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)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 37
- 试验地点
- 1
- 主要终点
- 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
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Tyrosine Kinase Inhibitor Naïve Epidermal Growth Factor Receptor *mutated Non Small Cell Lung Cancer
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
干预措施: osimertinib (Drug)
Tyrosine Kinase Inhibitor Naïve Epidermal Growth Factor Receptor *mutated Non Small Cell Lung Cancer
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
干预措施: Local Ablative Therapy (LAT) (Other)
EGFR mutated NSCLC Progressed on prior 1st/2nd Generation EGFR TKI therapy &acquired 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.
干预措施: osimertinib (Drug)
EGFR mutated NSCLC Progressed on prior 1st/2nd Generation EGFR TKI therapy &acquired 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.
干预措施: Local Ablative Therapy (LAT) (Other)
Epidermal Growth Factor Receptor mutated Non Small Cell Lung Cancer Progressed on Osimertinib
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.
干预措施: osimertinib (Drug)
Epidermal Growth Factor Receptor mutated Non Small Cell Lung Cancer Progressed on Osimertinib
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.
干预措施: Local Ablative Therapy (LAT) (Other)
结局指标
主要结局
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
时间窗: Cycle 1 Day 1 (each cycle is 28 days) to progression of disease, range 36-1231 days
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).
Progression Free Survival 2 (PFS 2) - Local Ablative Therapy (LAT Eligible Only)
时间窗: Retreatment Cycle 1 Day 1 (cycle is 28 days) to progression of disease, range 29-721 days
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).
Progression Free Survival 2 (PFS 2) - Local Ablative Therapy (LAT Eligible Only) - Cohort 1, Cohort 2, and Cohort 3
时间窗: Retreatment Cycle 1 Day 1 (cycle is 28 days) to progression of disease, range 29-721 days
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).
Serious Adverse Events Possibly, Probably, and/or Definitely Related to Treatment
时间窗: 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.
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.
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)
时间窗: 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.
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.
All Grades 1, Grade 2, Grade 3, Grade 4, and/or Grade 5 Adverse Events Possibly, Probably, and/or Definitely Related to Osimertinib
时间窗: 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.
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.
Number of Participants Who Had Osimertinib Acquired Resistant Mechanisms Identified on Tumors
时间窗: up to 757 days
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.
Number of Participants Who Had Osimertinib Acquired Resistant Mechanisms Identified on Tumors With First Line and/or Second Line Treatment
时间窗: up to 757 days
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.
次要结局
- Disease Control Rate (DCR) - All Participants(end of treatment, up to 693 days)
- 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)
研究者
Azam Ghafoor
Principal Investigator
National Cancer Institute (NCI)