Biomarker Identification of Radionuclide Therapy-induced Radiation Responses

NCT05513469 | Unknown

• 1 other identifier: 80190
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Neuroendocrine Tumors

Outcome Measures

Primary Outcomes (1)

• 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.

  2 years

Secondary Outcomes (2)

• mimic transcriptional regulation and DNA damage induction in PRRT ex vivo.

  2 years

• detection of ctDNA in NET patients

  2 years

Other Outcomes (2)

• Evaluate the effect of PRRT on ctDNA levels.

  2 years

• methylation sequencing ctDNA

  2 years

Study Arms (1)

Peptide receptor radionuclide therapy

OTHER

PRRT 4x7.4GBq

Drug: Lutathera

Interventions

Lutathera DRUG

regulair PRRT of 4 cycles with 7.4GBq

Also known as: 177lu-dotatate

Peptide receptor radionuclide therapy

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Erasmus Medical Center: lead

Study Sites (1)

Erasmus MC

Rotterdam, South Holland, 3015 GD, Netherlands

RECRUITING

MeSH Terms

Conditions

Neuroendocrine Tumors

Interventions

lutetium Lu 177 dotatate

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue

Central Study Contacts

M.N. Becx

CONTACT

43449; m.becx@erasmusmc.nl

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PhD-student / coordinating investigator

Study Record Dates

• First Submitted: August 11, 2022
• First Posted: August 24, 2022
• Study Start: January 1, 2023
• Primary Completion: October 1, 2024
• Study Completion: October 1, 2024
• Last Updated: April 7, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)