Biomarker Identification of Radionuclide Therapy-induced Radiation Responses (Radio-Marker)

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.

Study Overview

• Status: Recruiting
• Conditions: Neuroendocrine Tumors
• Intervention / Treatment: Drug: Lutathera

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 Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: M.N. Becx; Phone Number: 43449; Email: m.becx@erasmusmc.nl

Study Locations

• Netherlands
  • South Holland
    • Rotterdam, South Holland, Netherlands, 3015 GD
      • Recruiting
      • Erasmus MC
      • Contact: Erasmus N MC; Phone Number: 43449; Email: m.becx@erasmusmc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Peptide receptor radionuclide therapy; PRRT 4x7.4GBq	Drug: Lutathera; regulair PRRT of 4 cycles with 7.4GBq; Other Names: 177lu-dotatate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the effect of PRRT on ctDNA levels.	ctDNA levels will be measured in the blood before PRRT and 8 weeks after the first cycle.	2 years
methylation sequencing ctDNA	DNA methylation sequencing method will be used to analyze the ctDNA. The MeD-seq assay will be used for genome-wide DNA methylation profiling on cell-free DNA (cfDNA)	2 years

Collaborators and Investigators

• Sponsor: Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2023
• Primary Completion (Anticipated): October 1, 2024
• Study Completion (Anticipated): October 1, 2024

Study Registration Dates

• First Submitted: August 11, 2022
• First Submitted That Met QC Criteria: August 23, 2022
• First Posted (Actual): August 24, 2022

Study Record Updates

• Last Update Posted (Actual): April 7, 2023
• Last Update Submitted That Met QC Criteria: April 6, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Molecular Mechanisms of Pharmacological Action; Radiopharmaceuticals; Lutetium Lu 177 dotatate
• Other Study ID Numbers: 80190

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No