MelanomaPhase 1/2NCT02407171
Evaluating the Combination of MK-3475 and Sterotactic Body Radiotherapy in Patients With Metastatic Melanoma or NSCLC
A Phase 1/2 study testing MK-3475 and Stereotactic Body Radiation Therapy (SBRT) in people with Melanoma and Lung Cancer, run by Yale University at 1 site in United States.
Trial summary
This is a 2-part prospective trial examining the ability of Stereotactic Body Radiation Therapy (SBRT) to induce a response to MK-3475, a humanized antibody to PD-1, in patients who progress on this antibody. Patients with metastatic melanoma will be enrolled after they have progressed on anti-PD-1 therapy. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma, Lung Cancer
- What is being tested?
- MK-3475 and Stereotactic Body Radiation Therapy (SBRT)
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 61 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Apr 2015to 19 Feb 2019
- Phase
- Phase 1/2
- 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
- Be willing and able to provide written informed consent/assent for the trial.
- Have metastatic melanoma or NSCLC, or locally advanced NSCLC not suitable for curative-intent local therapy.
- For melanoma patients and NSCLC patients treated with prior anti-PD-1 therapy, patients must have received prior PD-1 therapy and have progressed (irPD) by irRC.
- Have 2 or more measurable sites of disease as defined by either RECIST 1.1, or cutaneous lesions at least 1 cm in greatest dimension
- Have at least one site of disease that is considered potentially suitable for treatment with SBRT
- Have provided tissue from an archival or newly obtained tissue sample of a tumor lesion, sufficient for analysis of PD-L1 and other biomarkers. Patients who have had PD-L1 analysis previously performed at Merck can substitute earlier analysis results and are not required to submit additional tissue for PD-L1 testing. Expression of PD-L1 is NOT required for study entry.
Show all 23Show fewer
- Have a performance status of 0, 1 or 2 on the ECOG Performance Scale.
- Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 28 days of protocol treatment.
- Table 1. Adequate Organ Function Laboratory Values (System/Laboratory Value)
- Hematological
- Absolute neutrophil count (ANC) ≥1,500 /mcL
- Platelets ≥100,000 / mcL
- Hemoglobin ≥9 g/dL
- Renal
- Measured or calculated creatinine** clearance ≤1.5 X upper limit of normal (ULN)
- (GFR can also be used in place of creatinine or CrCl) ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Hepatic
- Serum total bilirubin ≤ 1.5 X ULN OR
- Direct bilirubin Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
- AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
- (Creatinine clearance should be calculated per institutional standard. )
- Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication (Reference Section 5.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
- Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
Who cannot join
- Has had radiation therapy within 2 weeks of the first protocol treatment.
- Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 2 weeks of the first protocol treatment.
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 2 weeks of the first protocol treatment. The use of low-dose steroids for management of chronic conditions is allowed.
- Non-small cell lung cancer patients enrolling to MK-3475 as first protocol therapy (no prior anti-PD-1 therapy): Has had a prior monoclonal antibody within 4 weeks prior to first protocol treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks of the first protocol treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
- Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
Show all 17Show fewer
- Note: Patients who have had prior treatments with Tyrosine Kinase Inhibitors (e.g. Tarceva) require only a 72-hour washout period prior to starting protocol treatment.
- Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
- Has known active and untreated brain (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate.
- Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an example of an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Those with a history of hypothyroidism who are now stable on hormone replacement will not be excluded. Those with Sjorgen's syndrome will not be excluded from the study.
- Has a history of (non-infectious) pneumonitis that required steroids, current pneumonitis or evidence of interstitial lung disease.
- Has an active infection requiring systemic therapy.
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
- Has received a live vaccine within 30 days prior to the first protocol treatment.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Phase I/II Trial of Evaluating the Combination of MK-3475 and Stereotactic Body Radiotherapy in Patients With Metastatic Melanoma or NSCLC
This is a 2-part prospective trial examining the ability of Stereotactic Body Radiation Therapy (SBRT) to induce a response to MK-3475, a humanized antibody to PD-1, in patients who progress on this antibody. Patients with metastatic melanoma will be enrolled after they have progressed on anti-PD-1 therapy. Patients with metastatic NSCLC (previously untreated with anti-PD-1 or anti-PD-L1 therapy) will be enrolled and treated with MK-3475 until they exhibit progression of disease. At this point (when patients have demonstrated progression of disease) a single target lesion will be selected and treated with SBRT, and then MK-3475 will be restarted and continued until there is further progression of disease. The first phase of the study is a radiation dose escalation with a constant dose of MK-3475. The second part of the study includes expansion cohorts of NSCLC and melanoma patients.
Read the detailed description
The phase 1b portion of the trial is a radiation dose escalation study to determine the maximum tolerated dose (MTD) of SBRT when given to patients previously and subsequently exposed to MK-3475. Because the class of PD-1 inhibitory antibodies conveys a risk of pneumonitis, there will be two parallel dose escalation arms- Arm A will include SBRT targets in the lung parenchyma, and Arm B will be limited to targets outside the lung parenchyma. Each arm will be separately escalated, and two MTDs will be determined. The starting dose will be 3000 cGy in 5 fractions; there will be one dose escalation cohort (3000 cGy in 3 fractions), and if necessary one dose de-escalation cohort (1000 cGy in a single fraction). If there is dose-limiting toxicity at the lowest cohort, that arm will be closed and SBRT to that site will be discontinued.
The phase 2a portion of the study includes 2 expansion cohorts, for melanoma and NSCLC, with SBRT delivered at the MTD. The primary endpoint of this phase of the study is the overall response rate to post-SBRT MK-3475. Secondary endpoints include determining the time to progression, overall survival, and exploratory biomarkers.
IND exempt per FDA.
Inclusion/Exclusion Criteria Updated 4/7/2016
- Conditions
- Melanoma, Lung Cancer
- Being tested
- MK-3475, Stereotactic Body Radiation Therapy (SBRT)
- Medical subject headings
- Melanoma, Lung Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MK-3475Drug
200 mg every 2 weeks by IV infusion
Stereotactic Body Radiation Therapy (SBRT)Radiation
The starting dose will be 3000 cGy in 5 fractions; there will be one dose escalation cohort (3000 cGy in 3 fractions), and if necessary one dose de-escalation cohort (1000 cGy in a single fraction).
| Study group | Role | What they receive |
|---|---|---|
| Non Small Cell Lung Cancer, Phase I | Experimental | Dose escalation cohort for patients with Non Small Cell Lung Cancer (NSCLC). The starting dose will be 3000 cGy in 5 fractions; there will be one dose escalation cohort (3000 cGy in 3 fractions), and if necessary one dose de-escalation cohort (1000 cGy in a single fraction). If there is dose-limiting toxicity at the lowest cohort, that arm will be closed and SBRT to that site will be discontinued. Receives: Drug: MK-3475; Radiation: Stereotactic Body Radiation Therapy (SBRT) |
| Non-Lung, Phase I | Experimental | Dose escalation cohort for non lung cancer patients. The starting dose will be 3000 cGy in 5 fractions; there will be one dose escalation cohort (3000 cGy in 3 fractions), and if necessary one dose de-escalation cohort (1000 cGy in a single fraction). If there is dose-limiting toxicity at the lowest cohort, that arm will be closed and SBRT to that site will be discontinued. Receives: Drug: MK-3475; Radiation: Stereotactic Body Radiation Therapy (SBRT) |
| Melanoma Expansion Cohort | Experimental | Phase 2a expansion cohort for patients with melanoma. Patients will be treated at the maximum tolerated dose discovered in phase I. Receives: Drug: MK-3475; Radiation: Stereotactic Body Radiation Therapy (SBRT) |
| Non Small Cell Lung Cancer Expansion Cohort | Experimental | Phase 2a expansion cohort for patients with NSCLC. Patients will be treated at the maximum tolerated dose discovered in phase I. Receives: Drug: MK-3475; Radiation: Stereotactic Body Radiation Therapy (SBRT) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Phase 2, Overall Response
Phase 2 primary endpoint is the overall response count of patients to post-SBRT MK-3475. Overall response was evaluated using Response Evaluation Criteria In Solid Tumors (RECIST). The following are counts of those that were assessed to have the following responses: Complete response (CR), Partial response (PR), Stable disease (SD), Progressive disease (PD), Not Evaluable.
Measured: up to 12 months
Phase 1, Dose-Limiting Toxicity
Phase 1 primary endpoint will be the presence of a dose limiting toxicity. Maximum tolerated dose will be the highest dose at which there is not a dose limiting toxicity. This could be either 3000 cGy in 5 fractions or 3 fractions. Presented are counts of the maximum tolerated of participants per arm. Results are summarized by Lung or Non-Lung targets overall.
Measured: up to 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Apr 2015 (estimated)
- Study start1 Apr 2015
- Primary completion19 Feb 2019
- Study completion19 Feb 2019
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.
- Other trials for MelanomaStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe 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 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 61 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Allison Campbell, MD, Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02407171
- Sponsor's protocol ID
- 1411014879
- Status last verified
- Oct 2023
- First submitted
- 30 Mar 2015
- Last updated
- 31 Oct 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 31 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I/II Trial of Evaluating the Combination of MK-3475 and Stereotactic Body Radiotherapy in Patients With Metastatic Melanoma or NSCLC
- ClinicalTrials.gov ID
- NCT02407171
- Acronym / sponsor ID
- 1411014879
- Conditions
- Melanoma, Lung Cancer
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 61 participants (actual)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Study start
- 1 Apr 2015 (actual)
- Primary completion
- 19 Feb 2019 (actual)
- Study completion
- 19 Feb 2019 (actual)
- First posted
- 2 Apr 2015 (estimated)
- Results
- Posted 31 Oct 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a 2-part prospective trial examining the ability of Stereotactic Body Radiation Therapy (SBRT) to induce a response to MK-3475, a humanized antibody to PD-1, in patients who progress on this antibody. Patients with metastatic melanoma will be enrolled after they have progressed on anti-PD-1 therapy. Patients with metastatic NSCLC (previously untreated with anti-PD-1 or anti-PD-L1 therapy) will be enrolled and treated with MK-3475 until they exhibit progression of disease. At this point (when patients have demonstrated progression of disease) a single target lesion will be selected and treated with SBRT, and then MK-3475 will be restarted and continued until there is further progression of disease. The first phase of the study is a radiation dose escalation with a constant dose of MK-3475. The second part of the study includes expansion cohorts of NSCLC and melanoma patients.
Detailed description
The phase 1b portion of the trial is a radiation dose escalation study to determine the maximum tolerated dose (MTD) of SBRT when given to patients previously and subsequently exposed to MK-3475. Because the class of PD-1 inhibitory antibodies conveys a risk of pneumonitis, there will be two parallel dose escalation arms- Arm A will include SBRT targets in the lung parenchyma, and Arm B will be limited to targets outside the lung parenchyma. Each arm will be separately escalated, and two MTDs will be determined. The starting dose will be 3000 cGy in 5 fractions; there will be one dose escalation cohort (3000 cGy in 3 fractions), and if necessary one dose de-escalation cohort (1000 cGy in a single fraction). If there is dose-limiting toxicity at the lowest cohort, that arm will be closed and SBRT to that site will be discontinued.
The phase 2a portion of the study includes 2 expansion cohorts, for melanoma and NSCLC, with SBRT delivered at the MTD. The primary endpoint of this phase of the study is the overall response rate to post-SBRT MK-3475. Secondary endpoints include determining the time to progression, overall survival, and exploratory biomarkers.
IND exempt per FDA.
Inclusion/Exclusion Criteria Updated 4/7/2016
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Non Small Cell Lung Cancer, Phase I | Experimental | Drug: MK-3475, Radiation: Stereotactic Body Radiation Therapy (SBRT)Dose escalation cohort for patients with Non Small Cell Lung Cancer (NSCLC). The starting dose will be 3000 cGy in 5 fractions; there will be one dose escalation cohort (3000 cGy in 3 fractions), and if necessary one dose de-escalation cohort (1000 cGy in a single fraction). If there is dose-limiting toxicity at the lowest cohort, that arm will be closed and SBRT to that site will be discontinued. |
| Non-Lung, Phase I | Experimental | Drug: MK-3475, Radiation: Stereotactic Body Radiation Therapy (SBRT)Dose escalation cohort for non lung cancer patients. The starting dose will be 3000 cGy in 5 fractions; there will be one dose escalation cohort (3000 cGy in 3 fractions), and if necessary one dose de-escalation cohort (1000 cGy in a single fraction). If there is dose-limiting toxicity at the lowest cohort, that arm will be closed and SBRT to that site will be discontinued. |
| Melanoma Expansion Cohort | Experimental | Drug: MK-3475, Radiation: Stereotactic Body Radiation Therapy (SBRT)Phase 2a expansion cohort for patients with melanoma. Patients will be treated at the maximum tolerated dose discovered in phase I. |
| Non Small Cell Lung Cancer Expansion Cohort | Experimental | Drug: MK-3475, Radiation: Stereotactic Body Radiation Therapy (SBRT)Phase 2a expansion cohort for patients with NSCLC. Patients will be treated at the maximum tolerated dose discovered in phase I. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (23 listed)
- Be willing and able to provide written informed consent/assent for the trial.
- Have metastatic melanoma or NSCLC, or locally advanced NSCLC not suitable for curative-intent local therapy.
- For melanoma patients and NSCLC patients treated with prior anti-PD-1 therapy, patients must have received prior PD-1 therapy and have progressed (irPD) by irRC.
- Have 2 or more measurable sites of disease as defined by either RECIST 1.1, or cutaneous lesions at least 1 cm in greatest dimension
- Have at least one site of disease that is considered potentially suitable for treatment with SBRT
Key exclusion criteria (17 listed)
- Has had radiation therapy within 2 weeks of the first protocol treatment.
- Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 2 weeks of the first protocol treatment.
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 2 weeks of the first protocol treatment. The use of low-dose steroids for management of chronic conditions is allowed.
- Non-small cell lung cancer patients enrolling to MK-3475 as first protocol therapy (no prior anti-PD-1 therapy): Has had a prior monoclonal antibody within 4 weeks prior to first protocol treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks of the first protocol treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
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 |
|---|---|---|
| MK-3475200 mg every 2 weeks by IV infusion | Drug | Melanoma Expansion Cohort, Non Small Cell Lung Cancer Expansion Cohort, Non Small Cell Lung Cancer, Phase I, Non-Lung, Phase I |
| Stereotactic Body Radiation Therapy (SBRT)The starting dose will be 3000 cGy in 5 fractions; there will be one dose escalation cohort (3000 cGy in 3 fractions), and if necessary one dose de-escalation cohort (1000 cGy in a single fraction). | Radiation | Melanoma Expansion Cohort, Non Small Cell Lung Cancer Expansion Cohort, Non Small Cell Lung Cancer, Phase I, Non-Lung, Phase I |
Primary outcome
Phase 2, Overall Response
Time frame: up to 12 months
Phase 2 primary endpoint is the overall response count of patients to post-SBRT MK-3475. Overall response was evaluated using Response Evaluation Criteria In Solid Tumors (RECIST). The following are counts of those that were assessed to have the following responses: Complete response (CR), Partial response (PR), Stable disease (SD), Progressive disease (PD), Not Evaluable.
Phase 1, Dose-Limiting Toxicity
Time frame: up to 12 months
Phase 1 primary endpoint will be the presence of a dose limiting toxicity. Maximum tolerated dose will be the highest dose at which there is not a dose limiting toxicity. This could be either 3000 cGy in 5 fractions or 3 fractions. Presented are counts of the maximum tolerated of participants per arm. Results are summarized by Lung or Non-Lung targets overall.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Oct 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
Related trials for Melanoma
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
RecruitingPhase 1
IL-17 Blockade to Decrease irAEs (REPLAY)
Metastatic Melanoma
Enrolling by invitationObservational study
Natural History Study of Early Life Exposures in Agriculture (ELEA)
Prostate Cancer, Leukemia
RecruitingPhase 1
A Feasibility Study Utilizing Immune Recall to Increase Response to Checkpoint Therapy
Melanoma
Active, not recruitingPhase 1/2
A Study of Dapansutrile Plus Pembrolizumab in Patients With PD-1 Refractory Advanced Melanoma
Melanoma
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.
Allison Campbell, MD principal investigator
Yale University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing MK-3475 and Stereotactic Body Radiation Therapy (SBRT) in people with Melanoma and Lung Cancer, run by Yale University 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 23 inclusion and 17 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 31 Oct 2023. 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 combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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 31 Oct 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?
Phase 2, Overall Response (time frame: up to 12 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 31 Oct 2023.