)

  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.

  Date treatment consent signed to date off study, approximately 74 months and 16 days, 65 months and 16 days, and 40 months and 4 days for the first, second and third group respectively.

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

  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.

  Date treatment consent signed to date off study, approximately 74 months and 16 days, 65 months and 16 days, and 40 months and 4 days for the first, second and third group respectively.

• Number of Participants Who Had Osimertinib Acquired Resistant Mechanisms Identified on Tumors

  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.

  up to 757 days

• Number of Participants Who Had Osimertinib Acquired Resistant Mechanisms Identified on Tumors With First Line and/or Second Line Treatment

  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.

  up to 757 days

Secondary Outcomes (5)

• Best Overall Response (BOR)

  end of treatment, up to 693 days

• Best Overall Response - All Participants

  end of treatment, up to 693 days

• Overall Survival

  Duration of time from start of treatment to death from any cause. An average of 35.95 months.

• Disease Control Rate (DCR)

  end of treatment, up to 693 days

• Disease Control Rate (DCR) - All Participants

  end of treatment, up to 693 days

Other Outcomes (1)

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)

  Date treatment consent signed to date off study, approximately 74 months and 16 days, 65 months and 16 days, and 40 months and 4 days for the first, second and third group respectively.

Study Arms (3)

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

EXPERIMENTAL

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

Drug: osimertinib; Other: Local Ablative Therapy (LAT)

EGFR mutated NSCLC Progressed on prior 1st/2nd Generation EGFR TKI therapy &acquired T790M Mutation

EXPERIMENTAL

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.

Drug: osimertinib; Other: Local Ablative Therapy (LAT)

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

EXPERIMENTAL

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.

Drug: osimertinib; Other: Local Ablative Therapy (LAT)

Interventions

osimertinib DRUG

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.

Also known as: Tagrisso

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

Local Ablative Therapy (LAT) OTHER

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

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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (2)

• Kim C, Xi L, Cultraro CM, Wei F, Jones G, Cheng J, Shafiei A, Pham TH, Roper N, Akoth E, Ghafoor A, Misra V, Monkash N, Strom C, Tu M, Liao W, Chia D, Morris C, Steinberg SM, Bagheri H, Wong DTW, Raffeld M, Guha U. Longitudinal Circulating Tumor DNA Analysis in Blood and Saliva for Prediction of Response to Osimertinib and Disease Progression in EGFR-Mutant Lung Adenocarcinoma. Cancers (Basel). 2021 Jul 3;13(13):3342. doi: 10.3390/cancers13133342.

  PMID: 34283064 RESULT

• Roper N, Brown AL, Wei JS, Pack S, Trindade C, Kim C, Restifo O, Gao S, Sindiri S, Mehrabadi F, El Meskini R, Ohler ZW, Maity TK, Venugopalan A, Cultraro CM, Akoth E, Padiernos E, Chen H, Kesarwala A, Smart DK, Nilubol N, Rajan A, Piotrowska Z, Xi L, Raffeld M, Panchenko AR, Sahinalp C, Hewitt S, Hoang CD, Khan J, Guha U. Clonal Evolution and Heterogeneity of Osimertinib Acquired Resistance Mechanisms in EGFR Mutant Lung Cancer. Cell Rep Med. 2020 Apr 21;1(1):100007. doi: 10.1016/j.xcrm.2020.100007.

  PMID: 32483558 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Adenocarcinoma of Lung; Lung Neoplasms

Interventions

osimertinib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases

Results Point of Contact

• Title: Azam Ghafoor
• Organization: National Cancer Institute

azam.ghafoor@nih.gov

240-858-3289

Study Officials

• Azam Ghafoor, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 6, 2016
• First Posted: May 3, 2016
• Study Start: April 13, 2016
• Primary Completion: May 25, 2022
• Study Completion: September 20, 2022
• Last Updated: June 7, 2024
• Results First Posted: July 25, 2023

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing Plan (GDS) plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.

Locations

US (1)