Neuroendocrine TumorsRadio-MarkerNCT05513469
Biomarker Identification of Radionuclide Therapy-induced Radiation Responses
A study testing Lutathera in people with Neuroendocrine Tumors, run by Erasmus Medical Center at 1 site in Netherlands.
Trial summary
Peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-[Tyr3]octreotate (177Lu-DOTATATE) is a form of internal radiation treatment for patients with neuroendocrine tumors (NET) to reduce tumor growth and stabilize disease. Due to limited response rates, there is a need to improve this therapy. Read more about this study
- Who is it for?
- Ages 18 to 100 years
- Conditions the study is for
- Neuroendocrine Tumors
- What is being tested?
- Lutathera
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteNetherlands
- Study dates
- 1 Jan 2023to 1 Oct 2024
- Phase
- Interventional
- Are there results?
- None posted in the registry
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 to 100 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patient with an advanced, well-differentiated midgut neuroendocrine tumor.
- Indication for treatment with PRRT with 7.4 GBq 177Lu-DOTATATE as determined by the multidisciplinary team.
- Age ≥ 18 years.
Who cannot join
- Failure to obtain informed consent.
- Patient received IR for imaging purposes within one week prior to PRRT or IR for therapeutic purposes within 3 months prior to PRRT.
- Previous treatment with PRRT.
- Indication to receive another activity of PRRT than 7.4 GBq.
Trial locations and contacts
1 site in 1 country.
Netherlands1 site, 1 recruiting
- Recruiting
Erasmus MC
Rotterdam, South Holland, 3015 GD
Erasmus N MC, 43449, m.becx@erasmusmc.nl
About this study
Peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-[Tyr3]octreotate (177Lu-DOTATATE) is a form of internal radiation treatment for patients with neuroendocrine tumors (NET) to reduce tumor growth and stabilize disease. Due to limited response rates, there is a need to improve this therapy. A better understanding of therapeutic radiobiological responses, such as transcriptional and DNA damage responses, could contribute to identification of biomarkers for toxicity and/or efficacy prediction. Easy access to biological samples for biomarker discovery would be via a so-called liquid biopsy (drawing blood) to collect healthy peripheral blood mononuclear cells (PBMCs) or circulating tumor DNA (ctDNA) for further investigation.
Exposure to ionizing radiation (IR) such as by PRRT leads to complex cellular responses including activation of the DNA damage response and changes in gene expression which can differ between individuals. This was previously shown for ex vivo external beam radiation of blood cells in which radiation responsive genes were identified. These genes were also similarly up- or downregulated following in vivo exposure to total-body irradiation of patients. In addition, different studies have shown a good correlation between radiation dose to the blood and DNA double strand break induction in PBMCs for various PRRT-like treatments. These results show that such events can be measured in PBMCs and indicate that ex vivo irradiation can mimic the in vivo transcriptional regulation and DNA damage induction. Therefore, to identify PRRT-induced cellular responses, the investigators will analyze the effects of 177Lu-DOTATATE IR on the transcriptional regulation in PBMCs and compare this regulation to radiation dose and DNA damage induction.
Read more
In addition, it was shown that levels of ctDNA can be associated with treatment response and anticancer treatment is also shown to influence ctDNA methylation patterns. The investigators will therefore explore dynamics of ctDNA levels and methylation patterns before and after PRRT to provide more knowledge of the effect of radiation response on ctDNA.
This is a pilot study to validate the possibility of determining the radiation response of PRRT with 177Lu-DOTATATE in PBMCs and ctDNA.
Read the detailed description
Altogether, the PBMC and ctDNA analyses will provide essential information on the PRRT radiation response using blood as easily accessible material. Future research can focus on development of radiation response biomarkers based on the outcomes of this study.
Objective: This is a pilot study to validate the possibility of determining the radiation response of PRRT with 177Lu-DOTATATE in PBMCs and ctDNA.
Study design: Prospective translational study with additional blood collections at 4 timepoints during regular patient care for ex vivo characterisation.
Study population: Twenty patients with locally advanced or metastatic NET receiving the first PRRT cycle of 7.4 GBq 177Lu-DOTATATE.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
Participants who receive standard PRRT will undergo 4 additional venipunctures during their scheduled stay in the hospital for PRRT administration. The burden of the venipunctures is minimal. There is no benefit for particitants.
- Conditions
- Neuroendocrine Tumors
- Being tested
- Lutathera
- Medical subject headings
- Neuroendocrine Tumors
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LutatheraDrug
Also called 177lu-dotatate
regulair PRRT of 4 cycles with 7.4GBq
| Study group | Role | What they receive |
|---|---|---|
| Peptide receptor radionuclide therapy | Other | PRRT 4x7.4GBq Receives: Drug: Lutathera |
What is being measured
The primary outcome is the main question the study is designed to answer.
Transcriptional regulation and DNA damage induction in PBMCs after PRRT.
DNA damage will be assessed by immunofluorescent stainings and microscopic detection of γ-H2AX and 53BP1 RIF. RIF numbers of at least 50 cells from at least 4 fields of view per blood sample will be quantified using an automated quantification macro in ImageJ.
RNA isolation, sequencing, analysis and qPCR validation will be done. Validation of the identified differentially expressed genes will be performed in triplicate by qPCR. For sequencing, we will use an unique in-house analysis method using a Snakemake pipeline. RIF and sequencing analysis will be performed on blinded samples to perform unbiased analysis.
Measured: 2 years
Secondary outcomes (2)
mimic transcriptional regulation and DNA damage induction in PRRT ex vivo.
Untreated blood from the patient will be treated with 177Lu-DOTATATE ex vivo. Analysis of transcriptional regulation and DNA damage induction will be done as mentioned in the description of outcome 1.
Measured: 2 years
detection of ctDNA in NET patients
For the assessment of circulating biomarkers of the tumor cells we will measure ctDNA levels in the blood.
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Aug 2022
- Study start1 Jan 2023
- Primary completion1 Oct 2024 (estimated)
- Study completion1 Oct 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Neuroendocrine TumorsStudies of the same condition, open and under way.
- More trials run by Erasmus Medical CenterThe 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 N/A
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Erasmus Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, M.N. Becx, Erasmus Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05513469
- Sponsor's protocol ID
- 80190
- Acronym
- Radio-Marker
- Status last verified
- Apr 2023
- First submitted
- 11 Aug 2022
- Last updated
- 7 Apr 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 7 Apr 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Biomarker Identification of Radionuclide Therapy-induced Radiation Responses
- ClinicalTrials.gov ID
- NCT05513469
- Acronym / sponsor ID
- Radio-Marker / 80190
- Conditions
- Neuroendocrine Tumors
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- Erasmus Medical CenterUniversity, hospital or other
- Study start
- 1 Jan 2023 (actual)
- Primary completion
- 1 Oct 2024 (estimated)
- Study completion
- 1 Oct 2024 (estimated)
- First posted
- 24 Aug 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-[Tyr3]octreotate (177Lu-DOTATATE) is a form of internal radiation treatment for patients with neuroendocrine tumors (NET) to reduce tumor growth and stabilize disease. Due to limited response rates, there is a need to improve this therapy. A better understanding of therapeutic radiobiological responses, such as transcriptional and DNA damage responses, could contribute to identification of biomarkers for toxicity and/or efficacy prediction. Easy access to biological samples for biomarker discovery would be via a so-called liquid biopsy (drawing blood) to collect healthy peripheral blood mononuclear cells (PBMCs) or circulating tumor DNA (ctDNA) for further investigation.
Exposure to ionizing radiation (IR) such as by PRRT leads to complex cellular responses including activation of the DNA damage response and changes in gene expression which can differ between individuals. This was previously shown for ex vivo external beam radiation of blood cells in which radiation responsive genes were identified. These genes were also similarly up- or downregulated following in vivo exposure to total-body irradiation of patients. In addition, different studies have shown a good correlation between radiation dose to the blood and DNA double strand break induction in PBMCs for various PRRT-like treatments. These results show that such events can be measured in PBMCs and indicate that ex vivo irradiation can mimic the in vivo transcriptional regulation and DNA damage induction. Therefore, to identify PRRT-induced cellular responses, the investigators will analyze the effects of 177Lu-DOTATATE IR on the transcriptional regulation in PBMCs and compare this regulation to radiation dose and DNA damage induction.
In addition, it was shown that levels of ctDNA can be associated with treatment response and anticancer treatment is also shown to influence ctDNA methylation patterns. The investigators will therefore explore dynamics of ctDNA levels and methylation patterns before and after PRRT to provide more knowledge of the effect of radiation response on ctDNA.
This is a pilot study to validate the possibility of determining the radiation response of PRRT with 177Lu-DOTATATE in PBMCs and ctDNA.
Detailed description
Altogether, the PBMC and ctDNA analyses will provide essential information on the PRRT radiation response using blood as easily accessible material. Future research can focus on development of radiation response biomarkers based on the outcomes of this study.
Objective: This is a pilot study to validate the possibility of determining the radiation response of PRRT with 177Lu-DOTATATE in PBMCs and ctDNA.
Study design: Prospective translational study with additional blood collections at 4 timepoints during regular patient care for ex vivo characterisation.
Study population: Twenty patients with locally advanced or metastatic NET receiving the first PRRT cycle of 7.4 GBq 177Lu-DOTATATE.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
Participants who receive standard PRRT will undergo 4 additional venipunctures during their scheduled stay in the hospital for PRRT administration. The burden of the venipunctures is minimal. There is no benefit for particitants.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Peptide receptor radionuclide therapy | Other | Drug: LutatheraPRRT 4x7.4GBq |
Who may qualify
- Ages
- 18 to 100 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Patient with an advanced, well-differentiated midgut neuroendocrine tumor.
- Indication for treatment with PRRT with 7.4 GBq 177Lu-DOTATATE as determined by the multidisciplinary team.
- Age ≥ 18 years.
Key exclusion criteria (4 listed)
- Failure to obtain informed consent.
- Patient received IR for imaging purposes within one week prior to PRRT or IR for therapeutic purposes within 3 months prior to PRRT.
- Previous treatment with PRRT.
- Indication to receive another activity of PRRT than 7.4 GBq.
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 |
|---|---|---|
| LutatheraAlso: 177lu-dotatateregulair PRRT of 4 cycles with 7.4GBq | Drug | Peptide receptor radionuclide therapy |
Primary outcome
Transcriptional regulation and DNA damage induction in PBMCs after PRRT.
Time frame: 2 years
DNA damage will be assessed by immunofluorescent stainings and microscopic detection of γ-H2AX and 53BP1 RIF. RIF numbers of at least 50 cells from at least 4 fields of view per blood sample will be quantified using an automated quantification macro in ImageJ. RNA isolation, sequencing, analysis and qPCR validation will be done. Validation of the identified differentially expressed genes will be performed in triplicate by qPCR. For sequencing, we will use an unique in-house analysis method using a Snakemake pipeline. RIF and sequencing analysis will be performed on blinded samples to perform unbiased analysis.
2 secondary outcomes
mimic transcriptional regulation and DNA damage induction in PRRT ex vivo.
Time frame: 2 years
detection of ctDNA in NET patients
Time frame: 2 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Apr 2023.
- Individual participant dataSharing planned: No
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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.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Lutathera in people with Neuroendocrine Tumors, run by Erasmus Medical Center at 1 site in Netherlands.
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 3 inclusion and 4 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: status not confirmed, as of the sponsor's last update on 7 Apr 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 Netherlands. 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.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact M.N. Becx (43449, m.becx@erasmusmc.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Transcriptional regulation and DNA damage induction in PBMCs after PRRT. (time frame: 2 years). 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 7 Apr 2023.