Lung AdenocarcinomaPhase 2NCT02759835
Local Ablative Therapy for Treatment of Oligoprogressive, EGFR-Mutated, Non-Small Cell Lung Cancer After Treatment With Osimertinib
A Phase 2 study testing osimertinib and Local Ablative Therapy (LAT) in people with Lung Adenocarcinoma and Lung Neoplasms, run by National Cancer Institute (NCI) at 1 site in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Lung Adenocarcinoma, Lung Neoplasms
- What is being tested?
- osimertinib and Local Ablative Therapy (LAT)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 37 participants
- Where
- 1 siteUnited States
- Study dates
- 13 Apr 2016to 20 Sep 2022
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 20Show fewer
- -- 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.
Who cannot join
- 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.
Show all 25Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
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)
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.
Read more
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.
Read the detailed description
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.
- Conditions
- Lung Adenocarcinoma, Lung Neoplasms
- Being tested
- osimertinib, Local Ablative Therapy (LAT)
- Keywords
- EGFR Tyrosine Kinase Inhibitors, T790M Mutation, Local Ablative Therapies, Oligoprogressive Disease, Acquired Resistance
- Medical subject headings
- Adenocarcinoma of Lung, Lung Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
osimertinibDrug
Also called Tagrisso
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 (LAT)Other
local ablative therapy. Subjects may undergo 1 of 3 local ablative procedures after initial progression on osimertinib: surgery, radiotherapy, radiofrequency ablation
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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. Receives: 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. Receives: Drug: osimertinib; Other: Local Ablative Therapy (LAT) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 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).
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: up to 757 days
Secondary outcomes (5)
Best Overall Response (BOR)
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.
Measured: end of treatment, up to 693 days
Best Overall Response - All Participants
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.
Measured: end of treatment, up to 693 days
Overall Survival
Overall survival is defined as the duration of time from start of treatment to death from any cause.
Measured: Duration of time from start of treatment to death from any cause. An average of 35.95 months.
Disease Control Rate (DCR)
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.
Measured: end of treatment, up to 693 days
Disease Control Rate (DCR) - All Participants
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.
Measured: end of treatment, up to 693 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 May 2016 (estimated)
- Study start13 Apr 2016
- Primary completion25 May 2022
- Study completion20 Sep 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Lung AdenocarcinomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 37 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Azam Ghafoor, National Cancer Institute (NCI)
- Investigators
- Azam Ghafoor, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02759835
- Sponsor's protocol ID
- 160092
- Other IDs
- 16-C-0092
- Status last verified
- May 2024
- First submitted
- 6 Apr 2016
- Last updated
- 7 Jun 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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).
Publications
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.
PubMed 34283064Roper 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.
PubMed 32483558
Study at a glance
From the registry record, last updated by the sponsor on 7 Jun 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT02759835
- Acronym / sponsor ID
- 160092
- Conditions
- Lung Adenocarcinoma, Lung Neoplasms
- Keywords
- EGFR Tyrosine Kinase Inhibitors, T790M Mutation, Local Ablative Therapies, Oligoprogressive Disease, Acquired Resistance
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 37 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 13 Apr 2016 (actual)
- Primary completion
- 25 May 2022 (actual)
- Study completion
- 20 Sep 2022 (actual)
- First posted
- 3 May 2016 (estimated)
- Results
- Posted 25 Jul 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Tyrosine Kinase Inhibitor Naïve Epidermal Growth Factor Receptor *mutated Non Small Cell Lung Cancer | Experimental | Drug: osimertinib, Other: Local Ablative Therapy (LAT)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 |
| EGFR mutated NSCLC Progressed on prior 1st/2nd Generation EGFR TKI therapy &acquired T790M Mutation | Experimental | Drug: osimertinib, Other: Local Ablative Therapy (LAT)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. |
| Epidermal Growth Factor Receptor mutated Non Small Cell Lung Cancer Progressed on Osimertinib | Experimental | Drug: osimertinib, Other: Local Ablative Therapy (LAT)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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (20 listed)
- 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:
- OR
- -- Progressive disease after 1st or 2nd generation EGFR TKI therapy harboring somatic T790M mutation (Cohort 2)
Key exclusion criteria (25 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| osimertinibAlso: TagrissoSingle 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. | Drug | 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)local ablative therapy. Subjects may undergo 1 of 3 local ablative procedures after initial progression on osimertinib: surgery, radiotherapy, radiofrequency ablation | Other | 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 |
Primary outcome
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
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
5 secondary outcomes
Best Overall Response (BOR)
Time frame: end of treatment, up to 693 days
Best Overall Response - All Participants
Time frame: end of treatment, up to 693 days
Overall Survival
Time frame: Duration of time from start of treatment to death from any cause. An average of 35.95 months.
Disease Control Rate (DCR)
Time frame: end of treatment, up to 693 days
Disease Control Rate (DCR) - All Participants
Time frame: end of treatment, up to 693 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Jun 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 34283064Kim 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.
- Results publication: PubMed 32483558Roper 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.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. 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).
Related trials for Lung Adenocarcinoma
RecruitingPhase 1/2
Study of INBRX-106 and INBRX-106 in Combination With Pembrolizumab (Keytruda®) in Subjects With Locally Advanced or Metastatic Solid Tumors (Hexavalent OX40 Agonist)
Solid Tumor, Non-Small Cell Lung Cancer
Recruiting
The Vanguard Study: Testing a New Way to Screen for Cancer
Bladder Carcinoma, Breast Carcinoma
RecruitingObservational study
A Study to Evaluate Patient-Reported Satisfaction, Effectiveness, and Safety of Atezolizumab in Participants Treated in Routine Clinical Practice
Lung Cancer, Hepatocellular Carcinoma
RecruitingPhase 1
A Study of ERAS-0015 in Patients With Advanced or Metastatic Solid Tumors
Metastatic Solid Tumors
RecruitingPhase 2
At-Home Cancer Directed Therapy Versus in Clinic for the Treatment of Patients With Advanced Cancer
Advanced Anal Carcinoma, Advanced Biliary Tract Carcinoma
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Azam Ghafoor, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing osimertinib and Local Ablative Therapy (LAT) in people with Lung Adenocarcinoma and Lung Neoplasms, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 20 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Jun 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 Jul 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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 (time frame: Cycle 1 Day 1 (each cycle is 28 days) to progression of disease, range 36-1231 days). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02759835, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Jun 2024.